N-desmethyl tramadol (M2) was not immediately quantifiable in plasma after tramadol administration, with a lag time of 0.5 to 2 h.

Answer: accept

N

desmethyl

tramadol

M

was

not

immediately

quantifiable

in

plasma

after

tramadol

administration

with

a

lag

time

of

to

h


Relationships between change in log10 colony forming units (CFU) from baseline at 24 hours and total-drug ELF AUC/MIC ratio for each isolate and the isolates pooled together were evaluated using Hill-type models and non-linear least squares regression.

Answer: accept

Relationships

between

change

in

log

colony

forming

units

CFU

from

baseline

at

hours

and

total

drug

ELF

AUC

MIC

ratio

for

each

isolate

and

the

isolates

pooled

together

were

evaluated

using

Hill

type

models

and

non

linear

least

squares

regression


The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-β-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1).

Answer: accept

The

predicted

AUCRs

using

the

mechanism

based

inhibition

of

CYP

C

by

clopidogrel

acyl

β

glucuronide

were

similar

to

the

observed

AUCRs

and

the

predicted

AUCR

of

repaglinide

using

only

the

inhibition

of

OATP

B

did

not

reach

the

observed

AUCR


Absorption (ka) and elimination (ke) rate constants in plasma of 2-hydroxy-mesocarb were 0.0300 and 0.00485 min-1, respectively; those of 4-methyl-2-hydroxymesocarb were 0.0546 and 0.00797 min-1, respectively.

Answer: accept

Absorption

ka

and

elimination

ke

rate

constants

in

plasma

of

hydroxy

mesocarb

were

and

min

respectively

those

of

methyl

hydroxymesocarb

were

and

min

respectively


Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats we used a computer-controlled, intravenous METH procedure (dynamic infusion) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life.

Answer: accept

Accordingly

to

simulate

the

pharmacokinetic

profile

of

a

human

METH

binge

exposure

in

rats

we

used

a

computer

controlled

intravenous

METH

procedure

dynamic

infusion

to

overcome

species

differences

in

METH

pharmacokinetics

and

to

replicate

the

human

h

plasma

METH

half

life


Application of the Method in the Pharmacokinetic Study and Incurred Sample Analysis

Absorbed baricitinib and methotrexate were eliminated with a half-life of 2.57 and 1.94 hr, respectively.

Answer: accept

Absorbed

baricitinib

and

methotrexate

were

eliminated

with

a

half

life

of

and

hr

respectively


Predictive value of HCV RNA decline at week 4 of the treatment on SVR

When the cutoff value was 3.770, the corresponding AUROC, sensitivity, specificity, PPV and NPV were 0.854 (95% CI 0.705-1.003), 0.850, 0.833, 1.000 and 0.706.

Answer: accept

When

the

cutoff

value

was

the

corresponding

AUROC

sensitivity

specificity

PPV

and

NPV

were

CI

and


Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m−2 indicating extensive tissue/tubulin binding.

Answer: accept

Sagopilone

showed

multi

exponential

kinetics

with

a

mean

terminal

half

life

of

h

and

a

volume

of

distribution

of

l

m

indicating

extensive

tissue

tubulin

binding


Mean (±SD) CLss/F ranged from 37.9 (±19.9) to 87.9 (±9.37) L/h, which were lower than the CL/F values for single doses.

Answer: accept

Mean

SD

CLss

F

ranged

from

to

L

h

which

were

lower

than

the

CL

F

values

for

single

doses


At day 1, t(1/2beta) was 2.45 +- 0.56 h, V(ss) 0.36 +- 0.1 L/kg, total clearance 152 +- 25.2 mL/min, and AUC 217 +- 34 mg*h/L. There was no statistical difference between day 1 and day 3 for any of the pharmacokinetic parameters.

Answer: accept

At

day

t

beta

was

h

V

ss

L

kg

total

clearance

mL

min

and

AUC

mg

h

L

There

was

no

statistical

difference

between

day

and

day

for

any

of

the

pharmacokinetic

parameters


Dose-normalized geometric mean ratios for Cmax and AUC showed that abiraterone exposure decreased dose-proportionally at 750 mg (90 % confidence interval within 80–125 %) but not at 500 or 250 mg (Table 3).

Answer: accept

Dose

normalized

geometric

mean

ratios

for

Cmax

and

AUC

showed

that

abiraterone

exposure

decreased

dose

proportionally

at

mg

confidence

interval

within

but

not

at

or

mg

Table


The flow rate was 1 ml/min at the column temperature 45 degrees C. In these chromatographic conditions, the retention times were 2.3 min for O-desmethyltramadol and 3.5 min for tramadol, respectively.

Answer: accept

The

flow

rate

was

ml

min

at

the

column

temperature

degrees

C

In

these

chromatographic

conditions

the

retention

times

were

min

for

O

desmethyltramadol

and

min

for

tramadol

respectively


Mean plasma half-life for healthy foals < 24 hours old was 8.5 hours.

Answer: accept

Mean

plasma

half

life

for

healthy

foals

hours

old

was

hours


We investigated the relationship between methotrexate Cpss, methotrexate 42-h concentration, targeting success (Cpss ±20 % of target), leucovorin dose, methotrexate delayed excretion, and risk of gastrointestinal toxicity.

Answer: accept

We

investigated

the

relationship

between

methotrexate

Cpss

methotrexate

h

concentration

targeting

success

Cpss

of

target

leucovorin

dose

methotrexate

delayed

excretion

and

risk

of

gastrointestinal

toxicity


The AUC values obtained were also higher at 4.35 +- 1.31 microg h/ml and 5.34 +- 0.95 microg h/ml with Eud L and Eud S capsules, respectively.

Answer: accept

The

AUC

values

obtained

were

also

higher

at

microg

h

ml

and

microg

h

ml

with

Eud

L

and

Eud

S

capsules

respectively


The aminoglycoside clearance was 5.47 L/h.

Answer: accept

The

aminoglycoside

clearance

was

L

h


Results
Paclitaxel Pharmacokinetics
Unbound Concentrations of Paclitaxel

After 1.5 h the curves tended to separate and resulted in a mean AUC0–10h,u of 580 ± 172 h × ng/ml after nab-paclitaxel while it was 646 ± 154 h × ng/ml after paclitaxel micellar.

