Results and discussion
Pharmacokinetic evaluation of TK900D

According to the MMV (Medicines for Malaria Venture) compound progression criteria of August 2008 [14], a compound with oral bioavailability > 20% in rat after oral dosing is considered as a development candidate.

According

to

the

MMV

Medicines

for

Malaria

Venture

compound

progression

criteria

of

August

a

compound

with

oral

bioavailability

in

rat

after

oral

dosing

is

considered

as

a

development

candidate

Answer: accept


Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug concentration curve AUC(0–48 h) by 4-fold at a dose of 3 mg/kg when compared with DAT, and Cmax of NDAT (4363 ng/mL) was 8-fold greater than that of DAT (548 ng/mL).

Pharmacokinetic

studies

using

LC

MS

MS

analysis

in

male

C

BL

mice

showed

that

administration

of

NDAT

improved

the

area

under

the

drug

concentration

curve

AUC

h

by

fold

at

a

dose

of

mg

kg

when

compared

with

DAT

and

Cmax

of

NDAT

ng

mL

was

fold

greater

than

that

of

DAT

ng

mL

Answer: accept


Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80–90% of the total clearance.

Previously

published

physiologically

based

pharmacokinetic

PBPK

models

of

tolbutamide

are

based

on

an

assumption

that

its

metabolic

clearance

is

exclusively

through

CYP

C

however

many

studies

indicate

that

CYP

C

metabolism

is

only

responsible

for

of

the

total

clearance

Answer: accept


Values determined for T(max) (0.25-1.0 h) and T(1/2) (3.8-6.4 h) of garenoxacin in plasma did not vary with dose or study day.

Values

determined

for

T

max

h

and

T

h

of

garenoxacin

in

plasma

did

not

vary

with

dose

or

study

day

Answer: accept


The 90% confidence intervals for the least squares means derived from an analysis of the log-transformed pharmacokinetic parameters maximum serum concentration (Cmax), area under the serum concentration-time curve (AUC) from 0 to the last measurable concentration (AUC(0-t)) and AUC from 0 to infinity (AUC(0-∞)) for etanercept were between the limits of 80 and 125%.

The

confidence

intervals

for

the

least

squares

means

derived

from

an

analysis

of

the

log

transformed

pharmacokinetic

parameters

maximum

serum

concentration

Cmax

area

under

the

serum

concentration

time

curve

AUC

from

to

the

last

measurable

concentration

AUC

t

and

AUC

from

to

infinity

AUC

for

etanercept

were

between

the

limits

of

and

Answer: accept


The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep.

The

elimination

rate

constant

kel

in

goats

was

nearly

twice

as

large

as

the

value

determined

in

sheep

and

the

urea

under

the

i

v

plasma

curve

in

goats

was

only

of

the

value

in

sheep

indicating

that

goats

are

more

effective

in

their

capacity

to

eliminate

clorsulon

than

are

sheep

Answer: accept


Predicted Pharmacokinetic Profile of DPT in Human

The predicted results showed that DPT exhibited a high CL of 1.39 L/min (close to hepatic blood flow) in human, with a t1/2 of 70.22 min and a Vss close to total body volume (61.94 L).

The

predicted

results

showed

that

DPT

exhibited

a

high

CL

of

L

min

close

to

hepatic

blood

flow

in

human

with

a

t

of

min

and

a

Vss

close

to

total

body

volume

L

Answer: accept


Model L-PZQ AUC data from Studies 200661-001 and 200585-001 separately using a linear mixed effects model based on noncompartmental estimates (Eq. (1)).

Model

L

PZQ

AUC

data

from

Studies

and

separately

using

a

linear

mixed

effects

model

based

on

noncompartmental

estimates

Eq

Answer: accept


In plasma, the IC50 of sorafenib for P-FLT3 inhibition shifts to approximately 308nM (Figure 1A).

In

plasma

the

IC

of

sorafenib

for

P

FLT

inhibition

shifts

to

approximately

nM

Figure

A

Answer: accept


Group 2A patients were the main source of the paradoxical variability in C(min)/Dose (higher ratio of 2.7; CV = 100%), suggesting a lower clearance and difficulty in the recovery of stability.

Group

A

patients

were

the

main

source

of

the

paradoxical

variability

in

C

min

Dose

higher

ratio

of

CV

suggesting

a

lower

clearance

and

difficulty

in

the

recovery

of

stability

Answer: accept


The dose-normalised (to 1 mg) Cmax and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics.

The

dose

normalised

to

mg

Cmax

and

AUC

values

at

different

dose

levels

and

different

study

days

appeared

to

be

similar

indicating

linear

pharmacokinetics

Answer: accept


Half the dose of cefpodoxime orally administered as cefpodoxime proxetil in tablet form reaches the systemic circulation, while 80% of the cefpodoxime absorbed is excreted unchanged in urine.

Half

the

dose

of

cefpodoxime

orally

administered

as

cefpodoxime

proxetil

in

tablet

form

reaches

the

systemic

circulation

while

of

the

cefpodoxime

absorbed

is

excreted

unchanged

in

urine

Answer: accept


RESULTS
Pharmacokinetics and pharmacodynamics

The mean volume of distribution at steady state ranged from 5.0 to 6.3 liters, indicating the limited distribution of the monoclonal antibody.

The

mean

volume

of

distribution

at

steady

state

ranged

from

to

liters

indicating

the

limited

distribution

of

the

monoclonal

antibody

Answer: accept


Ara‐CTP could be determined at levels under 1μM. There was a close correlation between the elimination half‐life values of the plasma ara‐C and the intracellular ara‐CTP.

Ara

CTP

could

be

determined

at

levels

under

μ

M

There

was

a

close

correlation

between

the

elimination

half

life

values

of

the

plasma

ara

C

and

the

intracellular

ara

CTP

Answer: accept


On the other hand, apparent oral clearance (CL/F) of FEX was significantly decreased by 41.3% (37.03 versus 21.75 L/h) and there was no significant change was observed in Tmax, T1/2, and CLr (renal clearance) upon treatment with DSN when compared to control.

On

the

other

hand

apparent

oral

clearance

CL

F

of

FEX

was

significantly

decreased

by

versus

L

h

and

there

was

no

significant

change

was

observed

in

Tmax

T

and

CLr

renal

clearance

upon

treatment

with

DSN

when

compared

to

control

Answer: accept


Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose.

Estimates

of

distribution

volume

Vd

lambda

z

F

for

FCE

increased

from

L

kg

at

the

mg

dose

to

L

kg

at

the

mg

dose

and

renal

clearance

CLr

also

increased

with

dose

Answer: accept


We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC).

We

retrospectively

collected

pharmacokinetic

data

of

all

patients

treated

for

MAC

lung

disease

in

the

Adult

Care

Unit

at

National

Jewish

Health

Denver

Colorado

in

the

January

to

January

period

we

retrospectively

calculated

areas

under

the

time

concentration

curve

AUC

Answer: accept


4.1. Pharmacokinetic Studies on AR Extracts

Formononetin was absorbed and eliminated the most slowly among four isoflavones with tmax at 2.5 h and t1/2 at 1.207 h (Table 2).

Formononetin

was

absorbed

and

eliminated

the

most

slowly

among

four

isoflavones

with

tmax

at

h

and

t

at

h

Table

Answer: accept


Following oral administration, the absolute bioavailability of VCD was 94 +- 14%, and the terminal half-life was similar to that obtained after iv administration.

Following

oral

administration

the

absolute

bioavailability

of

VCD

was

and

the

terminal

half

life

was

similar

to

that

obtained

after

iv

administration

Answer: accept


PK parameters [Cmax, Tmax, and AUC(0–24h)] for LE in ocular tissues following ocular instillation of LE (submicron) gel 0.38% and the micronized comparators, LE gels 0.38%, 0.5%, and 0.75% are presented in Table 2.

PK

parameters

Cmax

Tmax

and

AUC

h

for

LE

in

ocular

tissues

following

ocular

instillation

of

LE

submicron

gel

and

the

micronized

comparators

LE

gels

and

are

presented

in

Table

Answer: accept


In vivo drug release profile of CβG/PLGA nanoparticles

The values of A, ka and ke for P1 were 1300 μg/ml, 0.75 hr-1, and 0.742 hr-1 respectively and for P2 it was 1350 μg/ml, 0.75 hr-1, and 0.742 hr-1 respectively.

The

values

of

A

ka

and

ke

for

P

were

μ

g

ml

hr

and

hr

respectively

and

for

P

it

was

μ

g

ml

hr

and

hr

respectively

Answer: accept


Results
Pharmacokinetic evaluation
Other pharmacokinetic parameters

A slightly shorter median tmax was measured for Prolastin-C compared with Prolastin (0.673 hour versus 0.820 hour, respectively).

A

slightly

shorter

median

tmax

was

measured

for

Prolastin

C

compared

with

Prolastin

hour

versus

hour

respectively

Answer: accept


Compared to control, consumption of GT with milk, caseinate, or soy protein significantly reduced the bioavailability (mean area under the plasma concentration-time curve) of total catechins (means ± SEM; GT + M, 87 ± 5%; GT + CS, 79 ± 5%; GT + S, 88 ± 4%), epigallocatechin gallate (GT + M, 68 ± 4%; GT + CS, 63 ± 5%; GT + S, 76 ± 5%), and epicatechin gallate (GT + M, 68 ± 5%; GT + CS, 66 ± 6%; GT + S, 77 ± 6%), while the bioavailability of non-galloylated catechins such as epigallocatechin (GT + M, 134 ± 9%; GT + CS, 118 ± 9 %; GT + S, 123 ± 8%) and epicatechin (GT + M, 125 ± 10%; GT + CS, 114 ± 11%; GT + S, 110 ± 8%) significantly increased.

Compared

to

control

consumption

of

GT

with

milk

caseinate

or

soy

protein

significantly

reduced

the

bioavailability

mean

area

under

the

plasma

concentration

time

curve

of

total

catechins

means

SEM

GT

M

GT

CS

GT

S

epigallocatechin

gallate

GT

M

GT

CS

GT

S

and

epicatechin

gallate

GT

M

GT

CS

GT

S

while

the

bioavailability

of

non

galloylated

catechins

such

as

epigallocatechin

GT

M

GT

CS

GT

S

and

epicatechin

GT

M

GT

CS

GT

S

significantly

increased

Answer: accept


The bioavailability of the exenatide-loaded microspheres, relative to subcutaneous injection of exenatide, reached 10.2%.

The

bioavailability

of

the

exenatide

loaded

microspheres

relative

to

subcutaneous

injection

of

exenatide

reached

Answer: accept


Clinical prediction of efficacy and toxicity

To integrate the above predictors, we classified 39 patients into 4 patients with high OPRT/TS, high AUC0–24h of 5-FU, low DPD (ORR 50.0%, median PFS 7.00 m, median OS 13.90 m), and other 35 patients (ORR 40.0%, median PFS 4.10 m, median OS 9.17 m).

To

integrate

the

above

predictors

we

classified

patients

into

patients

with

high

OPRT

TS

high

AUC

h

of

FU

low

DPD

ORR

median

PFS

m

median

OS

m

and

other

patients

ORR

median

PFS

m

median

OS

m

Answer: accept


It was shown that the cleavage of vicagrel was almost completed in intestine with great different clearance (53.28 vs. 3.643 L⋅h-1⋅kg-1, p < 0.05) in rats and dogs.

It

was

shown

that

the

cleavage

of

vicagrel

was

almost

completed

in

intestine

with

great

different

clearance

vs

L

h

kg

p

in

rats

and

dogs

Answer: accept


In the current study, absorption of CBD from SEDDS-CBD was substantially faster compared to the reference with 87.5% of subjects showing peak concentration within 1 h, whereas the median of Tmax for the MCT-CBD was 3.0 h. A fast absorption of CBD is favorable in various conditions, especially in the therapeutic field.

In

the

current

study

absorption

of

CBD

from

SEDDS

CBD

was

substantially

faster

compared

to

the

reference

with

of

subjects

showing

peak

concentration

within

h

whereas

the

median

of

Tmax

for

the

MCT

CBD

was

h

A

fast

absorption

of

CBD

is

favorable

in

various

conditions

especially

in

the

therapeutic

field

Answer: accept


CLtotal and CLr in humans were predicted to be 10.6 L/h and 1.24 L/h.

CLtotal

and

CLr

in

humans

were

predicted

to

be

L

h

and

L

h

Answer: accept


Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation.

