Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study.

Answer: accept

Plasma

concentrations

of

YH

reached

peak

levels

to

hours

after

single

dose

administration

and

then

declined

monoexponentially

with

a

terminal

half

life

t

of

to

hours

in

dosage

groups

up

to

mg

in

the

single

dose

study


The bioavailability of IGSC 20 % following 1.45 dose conversion and individual adjustment relative to IGIV 10 % was 1.09 (90 %CI 1.04 to 1.13, n = 49) as determined from the ratio of the geometric means of the AUC while on IGSC 20 % treatment once per week, compared to IGIV 10 % infusions (standardized to one week).

Answer: accept

The

bioavailability

of

IGSC

following

dose

conversion

and

individual

adjustment

relative

to

IGIV

was

CI

to

n

as

determined

from

the

ratio

of

the

geometric

means

of

the

AUC

while

on

IGSC

treatment

once

per

week

compared

to

IGIV

infusions

standardized

to

one

week


Geometric mean Cmax values were slightly reduced by food, 2.5 versus 2.8 mg/L, respectively (90% CI of fed versus fasted based on geometric least-square means was 0.78, 0.98).

Answer: accept

Geometric

mean

Cmax

values

were

slightly

reduced

by

food

versus

mg

L

respectively

CI

of

fed

versus

fasted

based

on

geometric

least

square

means

was


The correlation was similar for metabolic ratios of DM:3-MM with intravenous CsA clearance (r2 = 0.5, p<0.0001).

Answer: accept

The

correlation

was

similar

for

metabolic

ratios

of

DM

MM

with

intravenous

CsA

clearance

r

p


Samples from the arterial and venous blood catheters and from the ultradiafiltrate were collected over the next 12 hrs to calculate pharmacokinetic parameters and clearance of hemodiafiltration.

Answer: accept

Samples

from

the

arterial

and

venous

blood

catheters

and

from

the

ultradiafiltrate

were

collected

over

the

next

hrs

to

calculate

pharmacokinetic

parameters

and

clearance

of

hemodiafiltration


Pharmacokinetic equivalence was shown if the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the C0-max, AUC0-last, and AUC0-∞ were within the predefined bioequivalence margin of 80-125.00%.

Answer: accept

Pharmacokinetic

equivalence

was

shown

if

the

confidence

intervals

CIs

of

the

geometric

mean

ratios

GMRs

of

the

C

max

AUC

last

and

AUC

were

within

the

predefined

bioequivalence

margin

of


Determinations of values of Cmax, t max, and AUCC0-24 h. determined using the trapezoidal method, were obtained for a Markov simulation that would allow for determining the likelihood of achieving a AUC0-24 h/MIC ratio above 70 for infections caused by susceptible B. fragilis.

Answer: accept

Determinations

of

values

of

Cmax

t

max

and

AUCC

h

determined

using

the

trapezoidal

method

were

obtained

for

a

Markov

simulation

that

would

allow

for

determining

the

likelihood

of

achieving

a

AUC

h

MIC

ratio

above

for

infections

caused

by

susceptible

B

fragilis


Results
Single-Dose Pharmacokinetic Study

Moreover, the mean slopes of the plots for ln(Cmax) or ln(AUC) versus ln(dose) were all close to 1, and the 90% CIs of the slopes were completely contained within the predefined range (0.500, 1.500) for dose proportionality.

Answer: accept

Moreover

the

mean

slopes

of

the

plots

for

ln

Cmax

or

ln

AUC

versus

ln

dose

were

all

close

to

and

the

CIs

of

the

slopes

were

completely

contained

within

the

predefined

range

for

dose

proportionality


The objective of this study is to evaluate pharmacokinetic parameters, bioavailability of a potent HIV protease inhibitor, nelfinavir mesylate (NFV), following a single oral administration of 2 tablet formulations.

Answer: accept

The

objective

of

this

study

is

to

evaluate

pharmacokinetic

parameters

bioavailability

of

a

potent

HIV

protease

inhibitor

nelfinavir

mesylate

NFV

following

a

single

oral

administration

of

tablet

formulations


Because telithromycin is a low hepatic extraction ratio drug, the slower CL(NR) could have been due to the decreased protein expression of the hepatic CYP3A subfamily compared with that in control rats, and was supported by the significantly slower in vitro CL(int) in hepatic microsomes (13.1% decrease).

Answer: accept

Because

telithromycin

is

a

low

hepatic

extraction

ratio

drug

the

slower

CL

NR

could

have

been

due

to

the

decreased

protein

expression

of

the

hepatic

CYP

A

subfamily

compared

with

that

in

control

rats

and

was

supported

by

the

significantly

slower

in

vitro

CL

int

in

hepatic

microsomes

decrease


The plasma clearance increased (7.18 ml min-1 kg-1) compared to the corresponding single dose (4.17 ml min-1 kg-1).

Answer: accept

The

plasma

clearance

increased

ml

min

kg

compared

to

the

corresponding

single

dose

ml

min

kg


A half dose of FDC-IV provided a mean Cmax of 12,880 ng/mL. The concentration of paracetamol from the FDC-oral tablets peaked at 0.73 h, with a mean Cmax of 14,907 ng/mL.

Answer: accept

A

half

dose

of

FDC

IV

provided

a

mean

Cmax

of

ng

mL

The

concentration

of

paracetamol

from

the

FDC

oral

tablets

peaked

at

h

with

a

mean

Cmax

of

ng

mL


Area under the curve increased 1.5- to 2.1-fold with various combinations of parabens and d-a-tocopheryl polyethylene glycol 1000 succinate.

Answer: accept

Area

under

the

curve

increased

to

fold

with

various

combinations

of

parabens

and

d

a

tocopheryl

polyethylene

glycol

succinate


The predicted accumulation ratio to estimate linearity (i.e., ratio of AUCtau on Day 14 to AUCinf on Day 1) was less than 1 (0.826) suggesting that PF‐04895162 may have nonlinear (time‐dependent) pharmacokinetics.

Answer: accept

The

predicted

accumulation

ratio

to

estimate

linearity

i

e

ratio

of

AUCtau

on

Day

to

AUCinf

on

Day

was

less

than

suggesting

that

PF

may

have

nonlinear

time

dependent

pharmacokinetics


Results
Pharmacokinetics
OC Interaction Study

Ethinyl estradiol AUCss and Cmax,ss increased when OC was co-administered with fostamatinib, with geometric LS mean treatment ratios of 128.2 % (90 % CI 121.1–135.8) and 134.3 % (90 % CI 126.1–143.0), respectively (Table 2; Fig. 2).

Answer: accept

Ethinyl

estradiol

AUCss

and

Cmax

ss

increased

when

OC

was

co

administered

with

fostamatinib

with

geometric

LS

mean

treatment

ratios

of

CI

and

CI

respectively

Table

Fig


After the first IV infusion at the single dose of 600 μg/m2, OM-174 pharmacokinetic profile showed a Tmax longer than the end of the infusion, a Cmax reaching 394 ng/ml and a two phases elimination process (an initial phase of only a few minutes and a second phase lasting about 22 hr).

Answer: accept

After

the

first

IV

infusion

at

the

single

dose

of

μ

g

m

OM

pharmacokinetic

profile

showed

a

Tmax

longer

than

the

end

of

the

infusion

a

Cmax

reaching

ng

ml

and

a

two

phases

elimination

process

an

initial

phase

of

only

a

few

minutes

and

a

second

phase

lasting

about

hr


The extract alone, and in combination with glyburide (half-dose), significantly lowered elevated glucose (by more than 45% from baseline; without producing hypoglycemia), and other lipid and renal parameters.

Answer: accept

The

extract

alone

and

in

combination

with

glyburide

half

dose

significantly

lowered

elevated

glucose

by

more

than

from

baseline

without

producing

hypoglycemia

and

other

lipid

and

renal

parameters


Results
Pharmacokinetics
Statin Interaction Study

When rosuvastatin 20 mg was co-administered with fostamatinib, an increase in AUC [treatment difference 195.6 % (90 % CI 177.6–215.3)] and AUCt [197.1 % (90 % CI 178.8–217.3)] occurred (Table 4; Fig. 4a).

Answer: accept

When

rosuvastatin

mg

was

co

administered

with

fostamatinib

an

increase

in

AUC

treatment

difference

CI

and

AUCt

CI

occurred

Table

Fig

a


The sCT appeared rapidly in plasma with a median time to reach maximum (Tmax) at about 30 minutes post-dose irrespective of dosing time (Table 3).

Answer: accept

The

sCT

appeared

rapidly

in

plasma

with

a

median

time

to

reach

maximum

Tmax

at

about

minutes

post

dose

irrespective

of

dosing

time

Table


Peak plasma levels of CFDN were 0.85 microgram/ml in one patient and 0.56 microgram/ml in the other.

Answer: accept

Peak

plasma

levels

of

CFDN

were

microgram

ml

in

one

patient

and

microgram

ml

in

the

other


Flavonoid aglycones genistein and liquiritigenin but not glucuronides GEN7G and LQG7G directly bind to nuclear estrogen receptors

On the other hand, the IC50s of GEN7G, LQG7G, and LQG4′G were more than 30 µmol/L in both ERα and ERβ binding assays.

Answer: accept

On

the

other

hand

the

IC

s

of

GEN

G

LQG

G

and

LQG

G

were

more

than

µ

mol

L

in

both

ER

α

and

ER

β

binding

assays


With omeprazole 20 mg, AUC increased by 173% and with esomeprazole by 190%–265% for the 20 and 40 mg doses respectively (McColl and Kennerley 2002).

Answer: accept

With

omeprazole

mg

AUC

increased

by

and

with

esomeprazole

by

for

the

and

mg

doses

respectively

McColl

and

Kennerley


Mean serum peak concentrations on the first and last days of treatment, was 8.7 microgram/ml at 45 min after injection, 9.5 microgram/ml after 60 min.

Answer: accept

Mean

serum

peak

concentrations

on

the

first

and

last

days

of

treatment

was

microgram

ml

at

min

after

injection

microgram

ml

after

min


RESULTS
In Vitro ZgI Release from SMEDDS

The in vitro cumulative release of ZgI from D-SMEDDS was found to be 78.96 ± 2.83% within 12 h. Compared with the ZgI, ZgI-SMEDDS had a quicker release rate, which showed that the release of ZgI had been greatly improved by the SMEDDS.

Answer: accept

The

in

vitro

cumulative

release

of

ZgI

from

D

SMEDDS

was

found

to

be

within

h

Compared

with

the

ZgI

ZgI

SMEDDS

had

a

quicker

release

rate

which

showed

that

the

release

of

ZgI

had

been

greatly

improved

by

the

SMEDDS


Nineteen primary immunodeficiency patients were administered one cycle of their existing Intragam P dose (0.2-0.8 g/kg 3-4 weekly), followed by seven cycles of Intragam 10 NF administered at the same dosing schedule as Intragam P. The primary objective was to compare serum immunoglobulin G (IgG) trough levels.

Answer: accept

Nineteen

primary

immunodeficiency

patients

were

administered

one

cycle

of

their

existing

Intragam

P

dose

g

kg

weekly

followed

by

seven

cycles

of

Intragam

NF

administered

at

the

same

dosing

schedule

as

Intragam

P

The

primary

objective

was

to

compare

serum

immunoglobulin

G

IgG

trough

levels


The tissue distribution results showed that the lactone proportion in the liver increased up to the maximum value of 69.69% after aerosol administration, whereas the mean L/C equilibrium index for the liver was 2.07±1.06, and the C(max) and AUC(0-∞) values of the total HCPT were highest in the tissues.

Answer: accept

The

tissue

distribution

results

showed

that

the

lactone

proportion

in

the

liver

increased

up

to

the

maximum

value

of

after

aerosol

administration

whereas

the

mean

L

C

equilibrium

index

for

the

liver

was

and

the

C

max

and

AUC

values

of

the

total

HCPT

were

highest

in

the

tissues


Effects of andrographolide on the pharmacokinetics of warfarin

Some other research has also found that when andrographolide was co-administered with other drugs such as naproxen, nabumetone and glyburide, their bioavailability would be increased (Balap et al. 2016, 2017; Samala and Veeresham 2016).

Answer: accept

Some

other

research

has

also

found

that

when

andrographolide

was

co

administered

with

other

drugs

such

as

naproxen

nabumetone

and

glyburide

their

bioavailability

would

be

increased

Balap

et

al

Samala

and

Veeresham


The tertatolol elimination half-life was 9.0 +- 7.1 hours.