Answer: accept

After

h

the

curves

tended

to

separate

and

resulted

in

a

mean

AUC

h

u

of

h

ng

ml

after

nab

paclitaxel

while

it

was

h

ng

ml

after

paclitaxel

micellar


The linear relationship between the computed log Kvow and terminal elimination half-life was particularly strong, R2 = 0.99 and F = 467, and can be interpreted in terms of a simple pharmacokinetic model.

Answer: accept

The

linear

relationship

between

the

computed

log

Kvow

and

terminal

elimination

half

life

was

particularly

strong

R

and

F

and

can

be

interpreted

in

terms

of

a

simple

pharmacokinetic

model


Plasma clearances of theophylline and antipyrine were significantly correlated (p less than 0.05, r = 0.693, n = 10).

Answer: accept

Plasma

clearances

of

theophylline

and

antipyrine

were

significantly

correlated

p

less

than

r

n


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

However, 1 and 2 mg/kg treated rats were significantly more active than VEH at both the 15 min testing-onset, minimum t(11) = 2.98, p = 0.00 (Figure 4A), and at the 60 min testing-onset after 1 mg/kg (bins 4–6: minimum t(18) = 2.54, p = 0.02), and after 2 mg/kg (bins 2–5: minimum t(18) = 2.11, p = 0.05 (Figure 4B).

Answer: accept

However

and

mg

kg

treated

rats

were

significantly

more

active

than

VEH

at

both

the

min

testing

onset

minimum

t

p

Figure

A

and

at

the

min

testing

onset

after

mg

kg

bins

minimum

t

p

and

after

mg

kg

bins

minimum

t

p

Figure

B


Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios.

Answer: accept

Food

had

negligible

effects

on

bioavailability

as

assessed

by

confidence

intervals

for

Cmax

and

AUC

mean

ratios


The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg.

Answer: accept

The

AUC

and

the

cumulative

urinary

excretion

were

directly

proportional

to

dose

within

the

range

of

mg


Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia.

Answer: accept

Simulations

were

performed

to

illustrate

target

attainment

and

variability

of

paracetamol

exposure

following

current

dosing

regimens

mg

every

h

every

h

using

steady

state

concentration

Css

mean

of

mg

l

as

target

for

effective

analgesia


The mean values for terminal half life, steady state volume of distribution Vd(ss), renal clearance (ClR) and total body clearance (ClB) for cefaronide were 1.5 h, 0.39 l/kg, 0.06 l/h/kg and 0.16 l/h/kg, for ceftriaxone; 1.7 h, 0.30 l/kg, 0.08 l/h/kg, and 0.22 l/h/kg, and 0.7 h, 0.16 l/kg, 0.02 l/h/kg and 0.16 l/h/kg for cefoperazone, respectively.

Answer: accept

The

mean

values

for

terminal

half

life

steady

state

volume

of

distribution

Vd

ss

renal

clearance

ClR

and

total

body

clearance

ClB

for

cefaronide

were

h

l

kg

l

h

kg

and

l

h

kg

for

ceftriaxone

h

l

kg

l

h

kg

and

l

h

kg

and

h

l

kg

l

h

kg

and

l

h

kg

for

cefoperazone

respectively


The point estimates (ratios of geometric mean %) were 107.73 (96.57–120.17), 103.61 (94.03–114.16), and 104.23 (94.84–114.54) for peak plasma concentration (Cmax), Area Under the Curve (AUC)0→last, and AUC0→∞, respectively.

Answer: accept

The

point

estimates

ratios

of

geometric

mean

were

and

for

peak

plasma

concentration

Cmax

Area

Under

the

Curve

AUC

last

and

AUC

respectively


The global variability of CL/F, after accounting for variability to variation of body weight and serum creatinine, was about 50%, with 20% due to interindividual variability and 30% due to interoccasion variability.

Answer: accept

The

global

variability

of

CL

F

after

accounting

for

variability

to

variation

of

body

weight

and

serum

creatinine

was

about

with

due

to

interindividual

variability

and

due

to

interoccasion

variability


The mean (± SD) relative bioavailability (PO compared to IM) was 83 ± 20% and 63 ± 23% for S-ketoprofen and R-ketoprofen, respectively.

Answer: accept

The

mean

SD

relative

bioavailability

PO

compared

to

IM

was

and

for

S

ketoprofen

and

R

ketoprofen

respectively


The typical value for the terminal elimination half-life was 3.94 days, suggesting that T-DM1 conjugate does not accumulate after repeated q3w dosing, and steady state is reached during the first cycle.

Answer: accept

The

typical

value

for

the

terminal

elimination

half

life

was

days

suggesting

that

T

DM

conjugate

does

not

accumulate

after

repeated

q

w

dosing

and

steady

state

is

reached

during

the

first

cycle


In Vitro Pharmacokinetic Assays and IVIVE Modeling

To incorporate pharmacokinetics into the framework, data from in vitro hepatic metabolic clearance and plasma protein binding assays are included in the Tier 1 data package.

Answer: accept

To

incorporate

pharmacokinetics

into

the

framework

data

from

in

vitro

hepatic

metabolic

clearance

and

plasma

protein

binding

assays

are

included

in

the

Tier

data

package


Simulations of ddI concentration-time profiles in human tissues using the two models showed that pancreas and lymph nodes received about 2- to 30-fold higher ddI concentration than spleen and brain, and that coadministration of pentamidine increased the AUC of ddI in the pancreas by 20%.

Answer: accept

Simulations

of

ddI

concentration

time

profiles

in

human

tissues

using

the

two

models

showed

that

pancreas

and

lymph

nodes

received

about

to

fold

higher

ddI

concentration

than

spleen

and

brain

and

that

coadministration

of

pentamidine

increased

the

AUC

of

ddI

in

the

pancreas

by


However, the significant decrease in [p-HPPH] (61% when compared with NM/NM group) could only be compatible with a lower bioavailability of p-HPPH since its clearance should remain unchanged because of the constancy in CYP2C19 activity (NM and NM).