Cl

F

was

l

hr

CI

l

hr

after

intravenous

administration

and

l

hr

CI

l

hr

after

inhalation

Answer: accept


Elimination half life, mean residence time and apparent volume of distribution at steady state were not different in the two groups of patients (mean values: 142.4 and 120.2 min; 128.5 and 136.0 min; and 40.5 and 27.6 L, respectively in chronic renal failure patients and patients with normal renal function).

Elimination

half

life

mean

residence

time

and

apparent

volume

of

distribution

at

steady

state

were

not

different

in

the

two

groups

of

patients

mean

values

and

min

and

min

and

and

L

respectively

in

chronic

renal

failure

patients

and

patients

with

normal

renal

function

Answer: accept


Subjects and Methods
Outcome Measures
Assessment of Pharmacokinetic Variables

Other pharmacokinetic parameters analyzed included the maximum observed concentration (Cmax); the time to reach Cmax (Tmax); the area under the concentration-time curve from time 0 to infinity, calculated as AUC0–inf = AUC0–last + Clast/λz, where last is the time of the last quantifiable concentration, and Clast is the last quantifiable concentration; the terminal elimination half-life (T1/2), calculated as T1/2 = ln(2)/λz, and the apparent clearance after extravascular administration (CL/F), calculated as CL/F = Dose/AUC0–inf after a single dose and as CL/F = Dose/AUC0–tau after multiple dosing (at steady state).

Other

pharmacokinetic

parameters

analyzed

included

the

maximum

observed

concentration

Cmax

the

time

to

reach

Cmax

Tmax

the

area

under

the

concentration

time

curve

from

time

to

infinity

calculated

as

AUC

inf

AUC

last

Clast

λ

z

where

last

is

the

time

of

the

last

quantifiable

concentration

and

Clast

is

the

last

quantifiable

concentration

the

terminal

elimination

half

life

T

calculated

as

T

ln

λ

z

and

the

apparent

clearance

after

extravascular

administration

CL

F

calculated

as

CL

F

Dose

AUC

inf

after

a

single

dose

and

as

CL

F

Dose

AUC

tau

after

multiple

dosing

at

steady

state

Answer: accept


The maximum drug concentration (Cmax) and area under the receiver‐operating characteristic curve from 0 to infinity (AUC0–∞) increased dose‐dependently in the dose range 0.3 to 1.0 mg/kg (Table 2; Fig. 3B, C).

The

maximum

drug

concentration

Cmax

and

area

under

the

receiver

operating

characteristic

curve

from

to

infinity

AUC

increased

dose

dependently

in

the

dose

range

to

mg

kg

Table

Fig

B

C

Answer: accept


7.>0-t and AUC0-∞. Compared with the 3-months-old rats, ketamineexposure (AUC0-t) increased by factors of 1.98, 2.94, and 4.15 in the 6-, 12-,and 18-month-old rats, respectively, whereas xylazine exposure increased by factors of1.33, 1.85 and 2.78.

t

and

AUC

Compared

with

the

months

old

rats

ketamineexposure

AUC

t

increased

by

factors

of

and

in

the

and

month

old

rats

respectively

whereas

xylazine

exposure

increased

by

factors

of

and

Answer: accept


Results
Behaviour: open field and PPI
Locomotor stimulation in the open field

All other main effects and interactions, including the three-way drug × testing-onset × bins interaction were significant, minimum F(8, 183) = 3.23, p = 0.001.

All

other

main

effects

and

interactions

including

the

three

way

drug

testing

onset

bins

interaction

were

significant

minimum

F

p

Answer: accept


In the first group of patients, mean +- s.d. values of clearance, half-life and total distribution volume were 21.41 +- 14.59 1 h-1, 19.83 +- 23.95 h, 165.89 +- 134.75 1 respectively.

In

the

first

group

of

patients

mean

s

d

values

of

clearance

half

life

and

total

distribution

volume

were

h

h

respectively

Answer: accept


Relative bioavailability was evaluated by comparing the log-transformed C(max) and AUC(0-672) of the 2 formulations; Korean regulatory requirements for the assumption of bioequivalence were met if the 90% CIs fell within the range of 0.80 to 1.25.

Relative

bioavailability

was

evaluated

by

comparing

the

log

transformed

C

max

and

AUC

of

the

formulations

Korean

regulatory

requirements

for

the

assumption

of

bioequivalence

were

met

if

the

CIs

fell

within

the

range

of

to

Answer: accept


Area under the concentration curve (AUC) was 5.65 h X micrograms/mL and 10.37h X micrograms/mL. Serum clearance was 23L for both doses.

Area

under

the

concentration

curve

AUC

was

h

X

micrograms

mL

and

h

X

micrograms

mL

Serum

clearance

was

L

for

both

doses

Answer: accept


The same dose infused over 4 h results in a peak concentration of 0.92 mg L-1, falling to 0.005 mg L-1 at 8 h. Simultaneous modelling of dihydroartemisinin showed that while its peak plasma concentration was reduced by 27% and the peak delayed by 2.5 h following artesunate administration by infusion, substantially higher concentrations were maintained compared with those predicted after bolus artesunate.

The

same

dose

infused

over

h

results

in

a

peak

concentration

of

mg

L

falling

to

mg

L

at

h

Simultaneous

modelling

of

dihydroartemisinin

showed

that

while

its

peak

plasma

concentration

was

reduced

by

and

the

peak

delayed

by

h

following

artesunate

administration

by

infusion

substantially

higher

concentrations

were

maintained

compared

with

those

predicted

after

bolus

artesunate

Answer: accept


Both parameters were significantly influenced by postnatal age and current body weight, whereas volume of distribution in infants > 28 weeks' gestational age was higher than that in more premature babies.

Both

parameters

were

significantly

influenced

by

postnatal

age

and

current

body

weight

whereas

volume

of

distribution

in

infants

weeks

gestational

age

was

higher

than

that

in

more

premature

babies

Answer: accept


The oral and intravenous administrations of genaconazole yielded virtually superimposable plasma concentration-time curves, resulting in an absolute bioavailability of 100%.

The

oral

and

intravenous

administrations

of

genaconazole

yielded

virtually

superimposable

plasma

concentration

time

curves

resulting

in

an

absolute

bioavailability

of

Answer: accept


The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg x h/liter (IQR, 1.5 to 3.8 mg x h/liter) and 8.0 mg x h/liter (IQR, 6.7 to 8.6 mg x h/liter), respectively.

The

median

AUCs

of

CLA

and

hydroxyclarithromycin

OH

CLA

were

mg

x

h

liter

IQR

to

mg

x

h

liter

and

mg

x

h

liter

IQR

to

mg

x

h

liter

respectively

Answer: accept


Geometric mean ratios (90% confidence intervals) of the test to the reference formulation in Cmax and AUClast were 0.9652 (0.8302-1.1223) and 0.9891 (0.8541-1.1455), respectively.

Geometric

mean

ratios

confidence

intervals

of

the

test

to

the

reference

formulation

in

Cmax

and

AUClast

were

and

respectively

Answer: accept


Simulations of treatment dosing using our new candidate algorithm for twice daily v-GCV dosing resulted in a low probability of achieving an AUC0–12 of 40–60 mg*h/L. In addition to twice daily dosing for treatment, doses should also be increased by an additional 20% for all age and eGFR ranges (Fig.5), i.e., 1.2 * prophylactic dose given twice daily.

Simulations

of

treatment

dosing

using

our

new

candidate

algorithm

for

twice

daily

v

GCV

dosing

resulted

in

a

low

probability

of

achieving

an

AUC

of

mg

h

L

In

addition

to

twice

daily

dosing

for

treatment

doses

should

also

be

increased

by

an

additional

for

all

age

and

eGFR

ranges

Fig

i

e

prophylactic

dose

given

twice

daily

Answer: accept


3. Results
3.4. In Vivo Pharmacokinetic Evaluation

Compared with those in the IBU-CL-SF PM, the Cmax value of IBU was 2.95 times higher, and Tmax decreased by 15 min in the IBU-CL-SF SD.

Compared

with

those

in

the

IBU

CL

SF

PM

the

Cmax

value

of

IBU

was

times

higher

and

Tmax

decreased

by

min

in

the

IBU

CL

SF

SD

Answer: accept


The 90% CIs for the geometric mean ratios (4%, 20%, and 40% ethanol versus water) for Cmax and systemic exposure (AUC0-5, AUClast, and AUC0-∞) were within 80% to 125%.

The

CIs

for

the

geometric

mean

ratios

and

ethanol

versus

water

for

Cmax

and

systemic

exposure

AUC

AUClast

and

AUC

were

within

to

Answer: accept


The AUC0-infinity and Cmax values were proportional to doses (mg or mg/kg, P less than .001).

The

AUC

infinity

and

Cmax

values

were

proportional

to

doses

mg

or

mg

kg

P

less

than

Answer: accept


The molar AUC ratio of morphine-3-glucuronide/morphine was 1.8 +- 0.5 and the corresponding ratio for normorphine/morphine was 0.2 +- 0.06.

The

molar

AUC

ratio

of

morphine

glucuronide

morphine

was

and

the

corresponding

ratio

for

normorphine

morphine

was

Answer: accept


Half-life of 2OMePS RNA AONs in mdx tissue

The same phenomenon may explain the markedly longer half-life of the AON in cardiac muscle tissue (~46 days).

The

same

phenomenon

may

explain

the

markedly

longer

half

life

of

the

AON

in

cardiac

muscle

tissue

days

Answer: accept


The absorption of oral [14C]-bumetanide was rapid (absorption half-life 0.61 h) and complete with a urinary recovery of about 80% of the intravenous or oral dose during 48 h. 3.

The

absorption

of

oral

C

bumetanide

was

rapid

absorption

half

life

h

and

complete

with

a

urinary

recovery

of

about

of

the

intravenous

or

oral

dose

during

h

Answer: accept


The AUC((0-infinity)) of 5-FU with consecutive administrations (3089.7 ng.h/ml) was far greater than with single administration (430.4 ng.h/ml).

The

AUC

infinity

of

FU

with

consecutive

administrations

ng

h

ml

was

far

greater

than

with

single

administration

ng

h

ml

Answer: accept


Variability in 5FU 300 Css was considerably less than previously reported; 94 ± 25 ng ml−1(CV = 27%).

Variability

in

FU

Css

was

considerably

less

than

previously

reported

ng

ml

CV

Answer: accept


We observed a higher proportion of courses with Cpss within the target range for individualized doses in the latter two consolidation courses: for consolidation 3 and 4: 9.6, 74.6, and 15.8 % of courses were below target, within target and above target, respectively; vs for consolidation 1 and 2: 15.5, 63.6, and 20.9 % of courses were below, within and above target, respectively (p < 0.001).

We

observed

a

higher

proportion

of

courses

with

Cpss

within

the

target

range

for

individualized

doses

in

the

latter

two

consolidation

courses

for

consolidation

and

and

of

courses

were

below

target

within

target

and

above

target

respectively

vs

for

consolidation

and

and

of

courses

were

below

within

and

above

target

respectively

p

Answer: accept


The anti-PCSK9 Fc variants show improved PK parameters in non-human primates

Therefore, for a purpose to identify the relevance between Fc modification and increased half-lives, elimination half-life parameter was calculated only towards the linear section (0 to 336 h, Fig 2), while other parameters were calculated towards both the linear and nonlinear section (0-720h, Fig 2).

Therefore

for

a

purpose

to

identify

the

relevance

between

Fc

modification

and

increased

half

lives

elimination

half

life

parameter

was

calculated

only

towards

the

linear

section

to

h

Fig

while

other

parameters

were

calculated

towards

both

the

linear

and

nonlinear

section

h

Fig

Answer: accept


BMS‐962212 peak concentrations were observed within 1–2 h after administration.

BMS

peak

concentrations

were

observed

within

h

after

administration

Answer: accept


After single-dose oral administration, GSK2647544 was readily absorbed with a tmax of 1 – 4 hours.

After

single

dose

oral

administration

GSK

was

readily

absorbed

with

a

tmax

of

hours

Answer: accept


The geometric mean area under the curve ratio of the PI study group to the controls was 1.50, with a 90% confidence interval of 1.21 to 1.86 (P = 0.004).

The

geometric

mean

area

under

the

curve

ratio

of

the

PI

study

group

to

the

controls

was

with

a

confidence

interval

of

to

P

Answer: accept


The in vitro observation that Merand Flt3 were the kinases most potently inhibited by 11 was confirmed for Mer kinase in B-ALL 697 cell lysates using theATP ActivX probe assay,28 where it demonstratedan IC50 of 0.05 nM for Mer (although the redundancy ofMer and Tyro3 peptides does not distinguish these kinases).