Answer: accept

The

tertatolol

elimination

half

life

was

hours


Afatinib reached peak plasma concentration 1–4 h after administration in the A/C arm and 3–8 h after administration in the A/C/P arm.

Answer: accept

Afatinib

reached

peak

plasma

concentration

h

after

administration

in

the

A

C

arm

and

h

after

administration

in

the

A

C

P

arm


LZDO ester prodrugs 3–5 were synthesized with the aim of obtaining enzymatically labile drugs, prolonging the half-life of the parent drug 1ain vivo.

Answer: accept

LZDO

ester

prodrugs

were

synthesized

with

the

aim

of

obtaining

enzymatically

labile

drugs

prolonging

the

half

life

of

the

parent

drug

ain

vivo


Steady‐state was reached after a 4‐5 half‐life, i.e., 2.6 to 3.2 days.

Answer: accept

Steady

state

was

reached

after

a

half

life

i

e

to

days


Median PFS was 4.6 months (95% CI, 1.9–6.7) among placebo patients (n = 55), 8.1 months (95% CI, 6.4–10.8) among patients with AUCss ≥ 9.6 mg h/mL (n = 26; HR vs. placebo, 0.67 [95% CI, 0.40–1.14]), and 5.7 months (95% CI, 4.6–7.5) among patients with AUCss < 9.6 mg h/mL (n = 79; HR vs. placebo, 0.81 [95% CI, 0.55–1.21]).

Answer: accept

Median

PFS

was

months

CI

among

placebo

patients

n

months

CI

among

patients

with

AUCss

mg

h

mL

n

HR

vs

placebo

CI

and

months

CI

among

patients

with

AUCss

mg

h

mL

n

HR

vs

placebo

CI


When the half-life is 5 or more times the duration of infusion, the error in predicting concentration is 6.8% or less.

Answer: accept

When

the

half

life

is

or

more

times

the

duration

of

infusion

the

error

in

predicting

concentration

is

or

less


Plasma half-lives were 25 and 32 min for (-)3-PPP and (+)3-PPP, respectively.

Answer: accept

Plasma

half

lives

were

and

min

for

PPP

and

PPP

respectively


The mean Cmax levels of N-desmethyl ivabradine were 1.05, 2.03 and 3.16 ng/mL, and the mean AUC0-48 values were 20.61, 39.44 and 65.72 h·ng/mL, respectively.

Answer: accept

The

mean

Cmax

levels

of

N

desmethyl

ivabradine

were

and

ng

mL

and

the

mean

AUC

values

were

and

h

ng

mL

respectively


Lesinurad renal clearance was reduced by 26% and 82% with mild and moderate renal impairment, respectively, following a lesinurad 200 mg dose and by 74% and 88% with moderate and severe impairment, respectively, following a lesinurad 400 mg dose (Table 3).

Answer: accept

Lesinurad

renal

clearance

was

reduced

by

and

with

mild

and

moderate

renal

impairment

respectively

following

a

lesinurad

mg

dose

and

by

and

with

moderate

and

severe

impairment

respectively

following

a

lesinurad

mg

dose

Table


After iv administration of [14C]PTX to rats, the elimination profile of intact drug from plasma was first order with a half-life (t1/2) of 38 minutes.

Answer: accept

After

iv

administration

of

C

PTX

to

rats

the

elimination

profile

of

intact

drug

from

plasma

was

first

order

with

a

half

life

t

of

minutes


Metabolism of glimepiride and gliclazide by recombinant CYP2C9

The two variants, CYP2C9*2 and CYP2C9*3, caused the CLint of glimepiride to decrease to 55% and 32%, respectively, compared with the wild-type, and the CLint of gliclazide decreased to 71% and 24%, respectively, compared with the wild-type.

Answer: accept

The

two

variants

CYP

C

and

CYP

C

caused

the

CLint

of

glimepiride

to

decrease

to

and

respectively

compared

with

the

wild

type

and

the

CLint

of

gliclazide

decreased

to

and

respectively

compared

with

the

wild

type


Relationships between survival rate at 72 hours and AUC:MIC (minimum inhibitory concentration), peak:MIC, time above the MIC (percentage of dosing interval) for total and free drug concentrations were fit by using a sigmoid maximal effect (Emax) model.

Answer: accept

Relationships

between

survival

rate

at

hours

and

AUC

:MI

C

minimum

inhibitory

concentration

peak

:MI

C

time

above

the

MIC

percentage

of

dosing

interval

for

total

and

free

drug

concentrations

were

fit

by

using

a

sigmoid

maximal

effect

Emax

model


Out of the 28 individual covert/overt ratios, 23% were outside the ±25% range for AUCT, 30% for AUCI, 20% for AUCOverttmax, 30% for Cmax, and 43% for Tmax.

Answer: accept

Out

of

the

individual

covert

overt

ratios

were

outside

the

range

for

AUCT

for

AUCI

for

AUCOverttmax

for

Cmax

and

for

Tmax


On average, five imipenem levels per patient (138 levels in total) were drawn as peak, intermediate, and trough levels.

Answer: accept

On

average

five

imipenem

levels

per

patient

levels

in

total

were

drawn

as

peak

intermediate

and

trough

levels


Results
FST
DMPX Dose-Effect Relationship in FST

DMPX at a dose of 3 mg/kg had no statistically significant influence on mice behavior in the FST (one-way ANOVA: F(3,36) = 13.48, *p < 0.05, **

Answer: accept

DMPX

at

a

dose

of

mg

kg

had

no

statistically

significant

influence

on

mice

behavior

in

the

FST

one

way

ANOVA

F

p


Effect of atabecestat on cognition in Caucasians with early AD was explored to identify unexpected detrimental effects because cognitive changes were not expected over a period of 4 weeks.

Answer: accept

Effect

of

atabecestat

on

cognition

in

Caucasians

with

early

AD

was

explored

to

identify

unexpected

detrimental

effects

because

cognitive

changes

were

not

expected

over

a

period

of

weeks


The higher overall AUC(0-tlast) observed with the BREELIB was mainly related to the high exposure fraction during the first 10 min after the start of inhalation, although it should be noted that exposure was not measured during inhalation with the I-Neb or BREELIB.

Answer: accept

The

higher

overall

AUC

tlast

observed

with

the

BREELIB

was

mainly

related

to

the

high

exposure

fraction

during

the

first

min

after

the

start

of

inhalation

although

it

should

be

noted

that

exposure

was

not

measured

during

inhalation

with

the

I

Neb

or

BREELIB


The largest covariate effect on CL in phase III patients aside from renal function was a 19.7% decrease for APACHE II score > 10.

Answer: accept

The

largest

covariate

effect

on

CL

in

phase

III

patients

aside

from

renal

function

was

a

decrease

for

APACHE

II

score


Those rescued had slightly higher values of V/F compared with those patients not requiring rescue treatment (geometric mean [95% CI]: 3.42 [2.58, 4.53] versus 2.69 [2.49, 2.90] l/kg, p = 0.056).

Answer: accept

Those

rescued

had

slightly

higher

values

of

V

F

compared

with

those

patients

not

requiring

rescue

treatment

geometric

mean

CI

versus

l

kg

p


3.1. The Pharmacokinetic Changes of MDZ Induced by Baicalin in Rats

3.1.3. Pretreatment with Multiple Doses of Baicalin

Meanwhile, multiple doses of baicalin also decreased the CL and V values by 43% (P < 0.001) and 40% (P < 0.01), respectively.

Answer: accept

Meanwhile

multiple

doses

of

baicalin

also

decreased

the

CL

and

V

values

by

P

and

P

respectively


The mean study drug half-lives for ADAb-negative subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) treatment groups were 371, 281 and 366 hours, respectively, compared with 151, 169 and 176 hours in ADAb-positive subjects.

Answer: accept

The

mean

study

drug

half

lives

for

ADAb

negative

subjects

in

the

ABP

adalimumab

USA

and

adalimumab

EU

treatment

groups

were

and

hours

respectively

compared

with

and

hours

in

ADAb

positive

subjects


Upon intravenous administration (2.5 mg/kg), PTS had rapid clearance (Cl = 68.2 ± 9.8 mL/min/kg) and moderate terminal elimination half-life (t(1/2λz) = 93.9 ± 22.3 min).

Answer: accept

Upon

intravenous

administration

mg

kg

PTS

had

rapid

clearance

Cl

mL

min

kg

and

moderate

terminal

elimination

half

life

t

λ

z

min


Peak aqueous-humor concentrations of bromfenac occurred between 150 and 180 min following ophthalmic dosing, with a mean concentration of 78.7 ng/mL. The level of bromfenac decreased in a log-linear fashion with an elimination-rate constant of 1.4.

Answer: accept

Peak

aqueous

humor

concentrations

of

bromfenac

occurred

between

and

min

following

ophthalmic

dosing

with

a

mean

concentration

of

ng

mL

The

level

of

bromfenac

decreased

in

a

log

linear

fashion

with

an

elimination

rate

constant

of


After the 10-unit injection, the average difference between Tmax and tGIRmax was 19 min in healthy subjects and 74 min (P < 0.0007) in subjects with type 2 diabetes.

Answer: accept

After

the

unit

injection

the

average

difference

between

Tmax

and

tGIRmax

was

min

in

healthy

subjects

and

min

P

in

subjects

with

type

diabetes


The results show a good absorption rate of letosteine since about 90% of the dose was found in the urine.

Answer: accept

The

results

show

a

good

absorption

rate

of

letosteine

since

about

of

the

dose

was

found

in

the

urine


Results
Circulation in wild-type animals

This observation contrast with data obtained with PEGylated gold and polystyrene particles of different sizes (the former being coated with PEG1k, PEG2k, and PEG10k23 and the latter by physically adsorbing tocopheryl-PEG1k-succinate24) as well as non-PEGylated gold and chitosan nanoparticles25, 26.

Answer: accept

This

observation

contrast

with

data

obtained

with

PEGylated

gold

and

polystyrene

particles

of

different

sizes

the

former

being

coated

with

PEG

k

PEG

k

and

PEG

k

and

the

latter

by

physically

adsorbing

tocopheryl

PEG

k

succinate

as

well

as

non

PEGylated

gold

and

chitosan

nanoparticles


After a 200-mg oral dose of the drug given in a solution of polyethylene glycol-400, the peak plasma level of the dethioacetylated metabolite canrenone was 633 +- 154 ng/ml (mean +- SD) and was reached at 1.4 +- 0.43 hr.

Answer: accept

After

a

mg

oral

dose

of

the

drug

given

in

a

solution

of

polyethylene

glycol

the

peak

plasma

level

of

the

dethioacetylated

metabolite

canrenone

was

ng

ml

mean

SD

and

was

reached

at

hr


The bioavailability of oral MESNA is in the range of 20-50% and its unpleasant taste severely limits patient compliance.

Answer: accept

The

bioavailability

of

oral

MESNA

is

in

the

range

of

and

its

unpleasant

taste

severely

limits

patient

compliance


Acetaminophen disposition was studied in 11 children suffering from Protein Calorie Malnutrition (PCM) and 5 (age matched) control subjects using the time plasma concentration curve obtained after a single oral administration of 10 mg/kg of the drug.

Answer: accept

Acetaminophen

disposition

was

studied

in

children

suffering

from

Protein

Calorie

Malnutrition

PCM

and

age

matched

control

subjects

using

the

time

plasma

concentration

curve

obtained

after

a

single

oral

administration

of

mg

kg

of

the

drug


The geometric mean ratios (GMRs) (90% CI) for the C(max,ss) and AUC(τ,ss) of telmisartan (with or without S-amlodipine) were 1.039 (0.881-1.226) and 1.003 (0.926-1.087), respectively.

Answer: accept

The

geometric

mean

ratios

GMRs

CI

for

the

C

max

ss

and

AUC

τ

ss

of

telmisartan

with

or

without

S

amlodipine

were

and

respectively


Serum levels were similar from both dosage routes, with peak levels occurring at 1-3 hours after dosing and then declining slowly with an elimination half-life of about 90 hours.

Answer: accept

Serum

levels

were

similar

from

both

dosage

routes

with

peak

levels

occurring

at

hours

after

dosing

and

then

declining

slowly

with

an

elimination

half

life

of

about

hours


3: Clearances ranged between 1.0 and 2.1 ml min(-1) kg(-1) and varied with dose.