Answer: accept

However

the

significant

decrease

in

p

HPPH

when

compared

with

NM

NM

group

could

only

be

compatible

with

a

lower

bioavailability

of

p

HPPH

since

its

clearance

should

remain

unchanged

because

of

the

constancy

in

CYP

C

activity

NM

and

NM


The simulated clearances, which were based on changes in weight using the modified Marsh and Schnider models, are shown in Fig. 2.

Answer: accept

The

simulated

clearances

which

were

based

on

changes

in

weight

using

the

modified

Marsh

and

Schnider

models

are

shown

in

Fig


Including random effects for Q3 and V3 resulted in a drop in OFV of 62 and 96, respectively and allowing a full block covariance structure between random effects (excluding the correlation between CL and V1) further improved the model.

Answer: accept

Including

random

effects

for

Q

and

V

resulted

in

a

drop

in

OFV

of

and

respectively

and

allowing

a

full

block

covariance

structure

between

random

effects

excluding

the

correlation

between

CL

and

V

further

improved

the

model


Results
Single-dose serum PK in infected mice

In both doses, the 90% confidence intervals for the ratio of the natural logarithm of the AUC for the generics (test) relative to the innovator (reference) ranged from 0.91 to 1.08, indicating that all three generics were bioequivalents of the innovator.

Answer: accept

In

both

doses

the

confidence

intervals

for

the

ratio

of

the

natural

logarithm

of

the

AUC

for

the

generics

test

relative

to

the

innovator

reference

ranged

from

to

indicating

that

all

three

generics

were

bioequivalents

of

the

innovator


Determination of maximum tolerable doses

When we repeated the same experiments at 25 mg/kg, no seizures were seen and the glucose level of each animal remained within normal limits at both Cmax and Cmin.

Answer: accept

When

we

repeated

the

same

experiments

at

mg

kg

no

seizures

were

seen

and

the

glucose

level

of

each

animal

remained

within

normal

limits

at

both

Cmax

and

Cmin


Results and discussion
Pharmacokinetic study

1.30-fold and 1.43-fold increase in AUC0-12 (Brain) of TMP were observed when combined administrated with borneol or α-asarone.

Answer: accept

fold

and

fold

increase

in

AUC

Brain

of

TMP

were

observed

when

combined

administrated

with

borneol

or

α

asarone


Mean trough concentrations were 7.9 +- 1.4 microg/mL with carbamazepine alone, and 6.5 +- 2.0 microg/mL with carbamazepine-vigabatrin association (P < 0.03).

Answer: accept

Mean

trough

concentrations

were

microg

mL

with

carbamazepine

alone

and

microg

mL

with

carbamazepine

vigabatrin

association

P


The detection of pharmacokinetic parameters

The peak concentration (Cmax) was 158.429 ± 32.453 ug/mL. The elimination half-life (t1/2β) was 56.270 ± 15.398 h and the mean residence time (MRT) after administration was 37.441 ± 13.349 h.

Answer: accept

The

peak

concentration

Cmax

was

ug

mL

The

elimination

half

life

t

β

was

h

and

the

mean

residence

time

MRT

after

administration

was

h


We observed similar test characteristics for a target Cmax target of 6.6 mg/L, and a target area under the drug concentration-versus-time curve (AUC0–8) target of 24.1 mg•hour/L.

Answer: accept

We

observed

similar

test

characteristics

for

a

target

Cmax

target

of

mg

L

and

a

target

area

under

the

drug

concentration

versus

time

curve

AUC

target

of

mg

hour

L


2.3. Effects of Piperine, Capsaicin and [6]-Gingerol on Tissue Distribution of Doxorubicin

Doxorubicin was extensively distributed into the kidney, lung, heart and liver with Kp values of >35.4, whereas distribution into the testis and brain was lower.

Answer: accept

Doxorubicin

was

extensively

distributed

into

the

kidney

lung

heart

and

liver

with

Kp

values

of

whereas

distribution

into

the

testis

and

brain

was

lower


Using a two-compartment model, the median pharmacokinetic parameter estimates (ranges) were as follows: volume of distribution, 0.34 (0. 27 to 0.36) liter/kg; clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life, 3.6 (3.5 to 4.9) h.

Answer: accept

Using

a

two

compartment

model

the

median

pharmacokinetic

parameter

estimates

ranges

were

as

follows

volume

of

distribution

to

liter

kg

clearance

to

liters

h

elimination

half

life

to

h


The results from this assay for 40 compounds correlated with in vivo plasma clearance (r = 0.57).

Answer: accept

The

results

from

this

assay

for

compounds

correlated

with

in

vivo

plasma

clearance

r


The area under the plasma concentration-time curve (AUC) showed that TP accounted for 91 +- 4% (mean +- SD) of the total AUC in plasma with 1,3-U accounting for 3.1 +- 1.4%, 3-X for 3.4 +- 1.8% and 1-U for 2.5 +- 1.5%.

Answer: accept

The

area

under

the

plasma

concentration

time

curve

AUC

showed

that

TP

accounted

for

mean

SD

of

the

total

AUC

in

plasma

with

U

accounting

for

X

for

and

U

for


The transdermal clearance of nicotine, 1351 ml/min, coincided with reported values following intravenous nicotine administration; however, the terminal-phase half-life, 5.0 hr, did not.

Answer: accept

The

transdermal

clearance

of

nicotine

ml

min

coincided

with

reported

values

following

intravenous

nicotine

administration

however

the

terminal

phase

half

life

hr

did

not


The clearance of ranitidine from plasma (y) was correlated with creatinine clearance (x): y = 10.47 + 0.289x,r2 = 0.751, but there was no significant correlation of creatinine clearance with distribution volume or bioavailability.

Answer: accept

The

clearance

of

ranitidine

from

plasma

y

was

correlated

with

creatinine

clearance

x

y

x

r

but

there

was

no

significant

correlation

of

creatinine

clearance

with

distribution

volume

or

bioavailability


Oral absorption was slow an erratic, with fourfold individual variations in systemic bioavailability (22-86%).

Answer: accept

Oral

absorption

was

slow

an

erratic

with

fourfold

individual

variations

in

systemic

bioavailability


The pharmacokinetic parameters of bosentan did not differ significantly between the study groups: geometric means (95% confidence interval) for Cmax were 1.8 (1.2 - 2.8) and 1.1 microg/ml (0.74 - 1.7), and for AUC0-infinity 7.2 (5.1 - 10.4) and 6.4 (3.4 - 11.2) microg x h/ml in healthy subjects and renal patients, respectively.