Answer: accept

The

in

vitro

observation

that

Merand

Flt

were

the

kinases

most

potently

inhibited

by

was

confirmed

for

Mer

kinase

in

B

ALL

cell

lysates

using

theATP

ActivX

probe

assay

where

it

demonstratedan

IC

of

nM

for

Mer

although

the

redundancy

ofMer

and

Tyro

peptides

does

not

distinguish

these

kinases


However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min).

However

considering

both

plasma

concentrations

and

urinary

excretion

we

could

estimate

the

half

life

of

free

filterable

species

min

the

plasma

clearance

ml

min

and

the

renal

clearance

ml

min

Answer: accept


The PK of aripiprazole following aripiprazole lauroxil was characterized by a steady rise in plasma concentrations (Tmax 44-50 days), a broad peak, and prolonged exposure attributable to the dissolution of aripiprazole lauroxil and formation rate-limited elimination of aripiprazole (t1/2=15.4-19.2 days).

The

PK

of

aripiprazole

following

aripiprazole

lauroxil

was

characterized

by

a

steady

rise

in

plasma

concentrations

Tmax

days

a

broad

peak

and

prolonged

exposure

attributable

to

the

dissolution

of

aripiprazole

lauroxil

and

formation

rate

limited

elimination

of

aripiprazole

t

days

Answer: accept


A sorbitol bolus (5 mmol/kg) was given intravenously to 6 controls for determination of sorbitol elimination capacity (SEC) and distribution volume, V(sorb)d.

A

sorbitol

bolus

mmol

kg

was

given

intravenously

to

controls

for

determination

of

sorbitol

elimination

capacity

SEC

and

distribution

volume

V

sorb

d

Answer: accept


Cl was also four times higher in the HFB1iv compared to FB1iv group (6.7 and 1.8 L/kg/h respectively) which together with the differences in the volumes of distribution indicates that HFB1 is more rapidly cleared from the systemic circulation but also distributed more extensively into the extravasal space than FB1.

Cl

was

also

four

times

higher

in

the

HFB

iv

compared

to

FB

iv

group

and

L

kg

h

respectively

which

together

with

the

differences

in

the

volumes

of

distribution

indicates

that

HFB

is

more

rapidly

cleared

from

the

systemic

circulation

but

also

distributed

more

extensively

into

the

extravasal

space

than

FB

Answer: accept


The peak plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time 0 h to 36 h (AUC(0-36)), elimination half-life (t1/2), clearance rate (CL/F) and apparent volume of distribution (Vd) were (1.804 +- 1.706) ng/ml, (0.7 +- 0.3) h, (2.465 +- 1.693) ng x h/ml, (7.3 +- 7.0) h, (53.09 +- 34.65) x 10(3) L/h and (447.1 +- 440.8) x 10(3) L, respectively.

The

peak

plasma

concentration

Cmax

time

to

Cmax

Tmax

area

under

the

plasma

concentration

versus

time

curve

from

time

h

to

h

AUC

elimination

half

life

t

clearance

rate

CL

F

and

apparent

volume

of

distribution

Vd

were

ng

ml

h

ng

x

h

ml

h

x

L

h

and

x

L

respectively

Answer: accept


Protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin was determined just before and 12 weeks after ezetimibe introduction.

Protease

inhibitor

PI

or

non

nucleoside

reverse

transcriptase

inhibitor

NNRTI

Cmin

was

determined

just

before

and

weeks

after

ezetimibe

introduction

Answer: accept


Patients with advanced prostate cancer (castrate and noncastrate) were administered escalating doses of weekly 1-h infusion of i.v. EMP (500-1000-1500 mg/m(2)) in combination with weekly paclitaxel (100 mg/m(2) over 1 h) and i.v. carboplatin (area under the curve 6 mg/ml-min every 4 weeks).

Patients

with

advanced

prostate

cancer

castrate

and

noncastrate

were

administered

escalating

doses

of

weekly

h

infusion

of

i

v

EMP

mg

m

in

combination

with

weekly

paclitaxel

mg

m

over

h

and

i

v

carboplatin

area

under

the

curve

mg

ml

min

every

weeks

Answer: accept


The apparent V ss was 69.9 ± 25.4 L/m2, plasma clearance 13.4 ± 2.5 L/h/m2 and plasma T1/2 3.7 ± 1.3 h.

The

apparent

V

ss

was

L

m

plasma

clearance

L

h

m

and

plasma

T

h

Answer: accept


Antiplasmodial action of the compounds in vitro

Compound 1 on the other hand was less active than chloroquine with IC50 values of 0.505 and 0.463 µM for K1 and Dd2, respectively.

Compound

on

the

other

hand

was

less

active

than

chloroquine

with

IC

values

of

and

µ

M

for

K

and

Dd

respectively

Answer: accept


The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg.

The

mean

volume

of

distribution

of

the

central

compartment

was

liter

kg

and

the

steady

state

volume

of

distribution

using

noncompartmental

analysis

was

liter

kg

Answer: accept


Although the predose sampling occurred at least 12 h after the last known ingestion of I3C, 6 of 14 subjects exhibited Cmax for DIM in their predose plasma.

Although

the

predose

sampling

occurred

at

least

h

after

the

last

known

ingestion

of

I

C

of

subjects

exhibited

Cmax

for

DIM

in

their

predose

plasma

Answer: accept


Eritoran demonstrated a slow plasma clearance (0.679 to 0.930 ml/h/kg of body weight), a small volume of distribution (45.6 to 49.8 ml/kg), and a relatively long half-life (50.4 to 62.7 h).

Eritoran

demonstrated

a

slow

plasma

clearance

to

ml

h

kg

of

body

weight

a

small

volume

of

distribution

to

ml

kg

and

a

relatively

long

half

life

to

h

Answer: accept


A mean maximum concentration of 232 ng/ml was observed after 20 minutes.

A

mean

maximum

concentration

of

ng

ml

was

observed

after

minutes

Answer: accept


Results and discussion
Acute berberine pharmacokinetics

While BBR TD yielded higher berberine bioavailability (AUC0-8; 95.6 +- 23.7 ng·h/mL) as compared to oral (26.5 +- 2.9 ng·h/mL) this difference between routes of administration was not reflected in metabolite levels (Table 5).

While

BBR

TD

yielded

higher

berberine

bioavailability

AUC

ng

h

mL

as

compared

to

oral

ng

h

mL

this

difference

between

routes

of

administration

was

not

reflected

in

metabolite

levels

Table

Answer: accept


Bridging Dose Analysis Based on the Phase III Tramiprosate Plasma Area Under the Curve Bioequivalence and Projection of Brain Drug Exposure

In that study, the mean plasma exposure of tramiprosate at 78 weeks provided an AUC12 of 4429 ng/mL h.

In

that

study

the

mean

plasma

exposure

of

tramiprosate

at

weeks

provided

an

AUC

of

ng

mL

h

Answer: accept


The median value of dose-normalized tacrolimus trough concentrations was 5.3 ng/mL/mg (IQR: 4.8–5.8 ng/mL/mg) in Weeks 1–2, and 4.7 ng/mL/mg (IQR: 4.3–5.3 ng/mL/mg) in Weeks 3–4.

The

median

value

of

dose

normalized

tacrolimus

trough

concentrations

was

ng

mL

mg

IQR

ng

mL

mg

in

Weeks

and

ng

mL

mg

IQR

ng

mL

mg

in

Weeks

Answer: accept


Target values of fAUC/MIC for stasis and 1 log10 kill were 1.22-13.5 and 3.72-28.0, respectively; 2 log10 kill was not achieved for any strain, even at the highest tolerated dose.

Target

values

of

fAUC

MIC

for

stasis

and

log

kill

were

and

respectively

log

kill

was

not

achieved

for

any

strain

even

at

the

highest

tolerated

dose

Answer: accept


The optimized Formulae achieved a controlled drug release over 24 h and the pharmacokinetic data revealed that the Cmax and AUC0-24 in the rats' brain after the intranasal application of the dispersion and in situ gel were significantly higher relative to the vinpocetine solution applied intravenously at the same dose.

The

optimized

Formulae

achieved

a

controlled

drug

release

over

h

and

the

pharmacokinetic

data

revealed

that

the

Cmax

and

AUC

in

the

rats

brain

after

the

intranasal

application

of

the

dispersion

and

in

situ

gel

were

significantly

higher

relative

to

the

vinpocetine

solution

applied

intravenously

at

the

same

dose

Answer: accept


An emerging approach relies on estimating in vitro clearance of DMEs or transporters using recombinant enzymes or cells.10, 11 These in vitro clearance data can be extrapolated to in vivo by incorporating tissue protein expression in the PBPK models, as discussed elsewhere.13, 14, 15 Therefore, protein expression data in human tissues are important for in vitro‐in vivo extrapolation and PBPK modeling from either primary cells or recombinant systems.

An

emerging

approach

relies

on

estimating

in

vitro

clearance

of

DMEs

or

transporters

using

recombinant

enzymes

or

cells

These

in

vitro

clearance

data

can

be

extrapolated

to

in

vivo

by

incorporating

tissue

protein

expression

in

the

PBPK

models

as

discussed

elsewhere

Therefore

protein

expression

data

in

human

tissues

are

important

for

in

vitro

in

vivo

extrapolation

and

PBPK

modeling

from

either

primary

cells

or

recombinant

systems

Answer: accept


On day 2 of TC 1 the gMean AUC0−24 value for BIBF 1120 was 454 ng h ml−1.

On

day

of

TC

the

gMean

AUC

value

for

BIBF

was

ng

h

ml

Answer: accept


The mean plasma zinc area under the curve for zinc acetate at low pH (AL), zinc acetate at high pH (AH), zinc oxide at low pH (OL), and zinc oxide at high pH (OH) were 524, 378, 364, and 66 micrograms x h/dL, respectively.

The

mean

plasma

zinc

area

under

the

curve

for

zinc

acetate

at

low

pH

AL

zinc

acetate

at

high

pH

AH

zinc

oxide

at

low

pH

OL

and

zinc

oxide

at

high

pH

OH

were

and

micrograms

x

h

dL

respectively

Answer: accept


The objective was to investigate the in vivo pharmacokinetics and tissue distribution of full-length recombinant human OPG (rhOPG) as well as its clearance mechanism using (125)I-labelled protein ((125)I-rhOPG) after intravenous administration to female Fischer rats.

The

objective

was

to

investigate

the

in

vivo

pharmacokinetics

and

tissue

distribution

of

full

length

recombinant

human

OPG

rhOPG

as

well

as

its

clearance

mechanism

using

I

labelled

protein

I

rhOPG

after

intravenous

administration

to

female

Fischer

rats

Answer: accept


The plasma elimination half-lives and the clearance values were not altered by the 29 days of Bendectin treatment for any of the species.

The

plasma

elimination

half

lives

and

the

clearance

values

were

not

altered

by

the

days

of

Bendectin

treatment

for

any

of

the

species

Answer: accept


The maximum levels were observed in 2 hours.

The

maximum

levels

were

observed

in

hours

Answer: accept


Peak concentrations in serum noted in the absence of antacids ranged from 2.9 to 6.4 micrograms/ml, and peak concentrations in dialysate in the absence of antacids ranged from 1.8 to 4.5 micrograms/ml.

Peak

concentrations

in

serum

noted

in

the

absence

of

antacids

ranged

from

to

micrograms

ml

and

peak

concentrations

in

dialysate

in

the

absence

of

antacids

ranged

from

to

micrograms

ml

Answer: accept


All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%–125% margins.

All

limits

of

the

CIs

of

the

estimated

geometric

mean

ratios

for

Cmax

and

all

AUC

comparisons

fell

within

the

margins

Answer: accept


Since half of insulin that found in portal system is exposed to hepatic clearance to inhibit hepatic glucose production, portal insulin concentration is 2-4-folds higher than peripheral insulin concentration.

Since

half

of

insulin

that

found

in

portal

system

is

exposed

to

hepatic

clearance

to

inhibit

hepatic

glucose

production

portal

insulin

concentration

is

folds

higher

than

peripheral

insulin

concentration

Answer: accept


The population typical values of K12, CL/F, V/F, EC50, K(in), and E(max) were 0.259 h(-1), 179 L x h(-1), 632 L, 1.57 ng x mL(-1), 4.29 and 0.664, respectively.