Answer: accept

Clearances

ranged

between

and

ml

min

kg

and

varied

with

dose


After oral doses of 3 and 5 ml ethylene glycol (EG)/kg, half-lives of 4.5 and 4.1 h were estimated from cumulative urinary excretion data for non-metabolized EG.

Answer: accept

After

oral

doses

of

and

ml

ethylene

glycol

EG

kg

half

lives

of

and

h

were

estimated

from

cumulative

urinary

excretion

data

for

non

metabolized

EG


However, the clearance was six-fold lower than values given by Hnatowich et al. (130 ml/h) and Ho et al.

Answer: accept

However

the

clearance

was

six

fold

lower

than

values

given

by

Hnatowich

et

al

ml

h

and

Ho

et

al


Results: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 – 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show.

Answer: accept

Results

Comparing

generics

against

each

other

the

differences

in

point

estimates

of

the

geometric

mean

ratios

of

Cmax

of

two

of

the

comparisons

were

either

borderline

within

Renodapt

Cellmune

or

clearly

outside

Mycept

Cellmune

a

region

of

around

the

reference

mean

indicating

that

bioequivalence

between

these

generics

may

be

difficult

to

show


There was no change in the t(max) (120.00 +- 0.43m) but there was a decrease in the k(el) from 0.63 +- 0.20 hr(-1) to 0.46 +- 0.11 hr(-1) (p<0.05).

Answer: accept

There

was

no

change

in

the

t

max

m

but

there

was

a

decrease

in

the

k

el

from

hr

to

hr

p


Mean (+- SD) AUC0-infinity (area under the concentration-time curve) values of 105+-11 ng/mL x hours and 96+-12 ng/mL x hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean (+- SD) bioavailability of 91.3%+-6.7%.

Answer: accept

Mean

SD

AUC

infinity

area

under

the

concentration

time

curve

values

of

ng

mL

x

hours

and

ng

mL

x

hours

were

calculated

for

IV

administration

and

SC

administration

respectively

resulting

in

an

absolute

mean

SD

bioavailability

of


Similarly, AUC0-10 for AR was greater for slow (990.2 +- 582.1 pg/ml/h) than fast (512.4 +- 189.4 pg/ml/h) infusions.

Answer: accept

Similarly

AUC

for

AR

was

greater

for

slow

pg

ml

h

than

fast

pg

ml

h

infusions


Of the alternative intravenous regimens, only the 8‐g intravenous loading dose over 60 minutes followed by 2 g/h for a 10‐hour regimen nearly met the selection criteria, with the same mean eclampsia rate as the standard Zuspan regimen, but the upper range of predicted Cmax for this regimen was 3.55 mmol/L, just above the safety criteria.

Answer: accept

Of

the

alternative

intravenous

regimens

only

the

g

intravenous

loading

dose

over

minutes

followed

by

g

h

for

a

hour

regimen

nearly

met

the

selection

criteria

with

the

same

mean

eclampsia

rate

as

the

standard

Zuspan

regimen

but

the

upper

range

of

predicted

Cmax

for

this

regimen

was

mmol

L

just

above

the

safety

criteria


Intake of SOF/VEL with concomitant omeprazole use (intervention I) decreased the extent of VEL absorption and resulted in a reduction in area under the concentration‐time curve from zero to infinity (AUC0‐inf) and maximum plasma concentration (Cmax) of 27% and 31%, respectively.

Answer: accept

Intake

of

SOF

VEL

with

concomitant

omeprazole

use

intervention

I

decreased

the

extent

of

VEL

absorption

and

resulted

in

a

reduction

in

area

under

the

concentration

time

curve

from

zero

to

infinity

AUC

inf

and

maximum

plasma

concentration

Cmax

of

and

respectively


Antimycobacterial activity and in vitro ADME profiles of wollamide B

The ADME profiling included (1) a study of its physicochemical properties vis-a-vis water solubility, cell membrane permeability, human serum albumin binding affinity and lipophilicity, (2) determination of its plasma stability after 2 hour incubation of the compound with human and mouse plasma, and (3) metabolic stability, which was predicted from the experimentally measured intrinsic clearance of the compound in both mouse and human liver microsomes.

Answer: accept

The

ADME

profiling

included

a

study

of

its

physicochemical

properties

vis

a

vis

water

solubility

cell

membrane

permeability

human

serum

albumin

binding

affinity

and

lipophilicity

determination

of

its

plasma

stability

after

hour

incubation

of

the

compound

with

human

and

mouse

plasma

and

metabolic

stability

which

was

predicted

from

the

experimentally

measured

intrinsic

clearance

of

the

compound

in

both

mouse

and

human

liver

microsomes


For the U87MG tumor model, the Ki mapping area overlapped with approximately 95% of the entire tumor region at 1 h post PDT treatment while k3 mapping (Fig. 4) was shown only in a part of the tumor region near the tumor boundary area (approximately 21.5 ± 4% of the tumor volume, n = 4).

Answer: accept

For

the

U

MG

tumor

model

the

Ki

mapping

area

overlapped

with

approximately

of

the

entire

tumor

region

at

h

post

PDT

treatment

while

k

mapping

Fig

was

shown

only

in

a

part

of

the

tumor

region

near

the

tumor

boundary

area

approximately

of

the

tumor

volume

n


The flow rate was set at 1.1 mL/min.

Answer: accept

The

flow

rate

was

set

at

mL

min


Effects of probenecid on nemonoxacin pharmacokinetics

After a single oral dose of 500 mg of nemonoxacin, the mean Cmax was 5.67 μg/mL, which occurred at 1 hour, and the AUC0−∞ was 46.5 h·μg/mL. The mean Fe and CLr were 58.2% and 6.41 L/h, respectively.

Answer: accept

After

a

single

oral

dose

of

mg

of

nemonoxacin

the

mean

Cmax

was

μ

g

mL

which

occurred

at

hour

and

the

AUC

was

h

μ

g

mL

The

mean

Fe

and

CLr

were

and

L

h

respectively


Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4-1200 times higher than that produced by i.v. administration of a higher dose.

Answer: accept

Pharmacokinetic

analysis

indicated

that

tissue

exposure

to

carmustine

area

under

concentration

time

curve

achieved

by

polymeric

delivery

was

times

higher

than

that

produced

by

i

v

administration

of

a

higher

dose


In subjects who were hospitalized for the first 5 days of treatment, trough DASP and DACP concentrations were also measured each morning of hospitalization (day 1 through day 5).

Answer: accept

In

subjects

who

were

hospitalized

for

the

first

days

of

treatment

trough

DASP

and

DACP

concentrations

were

also

measured

each

morning

of

hospitalization

day

through

day


Dose proportionality in the dose range of 0.3–1.8 mg was indicated by the model-derived AUC24 slope: 1.05 (95 % CI 0.96–1.15).

Answer: accept

Dose

proportionality

in

the

dose

range

of

mg

was

indicated

by

the

model

derived

AUC

slope

CI


3.3. Pycnogenol® Constituents and Metabolites in Serum Samples

For example, catechin was detectable in 29 out of 30 V1 samples, and in 24 samples the concentrations were above 10 ng/mL. Thereby, catechin was primarily present as glucuronide-/sulfate-conjugate.

Answer: accept

For

example

catechin

was

detectable

in

out

of

V

samples

and

in

samples

the

concentrations

were

above

ng

mL

Thereby

catechin

was

primarily

present

as

glucuronide

sulfate

conjugate


A pharmacokinetic study in mice revealed suitable values for half-life (T1/2 = 3.4 h), clearance (CL = 2088 mL/h kg), distribution volume (Vz = 10.3 L/kg) and absolute bioavailability (F = 65%) when PBRM was injected sc at 14.7 mg/kg.

Answer: accept

A

pharmacokinetic

study

in

mice

revealed

suitable

values

for

half

life

T

h

clearance

CL

mL

h

kg

distribution

volume

Vz

L

kg

and

absolute

bioavailability

F

when

PBRM

was

injected

sc

at

mg

kg


When the data for both P. aeruginosa were combined, a correlation coefficient of r = 0.04 for AUC and r = 0.80 for AUIC was found.

Answer: accept

When

the

data

for

both

P

aeruginosa

were

combined

a

correlation

coefficient

of

r

for

AUC

and

r

for

AUIC

was

found


Potency differences of ≤ 50% resulted in differences of ≤ 2% and ≤ 15% in AUC and AUEC, respectively.

Answer: accept

Potency

differences

of

resulted

in

differences

of

and

in

AUC

and

AUEC

respectively


Bioavailability represents the ratio of the unchanged drug administered by the route of interest and after administration direct into the systemic circulation (44).

Answer: accept

Bioavailability

represents

the

ratio

of

the

unchanged

drug

administered

by

the

route

of

interest

and

after

administration

direct

into

the

systemic

circulation


Cmax and AUC0–∞ for skin tissue were 20.1±2.2 μg/mL and 113.9±21.8 μg × h/mL, respectively (Table 1).

Answer: accept

Cmax

and

AUC

for

skin

tissue

were

μ

g

mL

and

μ

g

h

mL

respectively

Table


Based on the full population pharmacokinetic model, values for CL/F and V/F in the reference subject profile were estimated to be 0.0478 l/h and 12.2 l, respectively (Table S3 in the ESM).

Answer: accept

Based

on

the

full

population

pharmacokinetic

model

values

for

CL

F

and

V

F

in

the

reference

subject

profile

were

estimated

to

be

l

h

and

l

respectively

Table

S

in

the

ESM


1. Six potent aldose reductase inhibitors (ARI), three spirohydantoin (I to III) and three spirosuccinimide (IV to VI) compounds, showed similar IC50 activities in vitro for the inhibition of rat lens aldose reductase, but their ED50 values in diabetic rats varied as much as 20-fold in the lens and 50-fold in the sciatic nerve tissue.

Answer: accept

Six

potent

aldose

reductase

inhibitors

ARI

three

spirohydantoin

I

to

III

and

three

spirosuccinimide

IV

to

VI

compounds

showed

similar

IC

activities

in

vitro

for

the

inhibition

of

rat

lens

aldose

reductase

but

their

ED

values

in

diabetic

rats

varied

as

much

as

fold

in

the

lens

and

fold

in

the

sciatic

nerve

tissue


3.2. Hepatic First-Pass Effect of Tofacitinib in Rats

As a result, the CL and CLNR of tofacitinib were 67% and 60% faster, respectively, after intraportal administration.

Answer: accept

As

a

result

the

CL

and

CLNR

of

tofacitinib

were

and

faster

respectively

after

intraportal

administration


Individual F values ranged from 97% to 111% for 8 subjects.

Answer: accept

Individual

F

values

ranged

from

to

for

subjects


Clearance decreased from 3.4 +- 1.0 to 0.6 +- 0.11 liter/min (P less than .01) and half-life increased from 5.0 +- 1.2 to 23.5 +- 6.1 min (P less than .01).

Answer: accept

Clearance

decreased

from

to

liter

min

P

less

than

and

half

life

increased

from

to

min

P

less

than


The effects of caffeine on the pharmacokinetics and bioavailability of aspirin were studied in 12 healthy adult male volunteers.

Answer: accept

The

effects

of

caffeine

on

the

pharmacokinetics

and

bioavailability

of

aspirin

were

studied

in

healthy

adult

male

volunteers


For the second volunteer, the nadir was estimated to occur between 150 and 160 h, with a ferroquine exposure between 16.4 and 25.2 ng/mL. The cohort parasite clearance half-life was 6.5 (CI 6.4–6.7) h.

Answer: accept

For

the

second

volunteer

the

nadir

was

estimated

to

occur

between

and

h

with

a

ferroquine

exposure

between

and

ng

mL

The

cohort

parasite

clearance

half

life

was

CI

h


Results
Population Pharmacokinetic Model

CL, V1, Q and V2 were estimated to be 1.10 L/h, 17.6 L, 0.363 L/h and 3.63 L.

Answer: accept

CL

V

Q

and

V

were

estimated

to

be

L

h

L

L

h

and

L


Design of IL-15 analogs for improving biological activities and developability

The measured in vivo half-life of P22339 in rat was about 13.7 hours (Fig. 6a and Supplementary Table S4).

Answer: accept

The

measured

in

vivo

half

life

of

P

in

rat

was

about

hours

Fig

a

and

Supplementary

Table

S


Effect of Fasting on Oral Bioavailability and Systemic Clearance

The mean pre-intake of caffeine was low since the typical bioavailability was 4.0%, whereas the variability was high (1250%) due to three subjects with observed caffeine plasma concentrations at baseline.