Answer: accept

The

pharmacokinetic

parameters

of

bosentan

did

not

differ

significantly

between

the

study

groups

geometric

means

confidence

interval

for

Cmax

were

and

microg

ml

and

for

AUC

infinity

and

microg

x

h

ml

in

healthy

subjects

and

renal

patients

respectively


The large volumes of distribution of these compounds (4.3 l/kg for EAPB0203 and 2.5 l/kg for EAPB0503) were consistent with extensive tissue binding.

Answer: accept

The

large

volumes

of

distribution

of

these

compounds

l

kg

for

EAPB

and

l

kg

for

EAPB

were

consistent

with

extensive

tissue

binding


The peak serum concentration of rh-activin A (104.7 ng/ml) was achieved 24.7 min after sc delivery of the drug.

Answer: accept

The

peak

serum

concentration

of

rh

activin

A

ng

ml

was

achieved

min

after

sc

delivery

of

the

drug


Estimates of kinetic variables following IV administration were: Vss= 400.0+-120.0 mL/kg and CL= 110.0+-14.0 (mL/h)/kg.

Answer: accept

Estimates

of

kinetic

variables

following

IV

administration

were

Vss

mL

kg

and

CL

mL

h

kg


Test 2, effects of sample-subset selection on model parameters

Test 2 uses subsets of actual sample concentrations to build up histograms of parameter values (or derived quantities such as CL and V) when all, or less than all, of the samples are used for fitting.

Answer: accept

Test

uses

subsets

of

actual

sample

concentrations

to

build

up

histograms

of

parameter

values

or

derived

quantities

such

as

CL

and

V

when

all

or

less

than

all

of

the

samples

are

used

for

fitting


This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 +- 3.4 vs. 4.7 +- 1.4; P less than 0.01).

Answer: accept

This

resulted

in

a

significantly

greater

enantiomeric

oral

clearance

ratio

in

the

young

when

compared

with

the

elderly

subjects

vs

P

less

than


Zolpidem clearance was estimated at 0.03 L·h(-1)·kg(-1) (relative standard error, 55%) and increased with body weight (P < 0.05).

Answer: accept

Zolpidem

clearance

was

estimated

at

L

h

kg

relative

standard

error

and

increased

with

body

weight

P


For ilaprazole, the peak concentration (Cmax) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70–1.22)].

Answer: accept

For

ilaprazole

the

peak

concentration

Cmax

slightly

decreased

from

ilaprazole

alone

to

ng

mL

triple

therapy

Geometric

least

square

mean

ratio

confidence

interval


Unbound darunavir AUC24h was 20-24% lower during pregnancy vs. postpartum.

Answer: accept

Unbound

darunavir

AUC

h

was

lower

during

pregnancy

vs

postpartum


Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin, a substrate for CYP3A4 and Pgp, in rats and pigs.

Answer: accept

Our

previous

study

reported

that

quercetin

significantly

decreased

the

bioavailability

of

cyclosporin

a

substrate

for

CYP

A

and

Pgp

in

rats

and

pigs


Most patients had an antibody response to 17-1A, with peak levels occurring 15-22 days after infusion.

Answer: accept

Most

patients

had

an

antibody

response

to

A

with

peak

levels

occurring

days

after

infusion


The terminal half-life is 15.4 days [5].

Answer: accept

The

terminal

half

life

is

days


Maximum plasma concentrations of 11.7 micrograms ml-1 were reached after an average of 3 h. 6 After oral administration isoxicam was completely bioavailable.

Answer: accept

Maximum

plasma

concentrations

of

micrograms

ml

were

reached

after

an

average

of

h

After

oral

administration

isoxicam

was

completely

bioavailable


The only significant difference for VEGFa can be observed on day 7 post-lesion which shows increased values compared to the baseline (day 0) and days 14 and 82.

Answer: accept

The

only

significant

difference

for

VEGFa

can

be

observed

on

day

post

lesion

which

shows

increased

values

compared

to

the

baseline

day

and

days

and


The pharmacokinetic experiments showed that after administration of amoxicillin, the area under the salicylic acid curve increased by 91.38%, the peak concentration increased by 60.43%, and the clearance rate decreased by 43.55%.The results demonstrated that amoxicillin affected the pharmacokinetics of aspirin active metabolite salicylic acid by slowing down the metabolic activity of intestinal flora on aspirin.

Answer: accept

The

pharmacokinetic

experiments

showed

that

after

administration

of

amoxicillin

the

area

under

the

salicylic

acid

curve

increased

by

the

peak

concentration

increased

by

and

the

clearance

rate

decreased

by

The

results

demonstrated

that

amoxicillin

affected

the

pharmacokinetics

of

aspirin

active

metabolite

salicylic

acid

by

slowing

down

the

metabolic

activity

of

intestinal

flora

on

aspirin


Although the mean Cpeak and Ctrough values were above the activity threshold of 0.5 µg/ml, 10 of the 26 patients did not reach the threshold within 24 h after the first administration and 2 of the 26 patients never reached the threshold in the first week of erlotinib therapy.

Answer: accept

Although

the

mean

Cpeak

and

Ctrough

values

were

above

the

activity

threshold

of

µ

g

ml

of

the

patients

did

not

reach

the

threshold

within

h

after

the

first

administration

and

of

the

patients

never

reached

the

threshold

in

the

first

week

of

erlotinib

therapy


The AUC0-inf for fentanyl and the low and high dose buprenorphine patches were 115 ± 14, 462 ± 74, and 778 ± 344 ng× h/mL, and the plasma half-lifes were 22 ± 4, 77 ± 27, and 42 ± 11 h, respectively.

Answer: accept

The

AUC

inf

for

fentanyl

and

the

low

and

high

dose

buprenorphine

patches

were

and

ng

h

mL

and

the

plasma

half

lifes

were

and

h

respectively


The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet.

Answer: accept

The

half

lives

of

EE

and

GSD

of

the

patch

were

and

times

respectively

than

the

half

life

of

the

tablet


Bosentan reduced the area under the concentration-versus-time curve of glyburide approximately 40% (P <.05).