The

population

typical

values

of

K

CL

F

V

F

EC

K

in

and

E

max

were

h

L

x

h

L

ng

x

mL

and

respectively

Answer: accept


Effect of Covariates on Population PK Parameters

ASV CL/F for cirrhotic subjects is expected to be 0.65‐fold lower relative to subjects without cirrhosis.

ASV

CL

F

for

cirrhotic

subjects

is

expected

to

be

fold

lower

relative

to

subjects

without

cirrhosis

Answer: accept


The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ~9.3 h in dogs.

The

terminal

elimination

phase

half

life

was

to

h

in

rodents

and

it

was

h

in

dogs

Answer: accept


During haemodialysis, the central volume V1 was estimated to be reduced by 0.198 L/h.

During

haemodialysis

the

central

volume

V

was

estimated

to

be

reduced

by

L

h

Answer: accept


DHA clearance increased 10.2% per unit (g/dl) of decrease of hemoglobin.

DHA

clearance

increased

per

unit

g

dl

of

decrease

of

hemoglobin

Answer: accept


All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15–30 minutes (Tmax).

All

three

i

n

doses

rapidly

achieved

plasma

levels

of

peak

concentrations

T

by

minutes

peaking

at

minutes

Tmax

Answer: accept


Peak concentrations of total GIP (intact+metabolite, mean+-SEM) and intact GIP (in brackets) were 920+-91 (442+-52) pmol/l in the type 2 diabetic patients and 775+-68 (424+-30) pmol/l in the healthy subjects (NS).

Peak

concentrations

of

total

GIP

intact

metabolite

mean

SEM

and

intact

GIP

in

brackets

were

pmol

l

in

the

type

diabetic

patients

and

pmol

l

in

the

healthy

subjects

NS

Answer: accept


The aim of the present study was to compare the bioavailability of ranitidine (CAS 66357-35-5) from two different ranitidine hydrochloride (CAS 66357-59-3) film tablets (Ranitab 150 mg film tablets as test preparation and 150 mg film tablets of the originator product as reference preparation).

The

aim

of

the

present

study

was

to

compare

the

bioavailability

of

ranitidine

CAS

from

two

different

ranitidine

hydrochloride

CAS

film

tablets

Ranitab

mg

film

tablets

as

test

preparation

and

mg

film

tablets

of

the

originator

product

as

reference

preparation

Answer: accept


Pharmacokinetic analysis in mice, rats and cynomolgus monkeys

We show here that the t1/2 of AD-114-PA600 administered IV to cynomolgus monkeys ranged from 6.69 to 24.27 h.

We

show

here

that

the

t

of

AD

PA

administered

IV

to

cynomolgus

monkeys

ranged

from

to

h

Answer: accept


HBK was well eliminated by hollow fiber type artificial kidney (HFAK) with a half-life of 0.13 hr.

HBK

was

well

eliminated

by

hollow

fiber

type

artificial

kidney

HFAK

with

a

half

life

of

hr

Answer: accept


After 30 min infusion of ABI-007, the concentration of paclitaxel began to decrease immediately upon cessation of the infusion with t1/2 of 17.3–27.3 h in the whole blood, which is nearly comparable with that of standard dose of solvent-based paclitaxel (6), and the decline of paclitaxel concentration from maximum was multiphasic.

After

min

infusion

of

ABI

the

concentration

of

paclitaxel

began

to

decrease

immediately

upon

cessation

of

the

infusion

with

t

of

h

in

the

whole

blood

which

is

nearly

comparable

with

that

of

standard

dose

of

solvent

based

paclitaxel

and

the

decline

of

paclitaxel

concentration

from

maximum

was

multiphasic

Answer: accept


Noninvasive and Real-Time TPE-TR Imaging of the TV Networks

The time evolution profile of each local ROI could be well accounted for by a monoexponential decay function: I(t)=I0+Ime−tτ,(1)where τ is the decay time constant representing the clearance time constant, and I0 and Im stand for the luminescence intensity of the long-lasting background and the maximum, respectively.

The

time

evolution

profile

of

each

local

ROI

could

be

well

accounted

for

by

a

monoexponential

decay

function

I

t

I

Ime

t

τ

where

τ

is

the

decay

time

constant

representing

the

clearance

time

constant

and

I

and

Im

stand

for

the

luminescence

intensity

of

the

long

lasting

background

and

the

maximum

respectively

Answer: accept


As the differences in peak concentration and AUC were less than 20%, even though they were statistically significant, the two formulations were considered bioequivalent according to FDA guidelines for bioequivalence.

As

the

differences

in

peak

concentration

and

AUC

were

less

than

even

though

they

were

statistically

significant

the

two

formulations

were

considered

bioequivalent

according

to

FDA

guidelines

for

bioequivalence

Answer: accept


The half-life of furaltadone was 13 min in the homogenates of caprine and bovine liver and 35 min in the in vivo study of the goat.

The

half

life

of

furaltadone

was

min

in

the

homogenates

of

caprine

and

bovine

liver

and

min

in

the

in

vivo

study

of

the

goat

Answer: accept


The Cmax was 9.64 mg/g, 9.62 mg/g, 34.88 mg/l, 0.52 mg/l, and 2.13 mg/g for cornea, conjunctiva, aqueous humor, vitreous, and sclera, respectively.

The

Cmax

was

mg

g

mg

g

mg

l

mg

l

and

mg

g

for

cornea

conjunctiva

aqueous

humor

vitreous

and

sclera

respectively

Answer: accept


After single intravenous dosing (2.5, 5, or 10 mg/kg) with the HPBCD-based formulation, the area under the plasma concentration-time curve of acitretin increased proportionally with the dose and its clearance remained unchanged within the tested dose range.

After

single

intravenous

dosing

or

mg

kg

with

the

HPBCD

based

formulation

the

area

under

the

plasma

concentration

time

curve

of

acitretin

increased

proportionally

with

the

dose

and

its

clearance

remained

unchanged

within

the

tested

dose

range

Answer: accept


AUC values in four brain regions by the nasal route were 54- to 121-fold compared with the i.v. route, the drug targeting index (DTI) values of nasal route were 71-158 for different brain regions, and about 99% of RTX content within 360 min in the brain were transported via the olfactory pathway.

AUC

values

in

four

brain

regions

by

the

nasal

route

were

to

fold

compared

with

the

i

v

route

the

drug

targeting

index

DTI

values

of

nasal

route

were

for

different

brain

regions

and

about

of

RTX

content

within

min

in

the

brain

were

transported

via

the

olfactory

pathway

Answer: accept


Absorption, distribution, metabolism, excretion

Mean maximum plasma concentrations of 3380 and 315 ng/mL for M461 and M557 respectively, occurred at 5 min post dose.

Mean

maximum

plasma

concentrations

of

and

ng

mL

for

M

and

M

respectively

occurred

at

min

post

dose

Answer: accept


The half-time clearance rate from blood for these 131I-lymphocytes was calculated to be 171 min.

The

half

time

clearance

rate

from

blood

for

these

I

lymphocytes

was

calculated

to

be

min

Answer: accept


3.4. Relative Bioavailability of WR299666 Mircroparticles

The mean AUCs determined for the larger particle size of this compound were 387.44 ng·h/mL, whereas the mean values for the smaller particles were 718.63 ng·h/mL (P value = 0.0132).

The

mean

AUCs

determined

for

the

larger

particle

size

of

this

compound

were

ng

h

mL

whereas

the

mean

values

for

the

smaller

particles

were

ng

h

mL

P

value

Answer: accept


However, like Cmax, both of these confidence intervals are indicative, per the 80 to 125% criteria, of a drug interaction effect.

However

like

Cmax

both

of

these

confidence

intervals

are

indicative

per

the

to

criteria

of

a

drug

interaction

effect

Answer: accept


After single and four weekly SC injections, the median tmax ranged from 47 to 49 hours post-dose, indicating slow absorption with SC dosing (Tables 3, 4; Fig. 1b, c).

After

single

and

four

weekly

SC

injections

the

median

tmax

ranged

from

to

hours

post

dose

indicating

slow

absorption

with

SC

dosing

Tables

Fig

b

c

Answer: accept


The Vss is 2 to 3 times the plasma volume.

The

Vss

is

to

times

the

plasma

volume

Answer: accept


However, the AUC of 4-hydroxycyclophosphamide was overestimated (mean prediction error = 16.9%-23.6%).

However

the

AUC

of

hydroxycyclophosphamide

was

overestimated

mean

prediction

error

Answer: accept


Cortisol peaks were observed 1h after each HC intake and a dose response was demonstrated for cortisol peak and cortisol AUC.

Cortisol

peaks

were

observed

h

after

each

HC

intake

and

a

dose

response

was

demonstrated

for

cortisol

peak

and

cortisol

AUC

Answer: accept


2.3. Pharmacokinetics of Gastrodin in Rats

The Cmax and AUC of 4-HBA in antibiotic-treated animals were significantly reduced from 4.2 µg/mL and 7.0 µg·h/mL to 2.5 µg/mL and 4.6 µg⋅h/mL, respectively.

The

Cmax

and

AUC

of

HBA

in

antibiotic

treated

animals

were

significantly

reduced

from

µ

g

mL

and

µ

g

h

mL

to

µ

g

mL

and

µ

g

h

mL

respectively

Answer: accept


HB-002.1 has a molecular weight of ~80 kDa, isoelectric point of ~6.7, and an optimal target binding affinity of <1 nM. The pharmacokinetic profile was excellent with a half-life of 5 days, maximal concentration of 20.27 μg/ml, and area under the curve of 81.46 μg · days/ml.

HB

has

a

molecular

weight

of

kDa

isoelectric

point

of

and

an

optimal

target

binding

affinity

of

nM

The

pharmacokinetic

profile

was

excellent

with

a

half

life

of

days

maximal

concentration

of

μ

g

ml

and

area

under

the

curve

of

μ

g

days

ml

Answer: accept


The respective MICs of marbofloxacin against E. coli and P. multocida were 0.03 μg/mL and 0.4 μg/mL. The AUC0-24h/MIC ratios were 226.64 ± 7.21 h for E. coli and 16.99 ± 0.541 h for P. multocida.

The

respective

MICs

of

marbofloxacin

against

E

coli

and

P

multocida

were

μ

g

mL

and

μ

g

mL

The

AUC

h

MIC

ratios

were

h

for

E

coli

and

h

for

P

multocida

Answer: accept


The hydrolysis was seen with half-life (t(1/2)) of about 9.9, 65.0, 14.2, 3.4, 2.1 9.5, and 1.6 minutes for KI-306, 309, 312, 313, 315, 316, and 317, respectively.

The

hydrolysis

was

seen

with

half

life

t

of

about

and

minutes

for

KI

and

respectively

Answer: accept


2.2. Pharmacokinetic (PK) Studies in Rat

However, compounds with aralkyl groups (compounds 1l, 1m) have lower F values, particularly 1l.

However

compounds

with

aralkyl

groups

compounds

l

m

have

lower

F

values

particularly

l

Answer: accept


The vitreous half-life of 1.25 mg/0.05 mL intravitreal bevacizumab was 6.61 days in this rabbit model.

The

vitreous

half

life

of

mg

mL

intravitreal

bevacizumab

was

days

in

this

rabbit

model

Answer: accept


The half-lives were 69 hours in normal vitreous and 14.53 hours in infected vitreous.

The

half

lives

were

hours

in

normal

vitreous

and

hours

in

infected

vitreous

Answer: accept


Pharmacokinetic studies with healthy subjects have shown that this drug is rapidly absorbed (time to Cmax about 0.65 h).

Pharmacokinetic

studies

with

healthy

subjects

have

shown

that

this

drug

is

rapidly

absorbed

time

to

Cmax

about

h

Answer: accept


A two-compartment model with mean t(1/2)alpha of 0.31 +- 0.27 hours and mean t(1/2)beta of 0.86 +- 0.78 hours best described the concentration-time curves for QC12.

A

two

compartment

model

with

mean

t

alpha

of

hours

and

mean

t

beta

of

hours

best

described

the

concentration

time

curves

for

QC

Answer: accept


The elimination of HTB was much slower with a t1/2 of 21.5 h and a Cl of 5.1 (mg/kg)/h.

The

elimination

of

HTB

was

much

slower

with

a

t

of

h

and

a

Cl

of

mg

kg

h

Answer: accept


The Ktrans values significantly decreased in five patients (18, 20, 21, 25 and 26), which is consistent with a reduction in tumour blood flow in response to study drug in these individuals (Galbraith et al, 2003).