Answer: accept

The

mean

pre

intake

of

caffeine

was

low

since

the

typical

bioavailability

was

whereas

the

variability

was

high

due

to

three

subjects

with

observed

caffeine

plasma

concentrations

at

baseline


Linezolid concentrations and PK parameters

The peak concentration in CSF (8.46 ± 1.99 μg/mL) was reached 3.10 ± 0.32 h after intravenous infusion, and AUC0–24 h was 45.10 ± 8.78 h⋅μg/mL.

Answer: accept

The

peak

concentration

in

CSF

μ

g

mL

was

reached

h

after

intravenous

infusion

and

AUC

h

was

h

μ

g

mL


The serum half-life was not affected by the dose of antibody administered or by serum CEA titers below 500 ng/mL. Despite a mean liver uptake of 18% injected dose (ID) 24 hours after administration, hepatic metastases were easily visualized as areas of increased uptake of radioactivity.

Answer: accept

The

serum

half

life

was

not

affected

by

the

dose

of

antibody

administered

or

by

serum

CEA

titers

below

ng

mL

Despite

a

mean

liver

uptake

of

injected

dose

ID

hours

after

administration

hepatic

metastases

were

easily

visualized

as

areas

of

increased

uptake

of

radioactivity


On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing.

Answer: accept

On

the

mg

dose

across

all

schedules

of

PK

evaluable

patients

achieved

total

drug

trough

concentrations

above

the

target

concentration

ng

mL

within

days

of

dosing


Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent.

Answer: accept

Bioavailability

approximately

with

low

intraindividual

variation

and

time

to

Cmax

were

dose

independent


Hypoalbuminemia correlated with low AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042).

Answer: accept

Hypoalbuminemia

correlated

with

low

AUC

r

P

and

was

associated

with

higher

clearance

r

P

and

somewhat

higher

V

r

P

resulting

in

a

negative

correlation

with

the

elimination

rate

constant

r

P


In addition, there were significant inverse linear relationships between the reduction in OGTT parameters and the PK parameters in the high-dose group when the Cmax and AUC0-12h exceeded 901 to 1086 μg/L and 4919 to 5100 h·μg/L, respectively.

Answer: accept

In

addition

there

were

significant

inverse

linear

relationships

between

the

reduction

in

OGTT

parameters

and

the

PK

parameters

in

the

high

dose

group

when

the

Cmax

and

AUC

h

exceeded

to

μ

g

L

and

to

h

μ

g

L

respectively


As a result of this, the area under curve for the 2 and 20 microg/kg endotoxin groups increased significantly 100.4 vs. 149.4 microg h/mL (P < 0.05) and 99.2 vs. 277.7 microg h/mL (P < 0.05), respectively.

Answer: accept

As

a

result

of

this

the

area

under

curve

for

the

and

microg

kg

endotoxin

groups

increased

significantly

vs

microg

h

mL

P

and

vs

microg

h

mL

P

respectively


The absorption of DDQ is also rapid in healthy humans and the plasma concentration decreases with an apparent half-life of 1 .

Answer: accept

The

absorption

of

DDQ

is

also

rapid

in

healthy

humans

and

the

plasma

concentration

decreases

with

an

apparent

half

life

of


Average maximum concentrations (Cmax) of THCCOOH were 107, 335 and 713 ng/mL, and average times to maximum concentration (Tmax) were 8, 6 and 9 h for the 10, 25 and 50 mg THC doses, respectively.

Answer: accept

Average

maximum

concentrations

Cmax

of

THCCOOH

were

and

ng

mL

and

average

times

to

maximum

concentration

Tmax

were

and

h

for

the

and

mg

THC

doses

respectively


Results
Pharmacodynamic Endpoints
Nasal Effects

Five minutes after insufflation, median Emax ratings for “need to blow your nose at this moment” and “rate any nasal congestion at this moment” were assessed as moderate (median = 2.0) after insufflation of high-volume morphine-ADER-IMT (data not shown).

Answer: accept

Five

minutes

after

insufflation

median

Emax

ratings

for

need

to

blow

your

nose

at

this

moment

and

rate

any

nasal

congestion

at

this

moment

were

assessed

as

moderate

median

after

insufflation

of

high

volume

morphine

ADER

IMT

data

not

shown


Both the Km and Vmax values were significantly smaller in CYP2D6*10 allele carriers than in the noncarriers (24.2±18.3 ng/mL versus 122.5±106.3 ng/mL, P=0.008; 44.2±16.1 mg/day versus 68.3±15.0 mg/day, P=0.022, respectively).

Answer: accept

Both

the

Km

and

Vmax

values

were

significantly

smaller

in

CYP

D

allele

carriers

than

in

the

noncarriers

ng

mL

versus

ng

mL

P

mg

day

versus

mg

day

P

respectively


The primary outcome was the comparison of the proportion of children with predicted lopinavir morning minimum concentrations (Cmin) of more than 1·0 mg/L during super-boosting with the proportion of more than 1·0 mg/L during standard lopinavir-ritonavir treatment without rifampicin.

Answer: accept

The

primary

outcome

was

the

comparison

of

the

proportion

of

children

with

predicted

lopinavir

morning

minimum

concentrations

Cmin

of

more

than

mg

L

during

super

boosting

with

the

proportion

of

more

than

mg

L

during

standard

lopinavir

ritonavir

treatment

without

rifampicin


The mean area under the concentration-time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively.

Answer: accept

The

mean

area

under

the

concentration

time

curve

AUCinf

for

midazolam

in

healthy

volunteers

ï

ve

patients

and

responders

was

coefficient

of

variation

CV

CV

and

CV

ng

h

mL

respectively


The neurounina-1 was rapidly eliminated, with mean CL values of 46.24, 47.57, and 69.15 L/h, Vd of 130.31, 154.15, and 210.79 L and t1/2 of 2.14, 2.54, and 2.04 h after intravenous administration of 0.1, 0.3, and 1 mg/kg, respectively.

Answer: accept

The

neurounina

was

rapidly

eliminated

with

mean

CL

values

of

and

L

h

Vd

of

and

L

and

t

of

and

h

after

intravenous

administration

of

and

mg

kg

respectively


The respective in vivo and in vitro pharmacokinetic parameters (SCh 1 mg.kg(-1) vs SCh 2 mg.kg(-1)) were as follows: Plasma clearance was 4.17 +- 2.37 and 1.85 +- 0.28 l.min(-1), P < 0.05, vs 2.91 +- 2.01 and 1.27 +- 0.43 l.min(-1), P < 0.05.

Answer: accept

The

respective

in

vivo

and

in

vitro

pharmacokinetic

parameters

SCh

mg

kg

vs

SCh

mg

kg

were

as

follows

Plasma

clearance

was

and

l

min

P

vs

and

l

min

P


Migalastat pharmacokinetics were dose-proportional (AUC∞ range: 1129-72 838 ng h/mL, Cmax range: 200.5-13 844 ng/mL, t1/2 3-4 hours).

Answer: accept

Migalastat

pharmacokinetics

were

dose

proportional

AUC

range

ng

h

mL

Cmax

range

ng

mL

t

hours


The Tmax of GPS after oral administration was 0.50 h, and the bioavailability was 39.6%.

Answer: accept

The

Tmax

of

GPS

after

oral

administration

was

h

and

the

bioavailability

was


Correlation between AUC(0-12) and C0 was relatively good (r2=0.74).

Answer: accept

Correlation

between

AUC

and

C

was

relatively

good

r


☑ The lack of relationship between ADC area under the curve (AUC)/time and modified progression‐free survival supports consistent benefits across the brentuximab vedotin exposure range seen in ECHELON‐1.

Answer: accept

The

lack

of

relationship

between

ADC

area

under

the

curve

AUC

time

and

modified

progression

free

survival

supports

consistent

benefits

across

the

brentuximab

vedotin

exposure

range

seen

in

ECHELON


4. Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated.

Answer: accept

Expressed

cytochromes

P

and

hepatocytes

indicated

clearance

was

primarily

CYP

A

mediated


A twofold increase in weight corresponded with a 170 and 238% increase in CL and Vc, respectively.

Answer: accept

A

twofold

increase

in

weight

corresponded

with

a

and

increase

in

CL

and

Vc

respectively


In T5, these trough values were 12, 13, and 16 μg/ml.

Answer: accept

In

T

these

trough

values

were

and

μ

g

ml


The blood clearance was very high (354 +- 131 mL/min) suggesting extrahepatic metabolism and/or nonrenal elimination and a significant volume of distribution (67 +- 76 L).

Answer: accept

The

blood

clearance

was

very

high

mL

min

suggesting

extrahepatic

metabolism

and

or

nonrenal

elimination

and

a

significant

volume

of

distribution

L


Results
Design and results of the Phase I trial

The mean penultimate thalf (when at least 80% of drug was eliminated) was 4 h, mean terminal thalf was 25 h and Vz was 1.1 L/kg with a moderate inter-individual variability.

Answer: accept

The

mean

penultimate

thalf

when

at

least

of

drug

was

eliminated

was

h

mean

terminal

thalf

was

h

and

Vz

was

L

kg

with

a

moderate

inter

individual

variability


Oral Bioavailability Enhancement Studies in Rat

Therefore, in our rat studies, the dynamic range for bioavailability of TFV extends from 35% for the control group to 100% for the IV group.

Answer: accept

Therefore

in

our

rat

studies

the

dynamic

range

for

bioavailability

of

TFV

extends

from

for

the

control

group

to

for

the

IV

group


3. Experimental
3.3. Biological Activity Methods
3.3.1. α-Glucosidase Inhibition Assay

The IC50 values were calculated by the program Prism 5.0 (GraphPad, San Diego, CA, USA).

Answer: accept

The

IC

values

were

calculated

by

the

program

Prism

GraphPad

San

Diego

CA

USA


Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC=7.5 associated with 2-log kill.

Answer: accept

Simulations

demonstrated

that

the

ratio

of

the

area

under

the

concentration

time

curve

for

free

drug

to

the

minimum

inhibitory

concentration

fAUC

MIC

was

the

pharmacokinetic

driver

for

relebactam

with

a

target

fAUC

MIC

associated

with

log

kill


The kinetic profile of the drug in serum after oral administration of a single dose of cefixime was similar, with mean Cmax values of 3.36 and 4.76 micrograms/ml after treatment with the capsule and suspension, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Answer: accept

The

kinetic

profile

of

the

drug

in

serum

after

oral

administration

of

a

single

dose

of

cefixime

was

similar

with

mean

Cmax

values

of

and

micrograms

ml

after

treatment

with

the

capsule

and

suspension

respectively

ABSTRACT

TRUNCATED

AT

WORDS


The geometric mean ratios (90% CI) of the Cmax and AUCinf were 0.908 (0.843-0.978) and 1.049 (0.999-1.101), respectively, both of which were within the regulatory range of 0.80-1.25.

Answer: accept

The

geometric

mean

ratios

CI

of

the

Cmax

and

AUCinf

were

and

respectively

both

of

which

were

within

the

regulatory

range

of


Although predominant clearance of (223)Ra was observed from the soft tissues within the first 24 h, the bone uptake of (223)Ra, which was not significantly different from maximum after only 1 h, was not significantly reduced during the 14 d. Furthermore, little redistribution of (223)Ra daughter products away from bone was found (2% at 6 h and less than 1% at 3 d).

Answer: accept

Although

predominant

clearance

of

Ra

was

observed

from

the

soft

tissues

within

the

first

h

the

bone

uptake

of

Ra

which

was

not

significantly

different

from

maximum

after

only

h

was

not

significantly

reduced

during

the

d

Furthermore

little

redistribution

of

Ra

daughter

products

away

from

bone

was

found

at

h

and

less

than

at

d


The T(1/2) of the elimination phase (T(1/2beta)) was 103, 297 and 170 min for sCR1, sCR1-BA and sCR1-BABA, respectively.

Answer: accept

The

T

of

the

elimination

phase

T

beta

was

and

min

for

sCR

sCR

BA

and

sCR

BABA

respectively


Of the range of storage times, 20 h was selected as it presented the most percent yield of CL-SFNP product of 35.5% ± 7.5%, despite the slightly larger size than at 4 h. CL-SFNP was negatively charged.