Answer: accept

Bosentan

reduced

the

area

under

the

concentration

versus

time

curve

of

glyburide

approximately

P


The Spearman correlations between AEs and age, body weight or MPA-AUC0-12h were 0.29, 0.24, and 0.12, respectively.

Answer: accept

The

Spearman

correlations

between

AEs

and

age

body

weight

or

MPA

AUC

h

were

and

respectively


The systemic clearance of HI-240 was 2194 +- 61 ml/h/kg after i.v. administration and 9339 +- 1160 ml/h/kg after i.p. administration.

Answer: accept

The

systemic

clearance

of

HI

was

ml

h

kg

after

i

v

administration

and

ml

h

kg

after

i

p

administration


The preMM pellets had the fastest redispersibility among the preparations, and thus had the highest Cmax, A∪C0–t, and A∪C0–∞ values, reaching 0.874 ± 0.395 μg/mL, 4.123 ± 2.263 μg/mL ⋅ hour, and 7.200 ± 5.347 μg/mL ⋅ hour, respectively.

Answer: accept

The

preMM

pellets

had

the

fastest

redispersibility

among

the

preparations

and

thus

had

the

highest

Cmax

A

C

t

and

A

C

values

reaching

μ

g

mL

μ

g

mL

hour

and

μ

g

mL

hour

respectively


The area under the serum levels-time curve from 0 to 24 h was 103 +- 14 micrograms/h/ml after the first dose.

Answer: accept

The

area

under

the

serum

levels

time

curve

from

to

h

was

micrograms

h

ml

after

the

first

dose


Cilostazol inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibitory concentration (IC(50)) of 8.7 μM. Compared with the control group, the area under the plasma concentration-time curve (AUC) of carvedilol was significantly (P < 0.05) increased by 38.0%.

Answer: accept

Cilostazol

inhibited

CYP

C

activity

in

a

concentration

dependent

manner

with

inhibitory

concentration

IC

of

μ

M

Compared

with

the

control

group

the

area

under

the

plasma

concentration

time

curve

AUC

of

carvedilol

was

significantly

P

increased

by


For doses ranging from 1 to 6 mg kg−1, mean CL was ~1.1–1.6-fold higher on Day 1 (vs Day 29), whereas mean T1/2 increased ~1.2–2.3-fold and exposure (AUC0–168) increased ~1.3–1.8-fold on Day 29 vs Day 1 (Table 3).

Answer: accept

For

doses

ranging

from

to

mg

kg

mean

CL

was

fold

higher

on

Day

vs

Day

whereas

mean

T

increased

fold

and

exposure

AUC

increased

fold

on

Day

vs

Day

Table


Pharmacokinetics and oral bioavailability of β-lapachone

Approximately 30 min after the administration, most β-lapachone was disappeared from the systemic circulation with a half-life of 2.48 h. Following oral administration of 40 mg/kg β-lapachone, the greatest plasma concentration of 0.218 mg/ml was achieved at 6 h. The calculated AUC(0-∞) was determined to be 4.866 mg·h/ml.

Answer: accept

Approximately

min

after

the

administration

most

β

lapachone

was

disappeared

from

the

systemic

circulation

with

a

half

life

of

h

Following

oral

administration

of

mg

kg

β

lapachone

the

greatest

plasma

concentration

of

mg

ml

was

achieved

at

h

The

calculated

AUC

was

determined

to

be

mg

h

ml


4.5. Pharmacokinetics of Furosemide in Neonates

When t1/2 was >24 h, tubular secretion accounted for 13.3 ± 19.2% of total Cl.

Answer: accept

When

t

was

h

tubular

secretion

accounted

for

of

total

Cl


Patients of group B received 6 ml/kg/h Plasmalyte A. Hemodynamic parameters MAP, HR and CVP were collected at 6 set points during the surgery: T1: before AHH; T2: before anesthesia induction; T3: right intubation; T4: 10 min after intubation; T5: 20 min after intubation; T6: skin incision.

Answer: accept

Patients

of

group

B

received

ml

kg

h

Plasmalyte

A

Hemodynamic

parameters

MAP

HR

and

CVP

were

collected

at

set

points

during

the

surgery

T

before

AHH

T

before

anesthesia

induction

T

right

intubation

T

min

after

intubation

T

min

after

intubation

T

skin

incision


The fraction of oral absorption (BA) was calculated according to Equation 1.

Answer: accept

The

fraction

of

oral

absorption

BA

was

calculated

according

to

Equation


Radioactivity disappeared exponentially from administration site at a rate constant of 0.46 day-1, corresponding to a half-life of 1.5 days.

Answer: accept

Radioactivity

disappeared

exponentially

from

administration

site

at

a

rate

constant

of

day

corresponding

to

a

half

life

of

days


The average bioavailability for the 100- and 300-mg tablets was 98 +- 0.03% (S.E.M.).

Answer: accept

The

average

bioavailability

for

the

and

mg

tablets

was

S

E

M


For each subject, the following single‐ and multiple‐dose pharmacokinetic parameters were derived from the total plasma and urine concentrations of AZL and M‐II on days 1 and 8 unless otherwise noted: area under the plasma concentration–time curve (AUC) from time 0 extrapolated to infinity (AUC∞; day 1 only), AUC from time 0 to tau (AUCτ) over a dosing interval, where τ was the length of the dosing interval (τ = 24 hours; day 8 only), AUC from time 0 to 24 hours (AUC24; day 1 only), maximum observed plasma concentration (Cmax), tmax, terminal elimination rate constant (λz; day 1 only), termination t1/2 (day 1 only), fraction of AZL and M‐II with molecular‐weight adjustment from AZL‐M excreted in urine from 0 to 72 hours on day 1 or 0 to 24 hours on day 8 (fe/F), total amount of AZL or M‐II excreted in urine over the collection interval postdose (Aet), calculated for the metabolite individually, where t = 72 on day 1 or 24 on day 8; renal clearance (CLR) of AZL and M‐II, calculated as total amount of drug excreted in urine from 0 to 72 hours on day 1 or total amount of drug excreted in urine from 0 to 24 hours on day 8 divided by AUC∞ on day 1 or AUCτ on day 8.