The

Ktrans

values

significantly

decreased

in

five

patients

and

which

is

consistent

with

a

reduction

in

tumour

blood

flow

in

response

to

study

drug

in

these

individuals

Galbraith

et

al

Answer: accept


Overall data corresponding to the final protocol (n = 6)

Nonetheless, an important IIV was evidenced by these data, given that coefficient of variation (CV) was as high as 60% for Cmax, 56% for plasma concentration-time curve (AUC), and 64% for CL.

Nonetheless

an

important

IIV

was

evidenced

by

these

data

given

that

coefficient

of

variation

CV

was

as

high

as

for

Cmax

for

plasma

concentration

time

curve

AUC

and

for

CL

Answer: accept


Pharmacokinetic of roflumilast and roflumilast‐N‐oxide

Apparent roflumilast clearance was estimated to be 2.34 L/h and 41.8 L/h for roflumilast and roflumilast‐N‐oxide dosing, respectively, whereas apparent roflumilast‐N‐oxide clearance was estimated to be 3.52 L/h and 1.09 L/h.

Apparent

roflumilast

clearance

was

estimated

to

be

L

h

and

L

h

for

roflumilast

and

roflumilast

N

oxide

dosing

respectively

whereas

apparent

roflumilast

N

oxide

clearance

was

estimated

to

be

L

h

and

L

h

Answer: accept


Although supplementation with 200 mg/day androstenedione increases AUC for serum androstenedione in the day 0 condition, continued supplementation is characterised by a diminished treatment response, coupled with time 0 increases in testosterone precursors but not testosterone.

Although

supplementation

with

mg

day

androstenedione

increases

AUC

for

serum

androstenedione

in

the

day

condition

continued

supplementation

is

characterised

by

a

diminished

treatment

response

coupled

with

time

increases

in

testosterone

precursors

but

not

testosterone

Answer: accept


Elimination followed a biphasic course, with a rapid initial decline followed after 12-24 h by a late phase with a terminal half-life of about 10 h. About 100% of the administered dose could be recovered in urine within 72 h, mostly in conjugated form.

Elimination

followed

a

biphasic

course

with

a

rapid

initial

decline

followed

after

h

by

a

late

phase

with

a

terminal

half

life

of

about

h

About

of

the

administered

dose

could

be

recovered

in

urine

within

h

mostly

in

conjugated

form

Answer: accept


Oral TAM bioavailability was 13,15% ± 4,18, with a steady state volume of distribution of 7831 ± 2922 (L/kg).

Oral

TAM

bioavailability

was

with

a

steady

state

volume

of

distribution

of

L

kg

Answer: accept


Linear calibration curves obtained with the peak-area ratio (y) of germacrone to internal standard (tanshinoneIIA) versus drug concentration (x) were found to be linear between 8.08 and 808 ng/ml.

Linear

calibration

curves

obtained

with

the

peak

area

ratio

y

of

germacrone

to

internal

standard

tanshinoneIIA

versus

drug

concentration

x

were

found

to

be

linear

between

and

ng

ml

Answer: accept


Results revealed significant tumor regression effects in S-180 and EAC as T/Cmax values of 138 and 189 were obtained at its optimum dose of 60 mg/kg for QD1-7 .

Results

revealed

significant

tumor

regression

effects

in

S

and

EAC

as

T

Cmax

values

of

and

were

obtained

at

its

optimum

dose

of

mg

kg

for

QD

Answer: accept


The loperamide from the syrup was absorbed more rapidly than from the capsule formulation, with the peak serum levels observed at a mean time of 2.4 +- 0.7 hours for the syrup and 5.2 +- 0.3 hours for the capsule formulation.

The

loperamide

from

the

syrup

was

absorbed

more

rapidly

than

from

the

capsule

formulation

with

the

peak

serum

levels

observed

at

a

mean

time

of

hours

for

the

syrup

and

hours

for

the

capsule

formulation

Answer: accept


Three-compartment modelling was performed for increasing fitting intervals (20-120 min) with both a 5-parameter (K1*-k4*, and vascular volume (Vo)) and a 4-parameter (K1*-k3*,Vo) model.

Three

compartment

modelling

was

performed

for

increasing

fitting

intervals

min

with

both

a

parameter

K

k

and

vascular

volume

Vo

and

a

parameter

K

k

Vo

model

Answer: accept


The k10 half-life ranged from 2.7 to 4.4 h. Cmax and AUC increased with dose in male rats, but these increases did not appear to be dose-proportional.

The

k

half

life

ranged

from

to

h

Cmax

and

AUC

increased

with

dose

in

male

rats

but

these

increases

did

not

appear

to

be

dose

proportional

Answer: accept


In rats, rabbits and dogs, the Vss were 23.0, 51.7 and 7.3 L/kg, respectively, and the Vc were 2.33, 2.13 and 0.38 L/kg, respectively.

In

rats

rabbits

and

dogs

the

Vss

were

and

L

kg

respectively

and

the

Vc

were

and

L

kg

respectively

Answer: accept


Results
Pharmacodynamics
Maximum 0–4‐Hour QTcF on Days 1 and 7

On day 7, small but statistically significant increases of 3.69 and 5.25 milliseconds in maximum 0–4‐hour QTcF were observed with FF/VI 50/25 and 100/25 μg, respectively.

On

day

small

but

statistically

significant

increases

of

and

milliseconds

in

maximum

hour

QTcF

were

observed

with

FF

VI

and

μ

g

respectively

Answer: accept


The mathematical relation between AUC0–24 h and particle size, AUC0–24 h = λ · sizen, is consistent across all sink-like ROIs with values of power coefficient n varying between 0.4 and 1.2, suggesting a moderate to strongly positive linear dependence (see Supplementary Fig. 19d, g, h).

The

mathematical

relation

between

AUC

h

and

particle

size

AUC

h

λ

sizen

is

consistent

across

all

sink

like

ROIs

with

values

of

power

coefficient

n

varying

between

and

suggesting

a

moderate

to

strongly

positive

linear

dependence

see

Supplementary

Fig

d

g

h

Answer: accept


The decline of morphine serum concentration after epidural administration of 0.1 mg/kg was described by a bi- or triexponential decay equation with a mean terminal half-life (t1/2) of 134.7 +- 107.9 min.

The

decline

of

morphine

serum

concentration

after

epidural

administration

of

mg

kg

was

described

by

a

bi

or

triexponential

decay

equation

with

a

mean

terminal

half

life

t

of

min

Answer: accept


No correlation was found between AUC and BMI, LBM or adipose index (p = 0.34, 0.11 and 0.23, respectively).

No

correlation

was

found

between

AUC

and

BMI

LBM

or

adipose

index

p

and

respectively

Answer: accept


Macrolides
Macrolides as Perpetrators
Immunosuppressants

An open-label placebo-controlled study of eight stable renal transplant patients found a 7% increase in AUC and 19% increase in Cmax of cyclosporine A, a CYP3A4 substrate, after co-administration of AZM, and concluded the drug-drug interaction not to be clinically significant [213].

An

open

label

placebo

controlled

study

of

eight

stable

renal

transplant

patients

found

a

increase

in

AUC

and

increase

in

Cmax

of

cyclosporine

A

a

CYP

A

substrate

after

co

administration

of

AZM

and

concluded

the

drug

drug

interaction

not

to

be

clinically

significant

Answer: accept


Mean Cmax increased from 0.52 to 9.75 μmol·L−1 after single i.v. doses of 0.3–4.8 mg·kg−1 lexaptepid respectively.

Mean

Cmax

increased

from

to

μ

mol

L

after

single

i

v

doses

of

mg

kg

lexaptepid

respectively

Answer: accept


Study A (Cytochrome P450 [CYP] 3A4 Induction)

When AUCct was compared, a 126% increase was observed following vandetanib and rifampicin compared with vandetanib alone (gmean 44.26 vs 19.56 ng · h/mL).

Answer: accept

When

AUCct

was

compared

a

increase

was

observed

following

vandetanib

and

rifampicin

compared

with

vandetanib

alone

gmean

vs

ng

h

mL


In vitro ADMET characterization of SCYX-7158

SCYX-7158 did not exhibit any significant binding to this channel in a radioligand binding assay (−6% at 10 µM), and we confirmed this result by investigation of the ability of SCYX-7158 to block the hERG channel expressed in HEK-293 cells using a whole-cell patch clamp technique.[34], [35] At test concentrations of 30 and 100 µM, SCYX-7158 produced a mean fractional block of 0.108±0.037 and 0.198±0.018, respectively, indicative of a hERG IC50 >100 µM.

SCYX

did

not

exhibit

any

significant

binding

to

this

channel

in

a

radioligand

binding

assay

at

µ

M

and

we

confirmed

this

result

by

investigation

of

the

ability

of

SCYX

to

block

the

hERG

channel

expressed

in

HEK

cells

using

a

whole

cell

patch

clamp

technique

At

test

concentrations

of

and

µ

M

SCYX

produced

a

mean

fractional

block

of

and

respectively

indicative

of

a

hERG

IC

µ

M

Answer: accept


LE was detected in all ocular tissues for both formulations within 5 min of dosing, and maximum concentrations were achieved within 1 h of instillation (Fig. 3).

LE

was

detected

in

all

ocular

tissues

for

both

formulations

within

min

of

dosing

and

maximum

concentrations

were

achieved

within

h

of

instillation

Fig

Answer: accept


The area under the drug concentration-time curves (AUC) and maximal blood concentration (C(max)) after oral administration of YH439 loaded on thermal reversible microemulsion were significantly increased than drug loaded on either Gelucire formulation or 5% Na-CMC suspension.

The

area

under

the

drug

concentration

time

curves

AUC

and

maximal

blood

concentration

C

max

after

oral

administration

of

YH

loaded

on

thermal

reversible

microemulsion

were

significantly

increased

than

drug

loaded

on

either

Gelucire

formulation

or

CMC

suspension

Answer: accept


3. Results
3.4. Pharmacokinetics of Phillygenin

The phillygenin was slowly distributed to tissues, with a half-life of 150 min.

The

phillygenin

was

slowly

distributed

to

tissues

with

a

half

life

of

min

Answer: accept


Geometric mean (CV% geometric mean) of AR relative to cefiderocol dose was 56.1% (12.2%), and Fr was 62.3% (8.4%), suggesting that intermittent HD removed approximately 60% of the cefiderocol dose.

Geometric

mean

CV

geometric

mean

of

AR

relative

to

cefiderocol

dose

was

and

Fr

was

suggesting

that

intermittent

HD

removed

approximately

of

the

cefiderocol

dose

Answer: accept


Following i.v. administration of PCr 500 mg x kg(-1) and 1 000 mg x kg(-1) the C-T curve could be described by the two-compartment model with t1/2beta 22.5-23.3 min, V(d) 0.956 4-0.978 6 L x kg(-1), CL 0.029 L. kg(-1) x min(-1).

Following

i

v

administration

of

PCr

mg

x

kg

and

mg

x

kg

the

C

T

curve

could

be

described

by

the

two

compartment

model

with

t

beta

min

V

d

L

x

kg

CL

L

kg

x

min

Answer: accept


Mean Cmax increased in a dose‐proportional manner to 75 mg.

Mean

Cmax

increased

in

a

dose

proportional

manner

to

mg

Answer: accept


3.4.2. Pharmacokinetics of Embelin in Rats after Oral Administration

The concentration of embelin in plasma was low and the absorption was incomplete, which was indicated by the V/F of more than 6 L and the Cmax of 1.04 ± 0.21 μg/mL compared with the Cmax of 3.91 ± 1.34 μg/mL for intravenous administration [27].

The

concentration

of

embelin

in

plasma

was

low

and

the

absorption

was

incomplete

which

was

indicated

by

the

V

F

of

more

than

L

and

the

Cmax

of

μ

g

mL

compared

with

the

Cmax

of

μ

g

mL

for

intravenous

administration

Answer: accept


The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+- SD) change in AUC0-12 of -13.6(+- 20.8) and +8.4(+- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+- 43.7) and -0.3(+- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively.