Answer: accept

Of

the

range

of

storage

times

h

was

selected

as

it

presented

the

most

percent

yield

of

CL

SFNP

product

of

despite

the

slightly

larger

size

than

at

h

CL

SFNP

was

negatively

charged


This difference in clearance was found to be primarily attributable to a greater metabolic clearance of acetaminophen to acetaminophen sulfate (0.080 +- 0.023 L/hr/kg for subjects with cystic fibrosis and 0.045 +- 0.008 L/hr/kg for control subjects; p less than 0.05) and to a greater metabolic clearance of acetaminophen to acetaminophen glucuronide (0.189 +- 0.051 L/hr/kg for subjects with cystic fibrosis and 0.114 +- 0.017 L/hr/kg for control subjects; p less than 0.05) in persons with cystic fibrosis.

Answer: accept

This

difference

in

clearance

was

found

to

be

primarily

attributable

to

a

greater

metabolic

clearance

of

acetaminophen

to

acetaminophen

sulfate

L

hr

kg

for

subjects

with

cystic

fibrosis

and

L

hr

kg

for

control

subjects

p

less

than

and

to

a

greater

metabolic

clearance

of

acetaminophen

to

acetaminophen

glucuronide

L

hr

kg

for

subjects

with

cystic

fibrosis

and

L

hr

kg

for

control

subjects

p

less

than

in

persons

with

cystic

fibrosis


Results
Pharmacokinetic analysis
Comparison to literature

The elimination half-life of artemether (1.96 h) is longer compared to the elimination half-life of dihydroartemisinin (1.39 h), which suggests formation rate limited elimination of dihydroartemisinin.

Answer: accept

The

elimination

half

life

of

artemether

h

is

longer

compared

to

the

elimination

half

life

of

dihydroartemisinin

h

which

suggests

formation

rate

limited

elimination

of

dihydroartemisinin


UAB-8 had values for t1/2 alpha and t1/2 beta of 0.47 and 17.1 hr, respectively.

Answer: accept

UAB

had

values

for

t

alpha

and

t

beta

of

and

hr

respectively


Hydrodynamic delivery allows long lasting plasma bioavailability of 35 K-Fc

To assess to what extent the long half life of our protein in the plasma was due to continued gene expression we performed quantitative real-time RT-PCR to detect 35 K mRNA in the liver, the primary site of gene expression following hydrodynamic delivery.

Answer: accept

To

assess

to

what

extent

the

long

half

life

of

our

protein

in

the

plasma

was

due

to

continued

gene

expression

we

performed

quantitative

real

time

RT

PCR

to

detect

K

mRNA

in

the

liver

the

primary

site

of

gene

expression

following

hydrodynamic

delivery


For elderly subjects >55 years, Cmax, AUC(0-τ) and Cτ was 10%, 14% and 18% lower compared with subjects ≤55 years.

Answer: accept

For

elderly

subjects

years

Cmax

AUC

τ

and

C

τ

was

and

lower

compared

with

subjects

years


This compares with the respective zolpidem tablet 5 and 10 mg Cmax mean values of 123 (range, 53 to 221) and 219 ng/mL (range, 101 to 446).

Answer: accept

This

compares

with

the

respective

zolpidem

tablet

and

mg

Cmax

mean

values

of

range

to

and

ng

mL

range

to


The effects of administered iron on the rate of blood clearance and the plasma binding of 67Ga have been measured.

Answer: accept

The

effects

of

administered

iron

on

the

rate

of

blood

clearance

and

the

plasma

binding

of

Ga

have

been

measured


3.2. Effects of Genistein on Celecoxib Conversion Mediated by CYP2C9, RLM, and HLM In Vitro

Figure 4 shows IC50 of genistein on celecoxib in 2C9∗1, 2C9∗3, and RLM.

Answer: accept

Figure

shows

IC

of

genistein

on

celecoxib

in

C

C

and

RLM


The Hill equation with a variable slope fitted the relationship between the 24-h AUC/MEC ratio and 14-day survival well (R(2) = 0.87; P < 0.05).

Answer: accept

The

Hill

equation

with

a

variable

slope

fitted

the

relationship

between

the

h

AUC

MEC

ratio

and

day

survival

well

R

P


In addition, bioavailability of the VO(6mpa)2 on ileal administration was enhanced compared with that using other administration sites such as the stomach and jejunum, and resulted in an enhancement about 1.8 fold that compared with oral administration.

Answer: accept

In

addition

bioavailability

of

the

VO

mpa

on

ileal

administration

was

enhanced

compared

with

that

using

other

administration

sites

such

as

the

stomach

and

jejunum

and

resulted

in

an

enhancement

about

fold

that

compared

with

oral

administration


2.3. Stereo-Selective Pharmacokinetics of IQ Epimers

The absolute oral bioavailability was 38% for IQ and 13% for epi-IQ.

Answer: accept

The

absolute

oral

bioavailability

was

for

IQ

and

for

epi

IQ


After 2 days of dose adjustments, Bu Css was reduced from median 1000 to 890 mcg/L (P < 0.001, Table 3) and 71% of the patients obtained drug exposure of 900 mcg/L ± 10%.

Answer: accept

After

days

of

dose

adjustments

Bu

Css

was

reduced

from

median

to

mcg

L

P

Table

and

of

the

patients

obtained

drug

exposure

of

mcg

L


In spite of its higher bioavailability (50–75%) the most important reason of its cessation are bone marrow suppression, anemia, neutropenia and various organs related toxicities.

Answer: accept

In

spite

of

its

higher

bioavailability

the

most

important

reason

of

its

cessation

are

bone

marrow

suppression

anemia

neutropenia

and

various

organs

related

toxicities


The carboplatin dose was chosen to produce a target area under the concentration/time curve (AUC) of 5.0 microg-min/ml according to a published formula.

Answer: accept

The

carboplatin

dose

was

chosen

to

produce

a

target

area

under

the

concentration

time

curve

AUC

of

microg

min

ml

according

to

a

published

formula


The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg.

Answer: accept

The

resulting

integrated

PBPK

predicts

that

bolus

oral

or

dietary

exposures

to

ethylene

glycol

would

result

in

typically

fold

higher

peak

oxalate

levels

and

fold

higher

AUC

's

for

calcium

oxalate

in

kidneys

of

humans

as

compared

with

comparably

exposed

male

Wistar

rats

over

a

dose

range

of

mg

kg


The model fit yielded an intercompartmental clearance of 82 +- 7 ml/min and a volume of distribution of 10.2 +- 0.6 l, corresponding to 14.3 +- 0.7% of body weight.

Answer: accept

The

model

fit

yielded

an

intercompartmental

clearance

of

ml

min

and

a

volume

of

distribution

of

l

corresponding

to

of

body

weight


Mass Balance and Biotransformation Study

The mean t½ of N-desmethyl enzalutamide and the carboxylic acid metabolite in plasma were 186 and 223 h (7.8 and 9.3 days), respectively.

Answer: accept

The

mean

t

½

of

N

desmethyl

enzalutamide

and

the

carboxylic

acid

metabolite

in

plasma

were

and

h

and

days

respectively


The analysis of plasma samples showed a significant reduction of plasma estradiol concentrations (50%) which coincided with the maximum concentration peak of the inhibitor, whereas no significant changes in androgen levels were observed.

Answer: accept

The

analysis

of

plasma

samples

showed

a

significant

reduction

of

plasma

estradiol

concentrations

which

coincided

with

the

maximum

concentration

peak

of

the

inhibitor

whereas

no

significant

changes

in

androgen

levels

were

observed


Plasma Pharmacokinetics of Vilaprisan and [14C]-Radioactivity After Oral Administration (Mass Balance Study)

The geometric mean blood/plasma ratio of [14C]-radioactivity varied between 0.71 and 0.76 during the first 24 h post-dose, indicating that the radioactivity was mainly distributed in plasma at that time.

Answer: accept

The

geometric

mean

blood

plasma

ratio

of

C

radioactivity

varied

between

and

during

the

first

h

post

dose

indicating

that

the

radioactivity

was

mainly

distributed

in

plasma

at

that

time


The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively.

Answer: accept

The

estimates

of

inter

individual

variability

in

maximal

rate

of

saturable

metabolism

and

residual

variability

were

and

respectively


A positive linear correlation was found between the serum trough levels and CSF levels (r = 0.970, P < 0.001).

Answer: accept

A

positive

linear

correlation

was

found

between

the

serum

trough

levels

and

CSF

levels

r

P


Serum half-lives were the same for the two antibiotics, with values of 60.3 (+-3.3) min for ampicillin and 61.3 (+-5.6) min for amoxicillin.

Answer: accept

Serum

half

lives

were

the

same

for

the

two

antibiotics

with

values

of

min

for

ampicillin

and

min

for

amoxicillin


Simulations demonstrated that the elimination rates of the individual atropisomers are bounded between 0 and 0.046 h(-1) and between 0.046 and 0.092 h(-1), respectively.

Answer: accept

Simulations

demonstrated

that

the

elimination

rates

of

the

individual

atropisomers

are

bounded

between

and

h

and

between

and

h

respectively


Calibration curves were MDA, 1 to 100 ng/mL; HMA, 2.5 to 100 ng/mL; and MDMA and HMMA, 2.5 to 400 ng/mL. Mean +- standard deviation maximum plasma concentrations (C(max)) of 162.9 +- 39.8 and 171.9 +- 79.5 ng/mL were observed for MDMA and HMMA, respectively, after low-dose MDMA.

Answer: accept

Calibration

curves

were

MDA

to

ng

mL

HMA

to

ng

mL

and

MDMA

and

HMMA

to

ng

mL

Mean

standard

deviation

maximum

plasma

concentrations

C

max

of

and

ng

mL

were

observed

for

MDMA

and

HMMA

respectively

after

low

dose

MDMA


This study aimed at assessing: (1) the isoflavone content of sixty-nine European soya-derivative products sold on the French market; (2) the bioavailability of isoflavones comparing supplement with food.

Answer: accept

This

study

aimed

at

assessing

the

isoflavone

content

of

sixty

nine

European

soya

derivative

products

sold

on

the

French

market

the

bioavailability

of

isoflavones

comparing

supplement

with

food


The mean BSA affected by AD decreased from baseline by 37.4% at Day 35 and 74.8% at Day 50.

Answer: accept

The

mean

BSA

affected

by

AD

decreased

from

baseline

by

at

Day

and

at

Day


Excretion levels after the consumption of raw vegetables and condiments were higher (bioavailability, 8.2-113%) as compared to cooked vegetables (bioavailability, 1.8-43%), but the excretion rate was similar (t1/2=2.1-3.9 h).

Answer: accept

Excretion

levels

after

the

consumption

of

raw

vegetables

and

condiments

were

higher

bioavailability

as

compared

to

cooked

vegetables

bioavailability

but

the

excretion

rate

was

similar

t

h


The distribution half-life (t1/2 alpha) was significantly (p less than 0.05) decreased in dogs after infection (0.14 hr) compared to 0.2 hr observed in the same animals before infection.

Answer: accept

The

distribution

half

life

t

alpha

was

significantly

p

less

than

decreased

in

dogs

after

infection

hr

compared

to

hr

observed

in

the

same

animals

before

infection


Also, relative bioavailability of the sc formulation was compared to im in 6 of the patients.

Answer: accept

Also

relative

bioavailability

of

the

sc

formulation

was

compared

to

im

in

of

the

patients


After coadministration of quinidine, morphine and morphine metabolites were not detectable in the plasma of either phenotype and mean (+- S.E.M.) O-demethylation clearance was reduced in the EMs from 162.7 +- 36.6 to 17.0 +- 5.0 ml/min (P < .003), but not in the PMs.

Answer: accept

After

coadministration

of

quinidine

morphine

and

morphine

metabolites

were

not

detectable

in

the

plasma

of

either

phenotype

and

mean

S

E

M

O

demethylation

clearance

was

reduced

in

the

EMs

from

to

ml

min

P

but

not

in

the

PMs


During the study period, the t1/2 was 20.86–22.52 hours, and the oral clearance (CL/F) was 1.2–1.4 L/hour.

Answer: accept

During

the

study

period

the

t

was

hours

and

the

oral

clearance

CL

F

was

L

hour


Relative contributions of metabolic routes in the liver

Although 9% of the drug has been reported as eliminated unchanged in the feces,5 due to the difficulty in separating out the amount of drug that remains unabsorbed from that which undergoes deconjugation after absorption and subsequent secretion/metabolism into the gastrointestinal tract, the exact amount of the parent drug eliminated via biliary clearance could not be estimated and is thus lumped with the non‐CYP clearance.