Answer: accept

For

each

subject

the

following

single

and

multiple

dose

pharmacokinetic

parameters

were

derived

from

the

total

plasma

and

urine

concentrations

of

AZL

and

M

II

on

days

and

unless

otherwise

noted

area

under

the

plasma

concentration

time

curve

AUC

from

time

extrapolated

to

infinity

AUC

day

only

AUC

from

time

to

tau

AUC

τ

over

a

dosing

interval

where

τ

was

the

length

of

the

dosing

interval

τ

hours

day

only

AUC

from

time

to

hours

AUC

day

only

maximum

observed

plasma

concentration

Cmax

tmax

terminal

elimination

rate

constant

λ

z

day

only

termination

t

day

only

fraction

of

AZL

and

M

II

with

molecular

weight

adjustment

from

AZL

M

excreted

in

urine

from

to

hours

on

day

or

to

hours

on

day

fe

F

total

amount

of

AZL

or

M

II

excreted

in

urine

over

the

collection

interval

postdose

Aet

calculated

for

the

metabolite

individually

where

t

on

day

or

on

day

renal

clearance

CLR

of

AZL

and

M

II

calculated

as

total

amount

of

drug

excreted

in

urine

from

to

hours

on

day

or

total

amount

of

drug

excreted

in

urine

from

to

hours

on

day

divided

by

AUC

on

day

or

AUC

τ

on

day


Among subgroups, the MDRD formula was a significantly better predictor of aminoglycoside clearance for patients with an estimated GFR less than 60 mL/min (p = 0.027).

Answer: accept

Among

subgroups

the

MDRD

formula

was

a

significantly

better

predictor

of

aminoglycoside

clearance

for

patients

with

an

estimated

GFR

less

than

mL

min

p


On day 1 the mean values (with interindividual variability as expressed by the coefficient of variation) were 1390 mg x h(-1) (20%), and 5.57 mg x L(-1) (22%) for the maximum rate of elimination, and the half-saturating plasma concentration.

Answer: accept

On

day

the

mean

values

with

interindividual

variability

as

expressed

by

the

coefficient

of

variation

were

mg

x

h

and

mg

x

L

for

the

maximum

rate

of

elimination

and

the

half

saturating

plasma

concentration


Differences in nivolumab baseline clearance and exposures between patients with NPC and NSCLC were not clinically meaningful (<20%).

Answer: accept

Differences

in

nivolumab

baseline

clearance

and

exposures

between

patients

with

NPC

and

NSCLC

were

not

clinically

meaningful


An analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) data base of 118,465 patients hospitalized with AHF showed that 91% of patients had some degree of renal dysfunction, of whom 64% had at least a moderate renal dysfunction.6 In the Pre‐RELAX‐AHF and RELAX‐AHF trials, the analyses of serelaxin systemic clearance in patients with renal dysfunction indicated no clinically relevant impact of impaired renal function on the pharmacokinetics (PK) of serelaxin.

Answer: accept

An

analysis

of

the

Acute

Decompensated

Heart

Failure

National

Registry

ADHERE

data

base

of

patients

hospitalized

with

AHF

showed

that

of

patients

had

some

degree

of

renal

dysfunction

of

whom

had

at

least

a

moderate

renal

dysfunction

In

the

Pre

RELAX

AHF

and

RELAX

AHF

trials

the

analyses

of

serelaxin

systemic

clearance

in

patients

with

renal

dysfunction

indicated

no

clinically

relevant

impact

of

impaired

renal

function

on

the

pharmacokinetics

PK

of

serelaxin


Calculated averages of Tmax were 2.2 ± 0.3 and 5.9 ± 0.5 min; while for T1/2 were 3.1 ± 0.3 and 8.4 ± 0.6 min for control and sulfa-treated rabbits, respectively (n = 20; P < 0.05).

Answer: accept

Calculated

averages

of

Tmax

were

and

min

while

for

T

were

and

min

for

control

and

sulfa

treated

rabbits

respectively

n

P


The absolute oral bioavailability of hederasaponin B was 0.24 ± 0.49%.

Answer: accept

The

absolute

oral

bioavailability

of

hederasaponin

B

was


The mean maximum plasma concentrations (Cmax ) of MPA in the CsA and Tac groups were 11.365 ± 9.522 and 9.748 ± 7.523 μg/ml, respectively (p = 0.137).

Answer: accept

The

mean

maximum

plasma

concentrations

Cmax

of

MPA

in

the

CsA

and

Tac

groups

were

and

μ

g

ml

respectively

p


DTX-NPs showed a sustained release over 24 h in phosphate-buffered saline and simulated gastric and intestinal fluids, while DTX-micelles released DTX completely within 12 h. The half-maximal inhibitory concentration (IC50) of DTX-NPs against human breast cancer MCF-7 cells was 1.9 times lower than that of DTX-micelles and DTX solution.

Answer: accept

DTX

NPs

showed

a

sustained

release

over

h

in

phosphate

buffered

saline

and

simulated

gastric

and

intestinal

fluids

while

DTX

micelles

released

DTX

completely

within

h

The

half

maximal

inhibitory

concentration

IC

of

DTX

NPs

against

human

breast

cancer

MCF

cells

was

times

lower

than

that

of

DTX

micelles

and

DTX

solution


Only the 14 and 29 mg Vuse Solo ECs were rated higher than nicotine gum (LS mean Emax = 5.47, p < 0.05 for both); the 36 mg Vuse Solo EC was not rated as significantly different from nicotine gum.

Answer: accept

Only

the

and

mg

Vuse

Solo

ECs

were

rated

higher

than

nicotine

gum

LS

mean

Emax

p

for

both

the

mg

Vuse

Solo

EC

was

not

rated

as

significantly

different

from

nicotine

gum


Compared to controls, the mean half-life of this group was increased from 10.9 +- 2.4 to 19.9 +- 9.5 h (mean +- s.d.; P less than or equal to 0.05) and clearance reduced from 3.81 +- 0.74 to 2.18 +- 0.80 l h-1 (P less than or equal to 0.01).

Answer: accept

Compared

to

controls

the

mean

half

life

of

this

group

was

increased

from

to

h

mean

s

d

P

less

than

or

equal

to

and

clearance

reduced

from

to

l

h

P

less

than

or

equal

to


For males, the peak concentration at 9.71 +- 5.94 h was 23.89 +- 5.46 micrograms/ml and that for females was 21.46 +- 5.08 micrograms/ml at 7.71 +- 3.73 h, respectively.