The

only

pharmacodynamic

parameter

showing

a

statistically

significant

difference

in

change

from

baseline

between

the

two

formulations

was

DBP

with

mean

SD

change

in

AUC

of

and

mm

Hg

h

p

and

in

AUC

of

and

mm

Hg

h

p

for

Cardizem

SR

and

Bi

Tildiem

respectively

Answer: accept


Peak and trough concentrations were significantly different between the continuous and intermittent groups both in the first (Cmax: 19.8 mg/L vs. 51.8 mg/L, P= 0.000; Cmin: 11.2 mg/L vs. 0.5 mg/L, P= 0.000) and third dosing periods (Cmax: 12.5 mg/L vs. 46.4 mg/L, P= 0.000; Cmin: 11.4 mg/L vs. 0.6 mg/L, P= 0.000).

Peak

and

trough

concentrations

were

significantly

different

between

the

continuous

and

intermittent

groups

both

in

the

first

Cmax

mg

L

vs

mg

L

P

Cmin

mg

L

vs

mg

L

P

and

third

dosing

periods

Cmax

mg

L

vs

mg

L

P

Cmin

mg

L

vs

mg

L

P

Answer: accept


Amsacrine was also found to be highly bound to plasma proteins (96.4%-97.7%), but changes in binding were not responsible for the reduced Cl and prolonged t1/2 beta observed between the first and third infusions.

Amsacrine

was

also

found

to

be

highly

bound

to

plasma

proteins

but

changes

in

binding

were

not

responsible

for

the

reduced

Cl

and

prolonged

t

beta

observed

between

the

first

and

third

infusions

Answer: accept


Total clearance (CLT) was similar at the doses of 10 and 50 mg/kg, with values of 2.80 and 2.73 L/h/kg, respectively.

Total

clearance

CLT

was

similar

at

the

doses

of

and

mg

kg

with

values

of

and

L

h

kg

respectively

Answer: accept


Fluoroquinolones
Fluoroquinolones as Victims
Di- and trivalent metallic agents

Remarkably, although the AUC remained unchanged, the Cmax of LVX [257] and the third-generation fluoroquinolone MXF [258] decreased by approximately 18% by means of concomitant treatment with calcium.

Remarkably

although

the

AUC

remained

unchanged

the

Cmax

of

LVX

and

the

third

generation

fluoroquinolone

MXF

decreased

by

approximately

by

means

of

concomitant

treatment

with

calcium

Answer: accept


Elimination clearance was 0.0061 +- 0.0006 liters/min/kg for the 12-mg/kg group and 0.0086 +- 0.0013 liters/min/kg for the 60-mg/kg group (P greater than .05).

Elimination

clearance

was

liters

min

kg

for

the

mg

kg

group

and

liters

min

kg

for

the

mg

kg

group

P

greater

than

Answer: accept


The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin).

The

occurrence

of

elevated

liver

enzymes

during

the

first

weeks

in

the

EFV

containing

arm

was

significantly

P

correlated

to

the

exposure

of

EFV

Cmin

Answer: accept


Results and Discussion
Method Validation
Sensitivity and Linearity

The calibration curve was prepared by determining the best fit of the peak-area ratios (peak area analyte/peak area IS) vs. concentration, and fitted to the y = mx + c using a weighing factor (1/x).

The

calibration

curve

was

prepared

by

determining

the

best

fit

of

the

peak

area

ratios

peak

area

analyte

peak

area

IS

vs

concentration

and

fitted

to

the

y

mx

c

using

a

weighing

factor

x

Answer: accept


2. Totally, 14 constituents (two parent compounds and 12 metabolites) of Fructus Gardeniae were identified in human plasma and urine either by comparing the retention time and mass spectrometry data with that of reference compounds or by the accurate high-resolution MS/MS data of the chemicals.

Totally

constituents

two

parent

compounds

and

metabolites

of

Fructus

Gardeniae

were

identified

in

human

plasma

and

urine

either

by

comparing

the

retention

time

and

mass

spectrometry

data

with

that

of

reference

compounds

or

by

the

accurate

high

resolution

MS

MS

data

of

the

chemicals

Answer: accept


The maximum levels were 54 to 106.4 ng/ml with the 30 mg dosage and 74.7 to 79.2 ng/ml with the 40 mg dosage, followed by a slow decline, with T1/2 ranging from 6.54 to 17.80 hr.

The

maximum

levels

were

to

ng

ml

with

the

mg

dosage

and

to

ng

ml

with

the

mg

dosage

followed

by

a

slow

decline

with

T

ranging

from

to

hr

Answer: accept


Moreover, the in situ gel achieved 2-3 fold higher peak plasma concentration (Cmax) and area under the curve (AUC) of THA in plasma and brain tissue, but lowered Cmax and AUC of the THA metabolites compared to that of oral solution.

Moreover

the

in

situ

gel

achieved

fold

higher

peak

plasma

concentration

Cmax

and

area

under

the

curve

AUC

of

THA

in

plasma

and

brain

tissue

but

lowered

Cmax

and

AUC

of

the

THA

metabolites

compared

to

that

of

oral

solution

Answer: accept


In an exploratory analysis, relatively smaller differences in AUC(INF) were observed among the 3 groups after the exclusion of 3 patients (2 in the NRF group and 1 in the ESRD group) who had developed antidrug antibodies on day 1 of cycle 2.

In

an

exploratory

analysis

relatively

smaller

differences

in

AUC

INF

were

observed

among

the

groups

after

the

exclusion

of

patients

in

the

NRF

group

and

in

the

ESRD

group

who

had

developed

antidrug

antibodies

on

day

of

cycle

Answer: accept


Results
Secondary endpoints
Pharmacokinetics

Cinacalcet was rapidly absorbed, with a median tmax of 1 h (range 0.50 to 4.0 h) (Table 2, Fig. 2).

Cinacalcet

was

rapidly

absorbed

with

a

median

tmax

of

h

range

to

h

Table

Fig

Answer: accept


The pharmacokinetic parameters such as elimination rate half-life (t1/2), area under curve (AUC), and plasma clearance (CL) were calculated to be 3.345±0.647 min, 5750±656.0 µg min/mL, and 5.891±0.458 mL/min/kg, respectively.

The

pharmacokinetic

parameters

such

as

elimination

rate

half

life

t

area

under

curve

AUC

and

plasma

clearance

CL

were

calculated

to

be

min

µ

g

min

mL

and

mL

min

kg

respectively

Answer: accept


Clinical Pharmacodynamics
Effects on Urinary Glucose Excretion

In addition, no significant differences in mean cumulative urine volume were observed in empagliflozin versus placebo in the first 24 h (3.11–3.98 L and 3.17 L, respectively), or in the first 72 h (7.12–8.71 L and 7.30 L, respectively) [20].

In

addition

no

significant

differences

in

mean

cumulative

urine

volume

were

observed

in

empagliflozin

versus

placebo

in

the

first

h

L

and

L

respectively

or

in

the

first

h

L

and

L

respectively

Answer: accept


In ISF, the observed versus population predicted r2, bias, and imprecision were 0.198, 20.1, and 1,394 (Fig. 2a), and the corresponding values for the observed versus individual MAP Bayesian plot were 0.887, −1.17, and 21.3, respectively (Fig. 2b).

In

ISF

the

observed

versus

population

predicted

r

bias

and

imprecision

were

and

Fig

a

and

the

corresponding

values

for

the

observed

versus

individual

MAP

Bayesian

plot

were

and

respectively

Fig

b

Answer: accept


The predicted bioavailability of the p.o. 25, 50, 100 and 400 mg doses of talinolol was 64, 76, 85, 94%, respectively.

The

predicted

bioavailability

of

the

p

o

and

mg

doses

of

talinolol

was

respectively

Answer: accept


The apparent volume of distribution (V/F) was significantly lower in patients receiving split doses of mefloquine monotherapy (mean, 8.14 L/kg; 95% CI, 7.49 to 8.86 L/kg) compared with a single dose (mean, 20.37 L/kg; 95% CI, 16.26 to 25.51 L/kg).

The

apparent

volume

of

distribution

V

F

was

significantly

lower

in

patients

receiving

split

doses

of

mefloquine

monotherapy

mean

L

kg

CI

to

L

kg

compared

with

a

single

dose

mean

L

kg

CI

to

L

kg

Answer: accept


Pharmacokinetics of QHS and its phase I metabolites

There was also a large inter-individual variability in QHS pharmacokinetic parameters, with a %CV of 43.5% (6.9-122.7%) for AUC0-t.

There

was

also

a

large

inter

individual

variability

in

QHS

pharmacokinetic

parameters

with

a

CV

of

for

AUC

t

Answer: accept


The metabolic ratio (1-hydroxytacrine AUC/tacrine AUC) was significantly (mean, 26%; P < .001) reduced in all 10 subjects.

The

metabolic

ratio

hydroxytacrine

AUC

tacrine

AUC

was

significantly

mean

P

reduced

in

all

subjects

Answer: accept


Median time to maximum concentration (Tmax) was 1h and 1.5h for suspension and solution formulation, respectively.

Median

time

to

maximum

concentration

Tmax

was

h

and

h

for

suspension

and

solution

formulation

respectively

Answer: accept


Volunteers and Methods
Statistical Analysis

This approach is based on the CVWR: if the CVWR is inferior or equal to 30 % (≤30 %), the 90 % geometric confidence intervals of the ratio T/R of least-squares means of the ln-transformed Cmax should be within the acceptable range of 80.00–125.00 % to conclude bioequivalence.

This

approach

is

based

on

the

CVWR

if

the

CVWR

is

inferior

or

equal

to

the

geometric

confidence

intervals

of

the

ratio

T

R

of

least

squares

means

of

the

ln

transformed

Cmax

should

be

within

the

acceptable

range

of

to

conclude

bioequivalence

Answer: accept


The mean Tmax was 1.82, 2.3, 2.79 and 3.39 h, respectively.

The

mean

Tmax

was

and

h

respectively

Answer: accept


Mean terminal half lives for total radioactivity ranged from 2.5 to 4.2 hours.

Mean

terminal

half

lives

for

total

radioactivity

ranged

from

to

hours

Answer: accept


Results
Pharmacokinetic Parameters
TFV Cervicovaginal Fluid Concentration

The estimated AUC for the MD QD and BID groups was 26.2×106 and 18.4×106, respectively (Table S1).

The

estimated

AUC

for

the

MD

QD

and

BID

groups

was

and

respectively

Table

S

Answer: accept


X‐82 blood pharmacokinetics appeared dose‐independent with a t1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively.

X

blood

pharmacokinetics

appeared

dose

independent

with

a

t

of

hours

and

hours

for

capsule

and

tablet

formulations

respectively

Answer: accept


We measured serum trough levels after week 1 in cohort 1 or after two consecutive weekly doses in cohorts 2 and 3.

We

measured

serum

trough

levels

after

week

in

cohort

or

after

two

consecutive

weekly

doses

in

cohorts

and

Answer: accept


Comparing paracetamol clearance in vertebrate species

Supplementary Figure S2 depicts this relationship and shows that the CL for paracetamol in zebrafish larvae obtained in this study does fall within the 95% confidence and prediction interval of this fit.

Supplementary

Figure

S

depicts

this

relationship

and

shows

that

the

CL

for

paracetamol

in

zebrafish

larvae

obtained

in

this

study

does

fall

within

the

confidence

and

prediction

interval

of

this

fit

Answer: accept


The mean half-life of the tracer in the lungs in Groups I-IV was 60, 58, 59 and 26 min, respectively.

The

mean

half

life

of

the

tracer

in

the

lungs

in

Groups

I

IV

was

and

min

respectively

Answer: accept


Between‐subject variability in Cmax and area under the curve (AUC), as calculated using noncompartmental analysis (NCA) was generally low to moderate, with a coefficient of variation between 10–40% (Table S2).

Between

subject

variability

in

Cmax

and

area

under

the

curve

AUC

as

calculated

using

noncompartmental

analysis

NCA

was

generally

low

to

moderate

with

a

coefficient

of

variation

between

Table

S

Answer: accept


The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM.

Answer: accept

The

lead

compound

in

the

series

N

phenethyl

N

thiazolyl

thiourea

inhibits

HIV

RT

using

rCdG

as

the

template

with

an

IC

of

microM

In

MT

cells

compound

inhibits

HIV

with

an

ED

of

microM


Subjects and Methods
Pharmacokinetics and pharmacodynamics

For pharmacokinetic analysis, single steady‐state trough samples were obtained from all consenting patients immediately prior to dose administration during cycle 1 on days 7, 14, 21, and 28 along with cycle 2 on days 1 and 28.