Answer: accept

Although

of

the

drug

has

been

reported

as

eliminated

unchanged

in

the

feces

due

to

the

difficulty

in

separating

out

the

amount

of

drug

that

remains

unabsorbed

from

that

which

undergoes

deconjugation

after

absorption

and

subsequent

secretion

metabolism

into

the

gastrointestinal

tract

the

exact

amount

of

the

parent

drug

eliminated

via

biliary

clearance

could

not

be

estimated

and

is

thus

lumped

with

the

non

CYP

clearance


Peak concentrations for i.v. ganciclovir averaged 8.39+-1.87 microg/mL with minimum concentrations of 0.48+-0.35 microg/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max=2.12+-0.58 microg/mL, min=1.15+-0.34 microg/mL).

Answer: accept

Peak

concentrations

for

i

v

ganciclovir

averaged

microg

mL

with

minimum

concentrations

of

microg

mL

Plasma

concentrations

were

lower

but

more

sustained

during

a

p

o

dosing

interval

max

microg

mL

min

microg

mL


Previous data suggest that Cmax >50 microg/ml is associated with a reduction in neutrophil (PMN) migration into the lung and that lower concentrations are associated with an increase in PMN migration.

Answer: accept

Previous

data

suggest

that

Cmax

microg

ml

is

associated

with

a

reduction

in

neutrophil

PMN

migration

into

the

lung

and

that

lower

concentrations

are

associated

with

an

increase

in

PMN

migration


With 200 mg/kg, Vd did not change, whereas AUC and MRT increased with both infections.

Answer: accept

With

mg

kg

Vd

did

not

change

whereas

AUC

and

MRT

increased

with

both

infections


Treatment Phase
Pharmacodynamic Parameters
Pharmacokinetic Parameters

Systemic hydrocodone exposure, as evaluated by mean AUClast and AUCinf, was similar following administration of hydrocodone solution (951 h•ng/mL and 971 h•ng/mL, respectively), HYD chewed (913 h•ng/mL and 943 h•ng/mL, respectively), and HYD intact (886 h•ng/mL/mL and 1059 h•ng/mL, respectively); treatment with HYD fine particles resulted in lower AUClast and AUCinf values (648 h•ng/mL and 656 h•ng/mL, respectively) (Table 4).

Answer: accept

Systemic

hydrocodone

exposure

as

evaluated

by

mean

AUClast

and

AUCinf

was

similar

following

administration

of

hydrocodone

solution

h

ng

mL

and

h

ng

mL

respectively

HYD

chewed

h

ng

mL

and

h

ng

mL

respectively

and

HYD

intact

h

ng

mL

mL

and

h

ng

mL

respectively

treatment

with

HYD

fine

particles

resulted

in

lower

AUClast

and

AUCinf

values

h

ng

mL

and

h

ng

mL

respectively

Table


3. Results and Discussion
3.5. Application of the Method

The t1/2 was found to be 7.33 ± 8.68 and 2.55 ± 1.26 h for NA and NUA, respectively.

Answer: accept

The

t

was

found

to

be

and

h

for

and

NUA

respectively


The mean plasma theophylline half-life (t1/2) following the single intravenous dose was 7.8 h and the mean apparent specific volume of distribution (V'd(area] was 0.46 1/kg.

Answer: accept

The

mean

plasma

theophylline

half

life

t

following

the

single

intravenous

dose

was

h

and

the

mean

apparent

specific

volume

of

distribution

V

d

area

was

kg


The bioavailability from the PBPK simulations correspond with typical values of bioavailability predicted using a Hill‐type model in a previously performed population PK analysis: 50% vs. 40% for the PBPK model vs. the population PK model, respectively, for the 200 mg dose, 70% vs. 67% for the 400 mg dose, 78% vs. 76% for the 600 mg dose, and 72% vs. 80% for the 800 mg dose on day 1 (sponsor data (Cempra) on file).

Answer: accept

The

bioavailability

from

the

PBPK

simulations

correspond

with

typical

values

of

bioavailability

predicted

using

a

Hill

type

model

in

a

previously

performed

population

PK

analysis

vs

for

the

PBPK

model

vs

the

population

PK

model

respectively

for

the

mg

dose

vs

for

the

mg

dose

vs

for

the

mg

dose

and

vs

for

the

mg

dose

on

day

sponsor

data

Cempra

on

file


Following IV administration of 5 to 50 mg/kg TAC, the corresponding TAb systemic clearance ranged from 4.53 to 5.72 mL/day/kg; t1/2λz ranged from 12.4 to 16.1 days, and Vss ranged from 91.4 to 97.6 mL/kg (Table 2).

Answer: accept

Following

IV

administration

of

to

mg

kg

TAC

the

corresponding

TAb

systemic

clearance

ranged

from

to

mL

day

kg

t

λ

z

ranged

from

to

days

and

Vss

ranged

from

to

mL

kg

Table


The half-life for R- and S-warfarin was 52 to 56 hours and 36 to 40 hours, respectively.

Answer: accept

The

half

life

for

R

and

S

warfarin

was

to

hours

and

to

hours

respectively


The T50% values were 0.35+-0.05 h for Florite RE 10 mg, 0.34+-0.03 h for Florite RE 20 mg, 0.26+-0.03 h for Neusilin US2, and 0.15+-0.01 h for Sylysia 320.

Answer: accept

The

T

values

were

h

for

Florite

RE

mg

h

for

Florite

RE

mg

h

for

Neusilin

US

and

h

for

Sylysia


The elimination half-life was 80 hours (48-152 hours and the area under the plasma concentration time curve normalized to a 100 mg cisplatin dose was 79 mg/liter x hours.

Answer: accept

The

elimination

half

life

was

hours

hours

and

the

area

under

the

plasma

concentration

time

curve

normalized

to

a

mg

cisplatin

dose

was

mg

liter

x

hours


The 90% CIs of GMR for both AUC0–72 hr and Cmax of ROS were contained within the prespecified bioequivalence bounds (0.80−1.25).

Answer: accept

The

CIs

of

GMR

for

both

AUC

hr

and

Cmax

of

ROS

were

contained

within

the

prespecified

bioequivalence

bounds


In normal subjects, the half-absorption period (Ka) was 0.63 hours.

Answer: accept

In

normal

subjects

the

half

absorption

period

Ka

was

hours


Incorporation of genetic effect in CYP2D6‐mediated clearance of substrates and inhibitors

Using rich data from the in‐house clinical studies mentioned in the Methods section, the CYP2D6‐mediated clearance of dextromethorphan, duloxetine, and paroxetine was 2.36‐fold, 1.2‐fold, and 1.93‐fold higher, respectively, in the AS2 subjects when compared with the AS1 subjects.

Answer: accept

Using

rich

data

from

the

in

house

clinical

studies

mentioned

in

the

Methods

section

the

CYP

D

mediated

clearance

of

dextromethorphan

duloxetine

and

paroxetine

was

fold

fold

and

fold

higher

respectively

in

the

AS

subjects

when

compared

with

the

AS

subjects


There was no significant difference between the control and treatment phases (P greater than 0.05) with respect to the area under the plasma phenytoin concentration-time curve, the fraction of phenytoin unbound in plasma, the area under the unbound phenytoin concentration-time curve, the elimination half-life of phenytoin or the fraction of the dose excreted in urine as free and conjugated hydroxyphenylphenylhydantoin.

Answer: accept

There

was

no

significant

difference

between

the

control

and

treatment

phases

P

greater

than

with

respect

to

the

area

under

the

plasma

phenytoin

concentration

time

curve

the

fraction

of

phenytoin

unbound

in

plasma

the

area

under

the

unbound

phenytoin

concentration

time

curve

the

elimination

half

life

of

phenytoin

or

the

fraction

of

the

dose

excreted

in

urine

as

free

and

conjugated

hydroxyphenylphenylhydantoin


When CHN alone was administered orally, the time to maximum plasma concentration (Tmax) of CHN was as short as 15 min, but that of CHL was 120 min.

Answer: accept

When

CHN

alone

was

administered

orally

the

time

to

maximum

plasma

concentration

Tmax

of

CHN

was

as

short

as

min

but

that

of

CHL

was

min


The half-life of total peptide activity after buccal administration was 17 min.

Answer: accept

The

half

life

of

total

peptide

activity

after

buccal

administration

was

min


Table4 shows that the bioequivalence ratios of the log‐transformed Cmax, AUC0‐4h, and AUC0–∞ values relative to the control were within the FDA's standard equivalence range of 80–125% for log‐transformed data.

Answer: accept

Table

shows

that

the

bioequivalence

ratios

of

the

log

transformed

Cmax

AUC

h

and

AUC

values

relative

to

the

control

were

within

the

FDA

's

standard

equivalence

range

of

for

log

transformed

data


The minimum inhibitory concentration (MIC) for flucytosine was reported as 2 μg/mL; however, it was noted that no Clinical Laboratory Standards Institute (CLSI) range exists for flucytosine and Cryptococcus neoformans for susceptibility interpretation.

Answer: accept

The

minimum

inhibitory

concentration

MIC

for

flucytosine

was

reported

as

μ

g

mL

however

it

was

noted

that

no

Clinical

Laboratory

Standards

Institute

CLSI

range

exists

for

flucytosine

and

Cryptococcus

neoformans

for

susceptibility

interpretation


Extended receptor residence time of 3D53

To determine the functional residence time of the three antagonists, washout cell experiments were performed in which HMDM were pre-treated with a saturating concentration of each antagonist (1 μM) for 1 h. HMDM were washed after 1 h to remove unbound antagonist, and then these antagonist-treated HMDM were subsequently challenged with 3 nM C5a at specified time points.

Answer: accept

To

determine

the

functional

residence

time

of

the

three

antagonists

washout

cell

experiments

were

performed

in

which

HMDM

were

pre

treated

with

a

saturating

concentration

of

each

antagonist

μ

M

for

h

HMDM

were

washed

after

h

to

remove

unbound

antagonist

and

then

these

antagonist

treated

HMDM

were

subsequently

challenged

with

nM

C

a

at

specified

time

points


Antimalarial pharmacokinetics. (i) Effect of dolutegravir on artemether-lumefantrine pharmacokinetics (study A).

The lumefantrine metabolite desbutyl-lumefantrine had a 3% decrease in Cmax (GMR, 0.97; 90% CI, 0.79 to 1.18) and a 4% decrease in AUC0–t (GMR, 0.96; 90% CI, 0.80 to 1.15), representing approximately 1.7% of the total circulating lumefantrine.

Answer: accept

The

lumefantrine

metabolite

desbutyl

lumefantrine

had

a

decrease

in

Cmax

GMR

CI

to

and

a

decrease

in

AUC

t

GMR

CI

to

representing

approximately

of

the

total

circulating

lumefantrine


Plasma Pefloxacin Disposition after Single IV and Oral Administration

The t½β of N-demethyl pefloxacin after oral pefloxacin administration was 10.93 ± 0.80 h (Table 2).

Answer: accept

The

t

½

β

of

N

demethyl

pefloxacin

after

oral

pefloxacin

administration

was

h

Table


Elimination rate constant, elimination half-life, AUC0-t, MRT, Vdss, and CLβ were 0.034/h, 10.63±0.10 h, 99.82±2.02 mg/ml h, 21.89±1.03 h, 1.82±0.01 L/kg, and 0.06±0.00 L/kg/h, respectively (Table-4).

Answer: accept

Elimination

rate

constant

elimination

half

life

AUC

t

MRT

Vdss

and

CL

β

were

h

h

mg

ml

h

h

L

kg

and

L

kg

h

respectively

Table


Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with the profiles being similar in shape to the corresponding plasma profiles and with the apparent terminal half-lives in plasma and ELF being 1.2 and 1.3 h, respectively, for relebactam and 1.0 h in both compartments for imipenem.

Answer: accept

Both

drugs

penetrated

the

epithelial

lining

fluid

ELF

to

a

similar

degree

with

the

profiles

being

similar

in

shape

to

the

corresponding

plasma

profiles

and

with

the

apparent

terminal

half

lives

in

plasma

and

ELF

being

and

h

respectively

for

relebactam

and

h

in

both

compartments

for

imipenem


For pyrimethamine, the day 1, 3, and 7 concentrations as well as the AUC and apparent clearance were similar.

Answer: accept

For

pyrimethamine

the

day

and

concentrations

as

well

as

the

AUC

and

apparent

clearance

were

similar


Compared with pretreatment values, the clearance of caffeine was reduced by about 54% and 55% after one treatment cycle with gestodene- and the levonorgestrel-containing oral contraceptive, respectively.