Answer: accept

For

males

the

peak

concentration

at

h

was

micrograms

ml

and

that

for

females

was

micrograms

ml

at

h

respectively


Results
Therapeutic effects of Asp-DOX in vivo

More importantly, after 17 days of treatment with Asp-DOX, the tumor volumes showed shrinkage, which indicated a good prognosis in LAT1-positive HepG2 tumors.

Answer: accept

More

importantly

after

days

of

treatment

with

Asp

DOX

the

tumor

volumes

showed

shrinkage

which

indicated

a

good

prognosis

in

LAT

positive

HepG

tumors


Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

Answer: accept

Compound

was

highly

potent

versus

PDE

A

IC

nM

demonstrated

high

selectivity

fold

against

other

PDEs

and

was

efficacious

when

dosed

orally

in

a

rat

model

of

psychosis

PCP

induced

hyperlocomotion

with

an

EC

of

mg

kg


Its half life is about three hours when administered intravenously which requires continuous infusion whereas subcutaneous administration can ensure stable plasma concentrations and antithrombotic activity over a period of approximatively 12 hours.

Answer: accept

Its

half

life

is

about

three

hours

when

administered

intravenously

which

requires

continuous

infusion

whereas

subcutaneous

administration

can

ensure

stable

plasma

concentrations

and

antithrombotic

activity

over

a

period

of

approximatively

hours


There was a trend toward higher Cmax in children <4 years [GM = 1.9 mg/L (95% confidence interval: 1.7–2.1)] vs. >4 years

Answer: accept

There

was

a

trend

toward

higher

Cmax

in

children

years

GM

mg

L

confidence

interval

vs

years


Statistical Methods and Pharmacokinetic Evaluations

The primary pharmacokinetic end-points for determination of drug–drug interaction were natural log (ln)-transformed AUC0–24 and maximum plasma concentration (Cmax) for atorvastatin, 2-hydroxyatorvastatin, and 4-hydroxyatorvastatin when administered at steady state either without or with icosapent ethyl (days 7 and 35, respectively).

Answer: accept

The

primary

pharmacokinetic

end

points

for

determination

of

drug

drug

interaction

were

natural

log

ln

transformed

AUC

and

maximum

plasma

concentration

Cmax

for

atorvastatin

hydroxyatorvastatin

and

hydroxyatorvastatin

when

administered

at

steady

state

either

without

or

with

icosapent

ethyl

days

and

respectively


The AUC and Cmax were 29% and 56% higher, respectively, for GBP-GR in comparison to GEn; however, following dose normalization, the AUC and Cmax were actually 45% and 54% lower, respectively, for GBP-GR in comparison to GEn (Figure 4A, B).

Answer: accept

The

AUC

and

Cmax

were

and

higher

respectively

for

GBP

GR

in

comparison

to

GEn

however

following

dose

normalization

the

AUC

and

Cmax

were

actually

and

lower

respectively

for

GBP

GR

in

comparison

to

GEn

Figure

A

B


The resulting free in vivo IC50 (0.081 μmol/L) showed a 62% interindividual variability which is substantially lower than for human.

Answer: accept

The

resulting

free

in

vivo

IC

μ

mol

L

showed

a

interindividual

variability

which

is

substantially

lower

than

for

human


The mean area under the inhibition time curve (extrapolated to infinity) increased from 2490%.h in subjects with normal renal function to 42241 %.h in patients with severe renal impairment.

Answer: accept

The

mean

area

under

the

inhibition

time

curve

extrapolated

to

infinity

increased

from

h

in

subjects

with

normal

renal

function

to

h

in

patients

with

severe

renal

impairment


Cotreatment with AlOH/MgOH resulted in greater decreases in riociguat bioavailability (mean decreases in AUC and C max were 34% and 56%, respectively).

Answer: accept

Cotreatment

with

AlOH

MgOH

resulted

in

greater

decreases

in

riociguat

bioavailability

mean

decreases

in

AUC

and

C

max

were

and

respectively


The novel dosage form is stable in vitro (t1/2 4 degree C = 187 days) as well as in vivo and, thus, may be successfully used in the therapy of carnitine deficiency, for instance in patients with renal failure or liver disease.

Answer: accept

The

novel

dosage

form

is

stable

in

vitro

t

degree

C

days

as

well

as

in

vivo

and

thus

may

be

successfully

used

in

the

therapy

of

carnitine

deficiency

for

instance

in

patients

with

renal

failure

or

liver

disease


A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~ 30% of the variability RVA AUC0-24 .

Answer: accept

A

multivariate

model

performed

confirmed

SLCO

B

c

T

C

genotype

as

the

primary

factor

contributing

to

RVA

systemic

exposure

in

this

pediatric

cohort

accounting

for

of

the

variability

RVA

AUC


3. Results and Discussion
3.4. Linearity and LLOQ

The linear calibration curves were determined from the peak-area ratios (peak-area analyte/peak-area IS) versus concentration in human serum using a weighting factor (1/x2), varying linearly over the concentration range tested (20–2000 ng/mL).

Answer: accept

The

linear

calibration

curves

were

determined

from

the

peak

area

ratios

peak

area

analyte

peak

area

IS

versus

concentration

in

human

serum

using

a

weighting

factor

x

varying

linearly

over

the

concentration

range

tested

ng

mL


The highest [25(OH)D] in any non-pregnant participant was 164 nmol/L, whereas the maximum in any pregnant participant was 116 nmol/L. On average, pregnant women had slightly lower absolute Cmax, but the mean maximal rise in [25(OH)D] (i.e., ΔCmax) and AUC were similar in pregnant and non-pregnant women (Table 1).

Answer: accept

The

highest

OH

D

in

any

non

pregnant

participant

was

nmol

L

whereas

the

maximum

in

any

pregnant

participant

was

nmol

L

On

average

pregnant

women

had

slightly

lower

absolute

Cmax

but

the

mean

maximal

rise

in

OH

D

i

e

Δ

Cmax

and

AUC

were

similar

in

pregnant

and

non

pregnant

women

Table


The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively.