For

pharmacokinetic

analysis

single

steady

state

trough

samples

were

obtained

from

all

consenting

patients

immediately

prior

to

dose

administration

during

cycle

on

days

and

along

with

cycle

on

days

and

Answer: accept


The overall differences in PK parameters among formulations for African Americans were similar to the main analysis, suggesting that LCPT provided a higher AUC0–24 (RGM 138.2, p < 0.01, and 149.1, p = 0.02), Cmax was similar despite a higher AUC0–24 (RGM 107.4, p = 0.54, and 109.8, p = 0.22), Cmin was higher (RGM 125.3, p = 0.02, and 151.0, p < 0.01), Tmax was delayed (RGM 2.48, p = 0.22, and 2.55, p < 0.01) and intraday peak‐to‐trough fluctuation was lower (−39.64, p = 0.07, and −54.08, p = 0.02) for LCPT versus IR‐Tac and LCPT versus ER‐Tac, respectively.

The

overall

differences

in

PK

parameters

among

formulations

for

African

Americans

were

similar

to

the

main

analysis

suggesting

that

LCPT

provided

a

higher

AUC

RGM

p

and

p

Cmax

was

similar

despite

a

higher

AUC

RGM

p

and

p

Cmin

was

higher

RGM

p

and

p

Tmax

was

delayed

RGM

p

and

p

and

intraday

peak

to

trough

fluctuation

was

lower

p

and

p

for

LCPT

versus

IR

Tac

and

LCPT

versus

ER

Tac

respectively

Answer: accept


Plasma concentrations of rikkunshito ingredients

When the tmax values of the ingredients at a dose of 7.5 g were compared, it was found that atractylodin carboxylic acid, isoliquiritigenin, nobiletin, atractylodin, and heptamethoxyflavone were all rapid-acting, with values of 1 h or shorter, while liquiritigenin, naringenin, pachymic acid, and 18β-glycyrrhetinic acid showed values exceeding 3 h. When t1/2 values of the components at a dose of 7.5 g were compared, atractylodin carboxylic acid, atractylodin, heptamethoxyflavone, nobiletin, isoliquiritigenin, liquiritigenin, and naringenin had values < 10 h, while 18β-glycyrrhetinic acid, and pachymic acid had values exceeding 10 h. The plasma concentrations of atractylodin and pachymic acid just before the administration were BQL in all subjects, whereas peaks for other compounds (atractylodin carboxylic acid, heptamethoxyflavone, liquiritigenin, isoliquiritigenin, nobiletin, naringenin, and 18β-glycyrrhetinic acid) were detected in some subjects.

When

the

tmax

values

of

the

ingredients

at

a

dose

of

g

were

compared

it

was

found

that

atractylodin

carboxylic

acid

isoliquiritigenin

nobiletin

atractylodin

and

heptamethoxyflavone

were

all

rapid

acting

with

values

of

h

or

shorter

while

liquiritigenin

naringenin

pachymic

acid

and

β

glycyrrhetinic

acid

showed

values

exceeding

h

When

t

values

of

the

components

at

a

dose

of

g

were

compared

atractylodin

carboxylic

acid

atractylodin

heptamethoxyflavone

nobiletin

isoliquiritigenin

liquiritigenin

and

naringenin

had

values

h

while

β

glycyrrhetinic

acid

and

pachymic

acid

had

values

exceeding

h

The

plasma

concentrations

of

atractylodin

and

pachymic

acid

just

before

the

administration

were

BQL

in

all

subjects

whereas

peaks

for

other

compounds

atractylodin

carboxylic

acid

heptamethoxyflavone

liquiritigenin

isoliquiritigenin

nobiletin

naringenin

and

β

glycyrrhetinic

acid

were

detected

in

some

subjects

Answer: accept


C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration-time curve AUC)], while a truncated AUC was a good surrogate of the 12-h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses.

C

was

a

poor

predictor

of

the

total

MPA

exposure

as

measured

by

the

area

under

the

concentration

time

curve

AUC

while

a

truncated

AUC

was

a

good

surrogate

of

the

h

profile

r

p

Graft

function

and

cyclosporine

therapy

influenced

MPA

pharmacokinetics

as

shown

by

the

univariate

and

multivariate

analyses

Answer: accept


The mean area under the concentration x time curve (AUC) was 498 ng.h/ml.

The

mean

area

under

the

concentration

x

time

curve

AUC

was

ng

h

ml

Answer: accept


Pharmacokinetics of cyadox in the plasma and intestinal tract

The absorption of cyadox after oral administration was limited, reaching the maximum plasma concentration (Cmax = 0.031 μg/mL) at 2.41 h. After this point, the concentration of the drug quickly decreased to the quantification limit (0.02 μg/mL) by 12 h. The pharmacokinetic parameters derived from non-compartmental analysis are presented in Table 2, and the area under the concentration-time curve (AUC)0–24h of plasma was 0.22 μg/h/mL. Compared to the cyadox concentration in plasma, the concentration in the ileum fluid was markedly higher, with a Cmax of 23.66 μg/mL at 1.96 h, and the AUC0–24h (106.40 μg/h/mL) was also much higher.

The

absorption

of

cyadox

after

oral

administration

was

limited

reaching

the

maximum

plasma

concentration

Cmax

μ

g

mL

at

h

After

this

point

the

concentration

of

the

drug

quickly

decreased

to

the

quantification

limit

μ

g

mL

by

h

The

pharmacokinetic

parameters

derived

from

non

compartmental

analysis

are

presented

in

Table

and

the

area

under

the

concentration

time

curve

AUC

h

of

plasma

was

μ

g

h

mL

Compared

to

the

cyadox

concentration

in

plasma

the

concentration

in

the

ileum

fluid

was

markedly

higher

with

a

Cmax

of

μ

g

mL

at

h

and

the

AUC

h

μ

g

h

mL

was

also

much

higher

Answer: accept


Measurements after cessation of treatment gave terminal half-lives in plasma of 11.5-23.0 h which is considerably longer than reported in the literature.

Measurements

after

cessation

of

treatment

gave

terminal

half

lives

in

plasma

of

h

which

is

considerably

longer

than

reported

in

the

literature

Answer: accept


After oral administration, the maximum plasma concentrations were obtained within 0.83-3.00 h and the half-life for each animal was almost the same as that after intravenous administration.

After

oral

administration

the

maximum

plasma

concentrations

were

obtained

within

h

and

the

half

life

for

each

animal

was

almost

the

same

as

that

after

intravenous

administration

Answer: accept


The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for Cmax , AUC0-last , and AUC0-∞ of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions.

The

SLS

formulation

demonstrated

bioequivalence

to

the

reference

SLS

formulation

for

Cmax

AUC

last

and

AUC

of

alectinib

M

and

alectinib

plus

M

under

both

fasted

and

fed

conditions

Answer: accept


Over the dose range 2–120 mg, the slopes (β) for Cmax and AUC0−∞ vs dose plots (1.6 [95% confidence interval (CI) 1.5–1.7] and 2.8 [95% CI 2.6–2.9], respectively) were well above unity.

Over

the

dose

range

mg

the

slopes

β

for

Cmax

and

AUC

vs

dose

plots

confidence

interval

CI

and

CI

respectively

were

well

above

unity

Answer: accept


Thirteen of 14 subjects with AUC(24,36 h)> or =700 nmol l(-1) h responded to pharmacotherapy.

Thirteen

of

subjects

with

AUC

h

or

nmol

l

h

responded

to

pharmacotherapy

Answer: accept


Actual areas under the concentration-time curve (AUC) (mg/ml min) were 5.4, 5.7, 6.2, and 9.0 for the four patients with a target AUC (mg/ml min) of 5; 5.7, 6.2, and 7.1 for the three patients with a target AUC (mg/ml min) of 4; and 5.1 and 8.7 for the two hemodialysis patients with a target AUC (mg/ml min) of 5.

Actual

areas

under

the

concentration

time

curve

AUC

mg

ml

min

were

and

for

the

four

patients

with

a

target

AUC

mg

ml

min

of

and

for

the

three

patients

with

a

target

AUC

mg

ml

min

of

and

and

for

the

two

hemodialysis

patients

with

a

target

AUC

mg

ml

min

of

Answer: accept


Macrolides
Macrolides as Perpetrators
Antiretroviral drugs

During co-administration the CLR AUC increased by 57% and the Cmax by 26%.

During

co

administration

the

CLR

AUC

increased

by

and

the

Cmax

by

Answer: accept


The 90% CI for dronabinol Cmax fell outside the bioequivalence range of 80%–125%.

The

CI

for

dronabinol

Cmax

fell

outside

the

bioequivalence

range

of

Answer: accept


PK and relative bioavailability
Sex effects

The female/male exposure ratios for the maximum (Cmax) and total (AUC0–t) exposure outcomes of all formulations are given in Tables 9 (Cmax data) and 10 (AUC data), respectively.

The

female

male

exposure

ratios

for

the

maximum

Cmax

and

total

AUC

t

exposure

outcomes

of

all

formulations

are

given

in

Tables

Cmax

data

and

AUC

data

respectively

Answer: accept


The apparent clearance was calculated to be 0.8 +- 0.4 ml x min-1 x kg-1.

The

apparent

clearance

was

calculated

to

be

ml

x

min

x

kg

Answer: accept


Peak concentration of morphine 79 +- 19 ng/ml was reached within 10 min after administration.

Peak

concentration

of

morphine

ng

ml

was

reached

within

min

after

administration

Answer: accept


The recombinant hirudin pharmacokinetic in plasma

The distribution half-life (t1/2α) was 6.42±2.60 minutes.

The

distribution

half

life

t

α

was

minutes

Answer: accept


The volume of distribution at steady-state was large (2.13 +- 0.17 l/kg), suggesting extensive tissue distribution, the clearance value was 0.60 +- 0.03 l/h.

The

volume

of

distribution

at

steady

state

was

large

l

kg

suggesting

extensive

tissue

distribution

the

clearance

value

was

l

h

Answer: accept


The retention time of tramadol, O-desmethyltramadol, and the internal standard were 7.2, 6.8, and 6.6 minutes, respectively.

The

retention

time

of

tramadol

O

desmethyltramadol

and

the

internal

standard

were

and

minutes

respectively

Answer: accept


Binding kinetics was determined by a mixture of two receptor subtypes, a low-affinity/high-capacity binding site (K(D,1) = 20.9 nmol, 89% of total receptors) and a high-affinity/low-capacity binding site (K(D,2) = 1.5 nmol, 11%).

Binding

kinetics

was

determined

by

a

mixture

of

two

receptor

subtypes

a

low

affinity

high

capacity

binding

site

K

D

nmol

of

total

receptors

and

a

high

affinity

low

capacity

binding

site

K

D

nmol

Answer: accept


Median time to progression was 2.8 months (95% confidence interval, 1.05–5.52) for group I and 3.2 months (95% confidence interval, 0.95–6.70) for group II.

Median

time

to

progression

was

months

confidence

interval

for

group

I

and

months

confidence

interval

for

group

II

Answer: accept


In the PK assessment of palbociclib 100 and 125 mg (part 1), higher than dose‐proportional exposure was observed at 125 mg (Table 4, Fig. 3), whereas median tmax (4–5 h) and t½ (23–26 h) values remained relatively constant (Table 4).

In

the

PK

assessment

of

palbociclib

and

mg

part

higher

than

dose

proportional

exposure

was

observed

at

mg

Table

Fig

whereas

median

tmax

h

and

t

½

h

values

remained

relatively

constant

Table

Answer: accept


Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25.

Comparability

was

declared

if

the

confidence

interval

for

the

geometric

mean

ratio

of

laropiprant

digoxin

to

digoxin

alone

of

the

area

under

the

plasma

concentration

time

curve

from

time

to

infinity

AUC

infinity

for

immunoreactive

digoxin

fell

within

to

Answer: accept


Ten pharmacokinetic profiles obtained from 8 patients showed a maximum plasma diflunisal concentration of 62.0 +- 26.5 mg/L after 2.76 +- 1.87 hours, and an area under the plasma concentration-time curve (AUC) of 678.3 +- 362.3 mg/L.h.

Ten

pharmacokinetic

profiles

obtained

from

patients

showed

a

maximum

plasma

diflunisal

concentration

of

mg

L

after

hours

and

an

area

under

the

plasma

concentration

time

curve

AUC

of

mg

L

h

Answer: accept


In contrast, 3 patients with trough levels < 4 ng/ml had ongoing rejection.