Answer: accept

Compared

with

pretreatment

values

the

clearance

of

caffeine

was

reduced

by

about

and

after

one

treatment

cycle

with

gestodene

and

the

levonorgestrel

containing

oral

contraceptive

respectively


After intravenous infusion of 22.8 mg to healthy subjects, plasma ximoprofen concentrations declined in a polyexponential manner with a terminal phase half-life of 1.9 h. The systemic clearance of ximoprofen was 115 ml.min-1 and the volumes of distribution were 18.01 Vz and 13.81 Vss.

Answer: accept

After

intravenous

infusion

of

mg

to

healthy

subjects

plasma

ximoprofen

concentrations

declined

in

a

polyexponential

manner

with

a

terminal

phase

half

life

of

h

The

systemic

clearance

of

ximoprofen

was

ml

min

and

the

volumes

of

distribution

were

Vz

and

Vss


Bioavailability averaged 42% over all doses at 15 degrees C and was decreased to an average of 25% at 10 degrees C. Peak serum concentrations appeared between 6 and 8 h following dosing.

Answer: accept

Bioavailability

averaged

over

all

doses

at

degrees

C

and

was

decreased

to

an

average

of

at

degrees

C

Peak

serum

concentrations

appeared

between

and

h

following

dosing


When alpha-tocopherol-loaded PLGA microspheres (100 mg/kg) were subcutaneously administered, the plasma concentrations of alpha-tocopherol increased slowly and remained about 2-fold higher than the endogenous level at 5 to 10 days after administration in both types of mice, and there was no significant difference between the AUC values.

Answer: accept

When

alpha

tocopherol

loaded

PLGA

microspheres

mg

kg

were

subcutaneously

administered

the

plasma

concentrations

of

alpha

tocopherol

increased

slowly

and

remained

about

fold

higher

than

the

endogenous

level

at

to

days

after

administration

in

both

types

of

mice

and

there

was

no

significant

difference

between

the

AUC

values


For categorical covariates, >80% of the simulations were identified as statistically significant, with an assumed effect size of ≥20% increase in clearance in ≥20% of patients.

Answer: accept

For

categorical

covariates

of

the

simulations

were

identified

as

statistically

significant

with

an

assumed

effect

size

of

increase

in

clearance

in

of

patients


We demonstrated that these inhibitors decreased cell viability in several human cancer cell lines with an IC50 in the 9.7 to 60.3 μM range and induced intrinsic apoptosis at concentrations of 50 μM.

Answer: accept

We

demonstrated

that

these

inhibitors

decreased

cell

viability

in

several

human

cancer

cell

lines

with

an

IC

in

the

to

μ

M

range

and

induced

intrinsic

apoptosis

at

concentrations

of

μ

M


Following oral administration, the t(1/2lambdaz) were 43 h (halibut) and 42 h (turbot).

Answer: accept

Following

oral

administration

the

t

lambdaz

were

h

halibut

and

h

turbot


The amount of atenolol excreted into urine was decreased by 38% (range 17-60%, P<0.01), but the renal clearance remained unaltered.

Answer: accept

The

amount

of

atenolol

excreted

into

urine

was

decreased

by

range

P

but

the

renal

clearance

remained

unaltered


CL/F in severely renally impaired subjects differed by <6 % from that in controls.

Answer: accept

CL

F

in

severely

renally

impaired

subjects

differed

by

from

that

in

controls


Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 μg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively.

Answer: accept

Adjusted

geometric

mean

AUClast

for

artemether

were

and

ng

h

mL

geometric

mean

ratio

GMR

CI

and

for

lumefantrine

were

and

μ

g

h

mL

GMR

CI

for

mg

tablet

versus

four

standard

tablets

respectively


The validated LC-ESI-MS method has been used successfully to study tolterodine tartrate pharmacokinetic, bioavailability and bioequivalence in 20 healthy male volunteers.

Answer: accept

The

validated

LC

ESI

MS

method

has

been

used

successfully

to

study

tolterodine

tartrate

pharmacokinetic

bioavailability

and

bioequivalence

in

healthy

male

volunteers


Significant differences in AUCs, Ae(0-30h) and GI(30h) values for baicalein and baicalin were observed after oral administration of pure baicalein (18 mg/kg) and PF-2405 (40 mg/kg).

Answer: accept

Significant

differences

in

AUCs

Ae

h

and

GI

h

values

for

baicalein

and

baicalin

were

observed

after

oral

administration

of

pure

baicalein

mg

kg

and

PF

mg

kg


The comparative analysis of bioavailability between oral GSH and the sublingual form is summarized in Tables 3 and 4.

Answer: accept

The

comparative

analysis

of

bioavailability

between

oral

GSH

and

the

sublingual

form

is

summarized

in

Tables

and


When the same dose was administered IM, enrofloxacin was rapidly and almost completely absorbed, with bioavailability of 85%.

Answer: accept

When

the

same

dose

was

administered

IM

enrofloxacin

was

rapidly

and

almost

completely

absorbed

with

bioavailability

of


For 100% protection with ciprofloxacin, the peak concentration/MIC ratio must reach a value of 10.6.

Answer: accept

For

protection

with

ciprofloxacin

the

peak

concentration

MIC

ratio

must

reach

a

value

of


2.4. Chromatographic Method for Screening Potential Prodrugs

The flow rate was 250 µL/min, injection volume: 10 µL, run time: 10 min.

Answer: accept

The

flow

rate

was

µ

L

min

injection

volume

µ

L

run

time

min


Following single oral doses of ER hydrocodone formulations, blood concentration reaches the peak (Cmax) at a median time (Tmax) of 14–16 h for the different doses (the range is 6–30 h).

Answer: accept

Following

single

oral

doses

of

ER

hydrocodone

formulations

blood

concentration

reaches

the

peak

Cmax

at

a

median

time

Tmax

of

h

for

the

different

doses

the

range

is

h


The half-life at alpha phase (t1/2 alpha) was 9.6 min (SD, 4.6), t1/2 beta was 94.8 min (SD, 5.4), area under the concentration-time curve (AUC) was 285.4 micrograms.h/ml (SD, 22.7), total body clearance was 0.115 liter/h.kg (SD, 0.022), and volume of distribution at steady state was 0.178 liter/kg (SD, 0.023).

Answer: accept

The

half

life

at

alpha

phase

t

alpha

was

min

SD

t

beta

was

min

SD

area

under

the

concentration

time

curve

AUC

was

micrograms

h

ml

SD

total

body

clearance

was

liter

h

kg

SD

and

volume

of

distribution

at

steady

state

was

liter

kg

SD


MW is the definite single factor affecting intravitreal half-lives of macromolecules (Log t1/2 = 0.148 + 0.370 Log MW, R2 = 0.769), while both MW and lipophilicity influence the intraocular pharmacokinetics of micromolecules (Log t1/2 = -1.213 + 0.762 Log MW - 0.115 Log p, R2 = 0.554).

Answer: accept

MW

is

the

definite

single

factor

affecting

intravitreal

half

lives

of

macromolecules

Log

t

Log

MW

R

while

both

MW

and

lipophilicity

influence

the

intraocular

pharmacokinetics

of

micromolecules

Log

t

Log

MW

Log

p

R


Results and discussion
Molecular docking studies

In agreement to the in-vitro results, molecular docking studies suggested that compounds 6b, 6h, 6i, and 6k represented better interaction than donepezil; (i) due to hydrogen bonding, (ii) due to extra π-π stacking with aromatic residues, and (iii) due to more interaction through water bridging as shown in Figure 7.

Answer: accept

In

agreement

to

the

in

vitro

results

molecular

docking

studies

suggested

that

compounds

b

h

i

and

k

represented

better

interaction

than

donepezil

i

due

to

hydrogen

bonding

ii

due

to

extra

π

π

stacking

with

aromatic

residues

and

iii

due

to

more

interaction

through

water

bridging

as

shown

in

Figure


The mean calculated absorption tl/2 was 2.73 +- 0.85 min for artesunate and 12.49 +- 2.49 min for dihydroartemisinin (see Table and Figure).

Answer: accept

The

mean

calculated

absorption

tl

was

min

for

artesunate

and

min

for

dihydroartemisinin

see

Table

and

Figure


Correlation between warfarin, RR/SS- and RS/SR-warfarin alcohols concentration in oral fluid and plasma samples

In the case of WAR and RS/SR-warfarin alcohols, Log Kow values at pH = 7 are in the range 0.83–0.94, which places the analytes in an intermediate zone compared to cases reported by Higashi et al. Although the OF flow rate may have influenced the measured concentration ratio of WAR and RS/SR-warfarin alcohols, it was not possible to quantitatively estimate this possible effect.

Answer: accept

In

the

case

of

WAR

and

RS

SR

warfarin

alcohols

Log

Kow

values

at

pH

are

in

the

range

which

places

the

analytes

in

an

intermediate

zone

compared

to

cases

reported

by

Higashi

et

al

Although

the

OF

flow

rate

may

have

influenced

the

measured

concentration

ratio

of

WAR

and

RS

SR

warfarin

alcohols

it

was

not

possible

to

quantitatively

estimate

this

possible

effect


Fluticasone Furoate Pharmacokinetic Model

The fixed-effect parameters RACE1 = 3 and RACE1 = 4 on CL/F were estimated with less precision [% relative standard error (RSE) 199 % for RACE1 = 3 and 51 % for RACE1 = 4).

Answer: accept

The

fixed

effect

parameters

RACE

and

RACE

on

CL

F

were

estimated

with

less

precision

relative

standard

error

RSE

for

RACE

and

for

RACE


Ktrans and Ve were shown to be correlated with CRP (r = 0.725, P < 0.001; r = 0.533, P = 0.002), meanwhile ADC showed negative correlation with CRP (r = −0.630, P < 0.001).

Answer: accept

Ktrans

and

Ve

were

shown

to

be

correlated

with

CRP

r

P

r

P

meanwhile

ADC

showed

negative

correlation

with

CRP

r

P


Combined analysis of renal study with previous studies

Results of the combined analysis showed that exenatide clearance was not significantly different between the normal renal function and mild renal impairment groups (P= 0.26), but was significantly reduced by 36% in the moderate renal impairment group (P= 0.008) and 84% in the ESRD group (P< 0.001) compared with the normal control group (Table 5).

Answer: accept

Results

of

the

combined

analysis

showed

that

exenatide

clearance

was

not

significantly

different

between

the

normal

renal

function

and

mild

renal

impairment

groups

P

but

was

significantly

reduced

by

in

the

moderate

renal

impairment

group

P

and

in

the

ESRD

group

P

compared

with

the

normal

control

group

Table


Rifamycines
Rifamycines as Perpetrators
Anti-retroviral drugs

RIF co-administration resulted in a 2700% increase of oral clearance, leading to nearly negligible delavirdine concentrations [72].

Answer: accept

RIF

co

administration

resulted

in

a

increase

of

oral

clearance

leading

to

nearly

negligible

delavirdine

concentrations


Concomitant administration of ramucirumab had no effect on pharmacokinetics of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab vs. alone) of 1.09 (90 % confidence interval [CI] 0.93, 1.29) for AUC(0–∞) and 0.97 (90 % CI 0.83, 1.13) for Cmax.

Answer: accept

Concomitant

administration

of

ramucirumab

had

no

effect

on

pharmacokinetics

of

paclitaxel

with

ratios

of

geometric

least

squares

LS

means

with

ramucirumab

vs

alone

of

confidence

interval

CI

for

AUC

and

CI

for

Cmax


Malathion exposure significantly increased maximum plasma drug concentration, t(1/2β), AUC and MRT of pefloxacin to 54, 22, 117 and 37% of control, respectively.

Answer: accept

Malathion

exposure

significantly

increased

maximum

plasma

drug

concentration

t

β

AUC

and

MRT

of

pefloxacin

to

and

of

control

respectively


Expression and characterisation of monoclonal phage clone E1 in a full antibody framework

Other antigens such as 3H5 hG1 and D29 hG1 were included as they possess the same framework structure as 14c10 hG1 but have different variable regions.

Answer: accept

Other

antigens

such

as

H

hG

and

D

hG

were

included

as

they

possess

the

same

framework

structure

as

c

hG

but

have

different

variable

regions


Examination of sex as a covariate indicated a 40.5% lower overall CL/F in female than in male patients.

Answer: accept

Examination

of

sex

as

a

covariate

indicated

a

lower

overall

CL

F

in

female

than

in

male

patients


After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1 +- 4.5 min and the mean elimination half-life was 69 +- 28 min.