In

contrast

patients

with

trough

levels

ng

ml

had

ongoing

rejection

Answer: accept


3.4. Pharmacokinetics and Statistical Analysis

The mean Cmax  (mean ± SD ng/mL) of test and reference formulation were 10.212 ± 2.23 and 11.422 ± 2.23, respectively, under fasting conditions.

The

mean

Cmax

mean

SD

ng

mL

of

test

and

reference

formulation

were

and

respectively

under

fasting

conditions

Answer: accept


Relative to ROP, whose half-life was approximately 0.7 hours, the two conjugates prepared, following intravenous administration, showed markedly prolonged retention in systemic circulation with half-lives in blood of 78.4 and 88.3 hours, respectively.

Relative

to

ROP

whose

half

life

was

approximately

hours

the

two

conjugates

prepared

following

intravenous

administration

showed

markedly

prolonged

retention

in

systemic

circulation

with

half

lives

in

blood

of

and

hours

respectively

Answer: accept


The HDV half‐life in blood was 1.87 days, and the average steady‐state LNF efficacy in blocking HDV production was ɛ = 87.7% for group 1 and ɛ = 95.2% for group 2.

The

HDV

half

life

in

blood

was

days

and

the

average

steady

state

LNF

efficacy

in

blocking

HDV

production

was

ɛ

for

group

and

ɛ

for

group

Answer: accept


Translational Pharmacokinetic (PK) Properties of Mipomersen

In patients receiving maximum lipid-lowering therapy, mipomersen plasma t½ of approximately 30 days was reported across all dose groups, with no significant change seen with extension of dosing from 5 to 13 weeks [34].

In

patients

receiving

maximum

lipid

lowering

therapy

mipomersen

plasma

t

½

of

approximately

days

was

reported

across

all

dose

groups

with

no

significant

change

seen

with

extension

of

dosing

from

to

weeks

Answer: accept


The % AUC of metabolite converted to parent upon its administration % A U C K - 09 K - 9 T was found to be 27.28 ± 2.67.

The

AUC

of

metabolite

converted

to

parent

upon

its

administration

A

U

C

K

K

T

was

found

to

be

Answer: accept


The kinetics of (R)-Casodex were similar in subjects with and without liver disease (Cmax: 750 vs 848 ng ml(-1); tmax: 24 - 30 h; t(1/2): 7.40 vs 7.22 days; AUC: 182 vs 225 microg ml(-1) h).

The

kinetics

of

R

Casodex

were

similar

in

subjects

with

and

without

liver

disease

Cmax

vs

ng

ml

tmax

h

t

vs

days

AUC

vs

microg

ml

h

Answer: accept


The volume of distribution of fenofibric acid (Vc/F) was 12.9 L, and the elimination rate constant of fenofibric acid (kel) was 0.27 h− 1.

The

volume

of

distribution

of

fenofibric

acid

Vc

F

was

L

and

the

elimination

rate

constant

of

fenofibric

acid

kel

was

h

Answer: accept


The mean +- SD for the effective half-life after IV administration was 1.25 +- 0.30 hours.

The

mean

SD

for

the

effective

half

life

after

IV

administration

was

hours

Answer: accept


Moreover, the oral bioavailability of Fpx could be dramatically increased up to 9% by including the nanoparticles into gastroresistant capsules.

Moreover

the

oral

bioavailability

of

Fpx

could

be

dramatically

increased

up

to

by

including

the

nanoparticles

into

gastroresistant

capsules

Answer: accept


The population area under the curve from 0 to 24 h (AUC0-24) was calculated as 158.5 mg · h/liter (±79.5 mg · h/liter; n = 13).

The

population

area

under

the

curve

from

to

h

AUC

was

calculated

as

mg

h

liter

mg

h

liter

n

Answer: accept


The estimated parameters [median (range)] were clearance half-life of 23.67 (14.79-59.93) min, synthesis onset time of 2206 (1940-0029), synthesis offset time of 0621 (0246-0817), and maximum N-acetyltransferase activity of 7.17(2.34-17.93) pmol x l(-1) x min(-1).

The

estimated

parameters

median

range

were

clearance

half

life

of

min

synthesis

onset

time

of

synthesis

offset

time

of

and

maximum

N

acetyltransferase

activity

of

pmol

x

l

x

min

Answer: accept


Non-compartmental pharmacokinetic analysis showed that the values for t(12)beta of 75.5 +- 16.9 h, the area under the curve (AUC(0-infinity)) of 1.33 +- 0.156 microg h ml(-1) and the MRT(0-infinity) of 32.8 +- 4.45 h obtained in cattle infected with the drug-resistant trypanosome population were significantly lower than the values of 424 +- 146 h for t(12)beta, 1.67 +- 0.233 microg h ml(-1) for AUC(0-infinity) and 297 +- 159 h for MRT(0-infinity) obtained in cattle infected with the drug-sensitive population.

Non

compartmental

pharmacokinetic

analysis

showed

that

the

values

for

t

beta

of

h

the

area

under

the

curve

AUC

infinity

of

microg

h

ml

and

the

MRT

infinity

of

h

obtained

in

cattle

infected

with

the

drug

resistant

trypanosome

population

were

significantly

lower

than

the

values

of

h

for

t

beta

microg

h

ml

for

AUC

infinity

and

h

for

MRT

infinity

obtained

in

cattle

infected

with

the

drug

sensitive

population

Answer: accept


Results
Pharmacokinetics of Mirabegron
Single Dose

In Study 1 Part I, Ae% was dose-dependent with mean values ranging from 7.20 % after 50 mg to 14.6 % after 300 mg.

In

Study

Part

I

Ae

was

dose

dependent

with

mean

values

ranging

from

after

mg

to

after

mg

Answer: accept


After IA bolus, IFN is distributed from the blood with a t1/2 below, 2 hours, with dose-dependent serum peak concentrations (c = 47 IU for 3 MU and 145 IU for 5 MU).

After

IA

bolus

IFN

is

distributed

from

the

blood

with

a

t

below

hours

with

dose

dependent

serum

peak

concentrations

c

IU

for

MU

and

IU

for

MU

Answer: accept


TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were higher in SP than in BP (median AUC0-24, 7.01 versus 2.97 mg · liter-1 · h, respectively).

TFV

exposures

area

under

the

concentration

time

curve

from

to

h

AUC

were

higher

in

SP

than

in

BP

median

AUC

versus

mg

liter

h

respectively

Answer: accept


The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively.

The

median

TC

area

under

the

curve

from

to

h

after

the

last

drug

intake

were

mg

h

liter

IQR

to

mg

h

liter

mg

h

liter

IQR

to

mg

h

liter

and

mg

h

liter

IQR

to

mg

h

liter

at

weeks

and

respectively

Answer: accept


In vitro plasma protein binding was described by a Langmuir model with a maximal binding capacity (Bmax = 767 microM) and an equilibrium dissociation constant (KD = 1.02 microM).

In

vitro

plasma

protein

binding

was

described

by

a

Langmuir

model

with

a

maximal

binding

capacity

Bmax

microM

and

an

equilibrium

dissociation

constant

KD

microM

Answer: accept


Given the peak and trough levels of colistin relative to the minimum inhibitory concentration for the organism (0.5 μg/ml), it would seem that the dosage of 2.5 mg/kg administered every 24 hours for this patient on dialysis was appropriate.

Given

the

peak

and

trough

levels

of

colistin

relative

to

the

minimum

inhibitory

concentration

for

the

organism

μ

g

ml

it

would

seem

that

the

dosage

of

mg

kg

administered

every

hours

for

this

patient

on

dialysis

was

appropriate

Answer: accept


Moreover, unchanged Pd-Ia recovered from the gastrointestinal tract at 24 hrs (GI24 h) was below detection limit for both groups; the total amount of unchanged Pd-Ia in 8 hrs bile (expressed in terms of percentage of i.v. dose) were 0.092% and 0.126% for control and LC rats, suggesting that the contribution of gastrointestinal and biliary excretion to CLNR of Pd-Ia was also negligible Hence, the CLNR could represent hepatic intrinsic clearance (CLint) of Pd-Ia which was metabolized almost completely after i.v. administration.

Moreover

unchanged

Pd

Ia

recovered

from

the

gastrointestinal

tract

at

hrs

GI

h

was

below

detection

limit

for

both

groups

the

total

amount

of

unchanged

Pd

Ia

in

hrs

bile

expressed

in

terms

of

percentage

of

i

v

dose

were

and

for

control

and

LC

rats

suggesting

that

the

contribution

of

gastrointestinal

and

biliary

excretion

to

CLNR

of

Pd

Ia

was

also

negligible

Hence

the

CLNR

could

represent

hepatic

intrinsic

clearance

CLint

of

Pd

Ia

which

was

metabolized

almost

completely

after

i

v

administration

Answer: accept


Maximum serum concentration of robenacoxib (Cmax) was 2.2µg/ml [range: 1.2–4.6] (median [range: minimum-maximum]) and time of Cmax (Tmax) was 90 min [range: 60–120] in the conscious dogs.

Maximum

serum

concentration

of

robenacoxib

Cmax

was

µ

g

ml

range

median

range

minimum

maximum

and

time

of

Cmax

Tmax

was

min

range

in

the

conscious

dogs

Answer: accept


The mean initial trough level was as low as 8.80 mcg/ml with a difference of 5.95 mcg/ml compared with the lower limit of the vancomycin target range.

The

mean

initial

trough

level

was

as

low

as

mcg

ml

with

a

difference

of

mcg

ml

compared

with

the

lower

limit

of

the

vancomycin

target

range

Answer: accept


Results and discussion
In vivo pharmacokinetics

Clearly, FLT-loaded CAS nanoparticles exhibited a longer circulation time and a markedly delayed blood clearance with a drug level of 440.35 ng/mL at 48 hours after administration.

Clearly

FLT

loaded

CAS

nanoparticles

exhibited

a

longer

circulation

time

and

a

markedly

delayed

blood

clearance

with

a

drug

level

of

ng

mL

at

hours

after

administration

Answer: accept


Assessing temporal in vivo whole body tissue distribution of a variety of different Fluorescent-labeled agents

Most notably, the small molecule integrin imaging agent cleared rapidly from the blood and achieved ~30% of the injected dose in the tissue at 1 h. In the absence of high plasma levels to drive tissue accumulation, this agent started clearing from the tissue immediately thereafter with a tissue half-life of approximately 20 h. The vascular and nanoparticle agents, despite sharing very similar plasma pharmacokinetics, differed in their tissue distribution kinetics, with the vascular agent showing peak tissue signal (~60%ID) at 5 h and a tissue half-life of ~40 h and the nanoparticles showing substantially lower peak tissue accumulation (~35%ID) but with a very long residence time (tissue t1/2>100 h).

Most

notably

the

small

molecule

integrin

imaging

agent

cleared

rapidly

from

the

blood

and

achieved

of

the

injected

dose

in

the

tissue

at

h

In

the

absence

of

high

plasma

levels

to

drive

tissue

accumulation

this

agent

started

clearing

from

the

tissue

immediately

thereafter

with

a

tissue

half

life

of

approximately

h

The

vascular

and

nanoparticle

agents

despite

sharing

very

similar

plasma

pharmacokinetics

differed

in

their

tissue

distribution

kinetics

with

the

vascular

agent

showing

peak

tissue

signal

ID

at

h

and

a

tissue

half

life

of

h

and

the

nanoparticles

showing

substantially

lower

peak

tissue

accumulation

ID

but

with

a

very

long

residence

time

tissue

t

h

Answer: accept


The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5 - 3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value.

The

mutant

selection

window

MSW

of

enrofloxacin

on

isolate

AH

was

determined

to

be

μ

g

mL

based

on

the

mutant

prevention

concentration

MPC

and

minimum

inhibitory

concentration

MIC

value

Answer: accept


Geometric least-squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette inhalator use.

Geometric

least

squares

means

for

maximum

plasma

nicotine

concentration

Cmax

generated

by

the

mixed

effect

model

for

exposure

comparison

were

and

ng

mL

for

the

and

µ

g

puff

P

L

variants

respectively

compared

to

ng

mL

after

Nicorette

inhalator

use

Answer: accept


The mean peak concentration was 30.2 +- 5.0 ng X ml-1, the mean half-life (t1/2) of the elimination phase was 3.4 +- 1.1 h, and the total body clearance was 628 +- 13 ml X min-1.

The

mean

peak

concentration

was

ng

X

ml

the

mean

half

life

t

of

the

elimination

phase

was

h

and

the

total

body

clearance

was

ml

X

min

Answer: accept