Answer: accept

After

an

i

v

bolus

of

ara

C

the

mean

plasma

distribution

half

life

was

min

and

the

mean

elimination

half

life

was

min


Experimental Procedures
Statistical Methods, Sample Size

When the true AUCτ ratio between Silexan and placebo is between 0.95 and 1.05, a sample size of 20 subjects will have at least 80 % power for rejecting the null hypothesis predicting an interaction between Silexan and EE or LNG according to the above criteria.

Answer: accept

When

the

true

AUC

τ

ratio

between

Silexan

and

placebo

is

between

and

a

sample

size

of

subjects

will

have

at

least

power

for

rejecting

the

hypothesis

predicting

an

interaction

between

Silexan

and

EE

or

LNG

according

to

the

above

criteria


The median area under the concentration curve at 24 hours, volume of distribution, total body clearance and half-life of daptomycin were 262.4 mg×h/L (166.7, 340.2), 0.21 L/kg (0.11, 0.34), 0.021 L/h/kg (0.016, 0.034) and 6.2 hours (3.7, 9.0), respectively.

Answer: accept

The

median

area

under

the

concentration

curve

at

hours

volume

of

distribution

total

body

clearance

and

half

life

of

daptomycin

were

mg

h

L

L

kg

L

h

kg

and

hours

respectively


Tmax values for nodakenin and DOH (0.67 and 0.64 h, respectively) were also similar to each other.

Answer: accept

Tmax

values

for

nodakenin

and

DOH

and

h

respectively

were

also

similar

to

each

other


High between-subject variability (50.9%) (Table 4) resulted in wide 90% confidence intervals around the dihydroartemisinin Cmax.

Answer: accept

High

between

subject

variability

Table

resulted

in

wide

confidence

intervals

around

the

dihydroartemisinin

Cmax


In vivo pharmacokinetic study in beagle dogs

Calculation of MbH parameters and statistical analysis

The Wagner–Nelson model was used to calculate the percentage of Mebeverine dose-absorbed profiles.33Fat=(Ct+Kel×AUC0–t)1/Kel×AUC0–∞,(2)where Fat is the fraction of drug absorbed at time t, Ct is the concentration of drug in the plasma at time t, and Kel is the elimination rate constant.

Answer: accept

The

Wagner

Nelson

model

was

used

to

calculate

the

percentage

of

Mebeverine

dose

absorbed

profiles

Fat

Ct

Kel

AUC

t

Kel

AUC

where

Fat

is

the

fraction

of

drug

absorbed

at

time

t

Ct

is

the

concentration

of

drug

in

the

plasma

at

time

t

and

Kel

is

the

elimination

rate

constant


Plasma concentrations were already measurable within 1 hour after drug administration, and, at 3 hours, plasma concentrations of netupitant and palonosetron represented approximately 80% of their mean Cmax.

Answer: accept

Plasma

concentrations

were

already

measurable

within

hour

after

drug

administration

and

at

hours

plasma

concentrations

of

netupitant

and

palonosetron

represented

approximately

of

their

mean

Cmax


In the 25 mg/kg group, maximum concentrations were detected after 2 h (urine, 2785 μg/mL) and 1.5 h (plasma, 23 μg/mL).

Answer: accept

In

the

mg

kg

group

maximum

concentrations

were

detected

after

h

urine

μ

g

mL

and

h

plasma

μ

g

mL


The plasma half-life was inversely correlated (p less than 0.05) to the postnatal age of the patients.

Answer: accept

The

plasma

half

life

was

inversely

correlated

p

less

than

to

the

postnatal

age

of

the

patients


Results and discussion
Pharmacokinetic study

It was well known that drugs can circulate for a certain period after injection before they are recognized as foreign matters and rapidly cleared by phagocytic cells of the mononuclear phagocyte system, which are abundant in special tissues and organs such as the liver and lung.

Answer: accept

It

was

well

known

that

drugs

can

circulate

for

a

certain

period

after

injection

before

they

are

recognized

as

foreign

matters

and

rapidly

cleared

by

phagocytic

cells

of

the

mononuclear

phagocyte

system

which

are

abundant

in

special

tissues

and

organs

such

as

the

liver

and

lung


Activity within a five-fold range of the IC50 of FGFR2 was observed in KIT, PDGFR, RET, and SRC family members, but ARQ 087 had limited activity against other kinases tested (Hall et al, 2016).

Answer: accept

Activity

within

a

five

fold

range

of

the

IC

of

FGFR

was

observed

in

KIT

PDGFR

RET

and

SRC

family

members

but

ARQ

had

limited

activity

against

other

kinases

tested

Hall

et

al


Results and discussion
Method validation
Linearity of calibration curves

The calibration curves for ciprofloxacin were linear over the range of 0.02–4.0 μg/mL. The mean linear regression equation of the calibration curves (n = 13) was: Y = 1.149X + 0.034; where Y represents the peak area ratio (ciprofloxacin/IS), and X represents the plasma concentration of ciprofloxacin (μg/mL).

Answer: accept

The

calibration

curves

for

ciprofloxacin

were

linear

over

the

range

of

μ

g

mL

The

mean

linear

regression

equation

of

the

calibration

curves

n

was

Y

X

where

Y

represents

the

peak

area

ratio

ciprofloxacin

IS

and

X

represents

the

plasma

concentration

of

ciprofloxacin

μ

g

mL


Twenty-six 1-, 2-, or 3-sample estimation models were fit (r(2) = 0.341-0.862) to a randomly selected subset of the profiles using linear regression and were used to estimate AUC(0-12h) for the profiles not included in the regression fit, comparing those estimates with the corresponding AUC(0-12h) values, calculated with the linear trapezoidal rule, including all 12 timed MPA concentrations.

Answer: accept

Twenty

six

or

sample

estimation

models

were

fit

r

to

a

randomly

selected

subset

of

the

profiles

using

linear

regression

and

were

used

to

estimate

AUC

h

for

the

profiles

not

included

in

the

regression

fit

comparing

those

estimates

with

the

corresponding

AUC

h

values

calculated

with

the

linear

trapezoidal

rule

including

all

timed

MPA

concentrations


The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose).

Answer: accept

The

MEDI

peak

serum

concentration

increased

dose

proportionally

from

μ

g

ml

mg

dose

to

μ

g

ml

mg

dose


Effect of prasugrel on montelukast pharmacokinetics

Additionally, the M1:montelukast AUC0‐∞ ratio was increased to 118% of that during the placebo phase (P = 0.033, 90% CI 105–133%).

Answer: accept

Additionally

the

M

:montelukas

t

AUC

ratio

was

increased

to

of

that

during

the

placebo

phase

P

CI


Primary endpoint was a non-inferiority analysis (10.8/3.6 mg) of the area under the concentration-time curve (AUC) of estradiol (E(2)) over the first 24 weeks.

Answer: accept

Primary

endpoint

was

a

non

inferiority

analysis

mg

of

the

area

under

the

concentration

time

curve

AUC

of

estradiol

E

over

the

first

weeks


The half-life of diflucortolone in the plasma was 4-5 h, that of the total 3H-steroids about 9 h. 80-40% of the 3H-steroids in the plasma were in unconjugated form.

Answer: accept

The

half

life

of

diflucortolone

in

the

plasma

was

h

that

of

the

total

H

steroids

about

h

of

the

H

steroids

in

the

plasma

were

in

unconjugated

form


Predicted Nivolumab Clearance in Chinese, Non‐Chinese Asian, and Non‐Asian Patients

The magnitude of the effects of baseline covariates on nivolumab clearance and volume of the central compartment, assessed using the current PPK model, was within ±20% of the reference values as assessed by 95%CI, with exception of body weight (Figure 1).

Answer: accept

The

magnitude

of

the

effects

of

baseline

covariates

on

nivolumab

clearance

and

volume

of

the

central

compartment

assessed

using

the

current

PPK

model

was

within

of

the

reference

values

as

assessed

by

CI

with

exception

of

body

weight

Figure


IGF-I was cleared more rapidly from plasma in pregnant rats compared with the virgins; metabolic clearance rate (MCR) = 2.88 +- 0.12 (S.E.M.) and 0.90 +- 0.05 ml/min per kg respectively.

Answer: accept

IGF

I

was

cleared

more

rapidly

from

plasma

in

pregnant

rats

compared

with

the

virgins

metabolic

clearance

rate

MCR

S

E

M

and

ml

min

per

kg

respectively


After the extravascular administration, the Cmax of enalapril was achieved in almost 1 h and time vs. serum concentration of enalapril showed a mono-exponential decay.

Answer: accept

After

the

extravascular

administration

the

Cmax

of

enalapril

was

achieved

in

almost

h

and

time

vs

serum

concentration

of

enalapril

showed

a

mono

exponential

decay


The correlation between the pre-dose MPA trough level (C(0)) and the MPA AUC(12) was poor (r(2) = 0.02, p = 0.33).

Answer: accept

The

correlation

between

the

pre

dose

MPA

trough

level

C

and

the

MPA

AUC

was

poor

r

p


The elimination half-lives in subjects with normal (Group 1) and impaired renal function (Group 2) or requiring chronic hemodialysis (Group 3) were 4.14 +- 1.55, 5.10 +- 2.24, and 10.1 +- 6.01 hours, respectively (Group 3 versus 1 or 2, P < .05; Group 1 versus 2, P > .05).

Answer: accept

The

elimination

half

lives

in

subjects

with

normal

Group

and

impaired

renal

function

Group

or

requiring

chronic

hemodialysis

Group

were

and

hours

respectively

Group

versus

or

P

Group

versus

P


Using simple linear regression, for every 1 L/h increase in dialysate flow rate, the clearance rate increased by 23.6 mL/min (95% CI 1.7–45.4 mL/min; P = 0.037).

Answer: accept

Using

simple

linear

regression

for

every

L

h

increase

in

dialysate

flow

rate

the

clearance

rate

increased

by

mL

min

CI

mL

min

P


Consequently, the absolute bioavailability of loratadine in the presence of silybinin (1.5 and 6 mg x kg(-1)) was 8.6-10.2%, which was significantly (1.5 mg x kg(-1), P < 0.05; 6 mg x kg(-1), P < 0.01) enhanced compared to that in oral control group (5.8%).

Answer: accept

Consequently

the

absolute

bioavailability

of

loratadine

in

the

presence

of

silybinin

and

mg

x

kg

was

which

was

significantly

mg

x

kg

P

mg

x

kg

P

enhanced

compared

to

that

in

oral

control

group


In the 16 mg/kg cohort, mean ± standard deviation (SD) Cmax was 405.75 ± 72.50 μg/mL after the first full infusion and 993.65 ± 127.04 μg/mL after the last infusion, whereas mean ± SD AUCinf was 56,893.56 ± 22,030.42 and 371,159.32 μg·h/mL after the first and last infusions, respectively.

Answer: accept

In

the

mg

kg

cohort

mean

standard

deviation

SD

Cmax

was

μ

g

mL

after

the

first

full

infusion

and

μ

g

mL

after

the

last

infusion

whereas

mean

SD

AUCinf

was

and

μ

g

h

mL

after

the

first

and

last

infusions

respectively


Conversely, the sums of the maximum and minimum concentrations following the first dose, as percent of the steady-state Cmax plus Cmin are respectively 75, 50, 30, and 17.

Answer: accept

Conversely

the

sums

of

the

maximum

and

minimum

concentrations

following

the

first

dose

as

percent

of

the

steady

state

Cmax

plus

Cmin

are

respectively

and


Venous blood samples were taken every 30 min for 4 h, every 60 min for 4 h, and every 4 h for 16 h. Data were analyzed using a mixed-effects modeling technique (using NONMEM software) to determine the volume of distribution and clearance normalized for bioavailability.

Answer: accept

Venous

blood

samples

were

taken

every

min

for

h

every

min

for

h

and

every

h

for

h

Data

were

analyzed

using

a

mixed

effects

modeling

technique

using

NONMEM

software

to

determine

the

volume

of

distribution

and

clearance

normalized

for

bioavailability


AZM is also effective in gingival enlargement associated with cyclosporine (3).

Answer: accept

AZM

is

also

effective

in

gingival

enlargement

associated

with

cyclosporine


The point estimates for Cmax for the 4 μg/kg range, as well as AUC(0–72) and Cmax for the 8 μg/kg dose show slightly higher values for filgrastim.

Answer: accept

The

point

estimates

for

Cmax

for

the

μ

g

kg

range

as

well

as

AUC

and

Cmax

for

the

μ

g

kg

dose

show

slightly

higher

values

for

filgrastim