Answer: accept

The

i

p

and

s

c

bioavailabilities

were

about

and

respectively


Simulated median and the 95% prediction interval (2.5th–97.5th percentiles) of AUC24h and ΔUGE24h at steady state for each treatment are summarized in Table 4 and Figure 5.

Answer: accept

Simulated

median

and

the

prediction

interval

th

th

percentiles

of

AUC

h

and

Δ

UGE

h

at

steady

state

for

each

treatment

are

summarized

in

Table

and

Figure


Coadministration of etravirine with atazanavir/ritonavir 300/100 mg qd decreased atazanavir Cmin  by 18% (Table 2) and Cmax  and AUC24 h were relatively unchanged (Table 2) compared with atazanavir/ritonavir 300/100 mg qd alone.

Answer: accept

Coadministration

of

etravirine

with

atazanavir

ritonavir

mg

qd

decreased

atazanavir

Cmin

by

Table

and

Cmax

and

AUC

h

were

relatively

unchanged

Table

compared

with

atazanavir

ritonavir

mg

qd

alone


Patients with the CYP3A5*3 alleles showed higher dose-adjusted tacrolimus concentrations for 12 months and higher trough levels until 6 months after transplantation.

Answer: accept

Patients

with

the

CYP

A

alleles

showed

higher

dose

adjusted

tacrolimus

concentrations

for

months

and

higher

trough

levels

until

months

after

transplantation


Increases in C(max), AUC(0-t), C(max,ss), and AUC(ss) were observed with increasing single and multiple doses of rosuvastatin 5, 10, and 20 mg.

Answer: accept

Increases

in

C

max

AUC

t

C

max

ss

and

AUC

ss

were

observed

with

increasing

single

and

multiple

doses

of

rosuvastatin

and

mg


RESULTS
Pharmacodynamics
Pathway engagement—MIP‐1α and MIP‐1β

IC50 for MIP‐1β inhibition was similar to that for MIP‐1α (data not shown).

Answer: accept

IC

for

MIP

β

inhibition

was

similar

to

that

for

MIP

α

data

not

shown


For HBK-15, the terminal half-lives were 71 min after i.v. and 84 min after i.p. administration.

Answer: accept

For

HBK

the

terminal

half

lives

were

min

after

i

v

and

min

after

i

p

administration


The accumulation index for a drug with a half-life of 2 days given every 2–3 days should be approximately 2, in agreement with the 1.9-fold increase in AUC0–48 observed after the first dose compared to that after 4 weeks of dosing.

Answer: accept

The

accumulation

index

for

a

drug

with

a

half

life

of

days

given

every

days

should

be

approximately

in

agreement

with

the

fold

increase

in

AUC

observed

after

the

first

dose

compared

to

that

after

weeks

of

dosing


The maximum plasma concentation, area under the plasma concentration–time curve from time zero to infinity, and area under the plasma concentration–time curve from time zero to the time of the last measurable concentration were similar between treatment regimens; 90% confidence interval of the geometric least-squares means ratios were within the predefined 80–125% bioequivalence criterion.

Answer: accept

The

maximum

plasma

concentation

area

under

the

plasma

concentration

time

curve

from

time

zero

to

infinity

and

area

under

the

plasma

concentration

time

curve

from

time

zero

to

the

time

of

the

last

measurable

concentration

were

similar

between

treatment

regimens

confidence

interval

of

the

geometric

least

squares

means

ratios

were

within

the

predefined

bioequivalence

criterion


The method was validated over a concentration range of 1-3500 ng/mL and the lower limit of quantitation was determined to be 1 ng/mL. Validation of the assay demonstrated that the developed UPLC/MS/MS method was sensitive, accurate and selective for the determination of AZ66 in rat plasma.

Answer: accept

The

method

was

validated

over

a

concentration

range

of

ng

mL

and

the

lower

limit

of

quantitation

was

determined

to

be

ng

mL

Validation

of

the

assay

demonstrated

that

the

developed

UPLC

MS

MS

method

was

sensitive

accurate

and

selective

for

the

determination

of

AZ

in

rat

plasma


Effect of lopinavir-based ART on lumefantrine plasma concentrations following six-dose artemether-lumefantrine regimen (Phase 2)

However, the increase in exposure with mg/kg dose was only seen in the lopinavir group in whom the Cmax increased by 4.8 % (95%CI 0.9–8.6 %; p = 0.019) and the AUC(0-inf) increased by 5.4 % (95%CI 0.7–10.0 %; p = 0.026), respectively with each 1 mg/kg increase in lumefantrine dose (Fig. 2).

Answer: accept

However

the

increase

in

exposure

with

mg

kg

dose

was

only

seen

in

the

lopinavir

group

in

whom

the

Cmax

increased

by

CI

p

and

the

AUC

inf

increased

by

CI

p

respectively

with

each

mg

kg

increase

in

lumefantrine

dose

Fig


The absolute bioavailability and pharmacokinetics of three formulations of ondansetron hydrochloride 24 mg--an oral tablet, an intravenous solution, and an extemporaneous rectal suppository--were studied.

Answer: accept

The

absolute

bioavailability

and

pharmacokinetics

of

three

formulations

of

ondansetron

hydrochloride

mg

an

oral

tablet

an

intravenous

solution

and

an

extemporaneous

rectal

suppository

were

studied


These 2 pharmacokinetic parameters are critical for estimating steady-state blood concentrations.

Answer: accept

These

pharmacokinetic

parameters

are

critical

for

estimating

steady

state

blood

concentrations


Results
Pharmacokinetics and bioequivalence

For 60/360 mg and three standard tablet formulations, artemether was absorbed rapidly with median Tmax of 3.00 h (Table 2).

Answer: accept

For

mg

and

three

standard

tablet

formulations

artemether

was

absorbed

rapidly

with

median

Tmax

of

h

Table


Unchanged edoxaban was the most abundant species in plasma, with a mean area under the curve (AUC)(0-∞) of 1596 ng · h/ml.

Answer: accept

Unchanged

edoxaban

was

the

most

abundant

species

in

plasma

with

a

mean

area

under

the

curve

AUC

of

ng

h

ml


Blood data gave a half-life of 1.44+-0.33 h. Comparable but slightly more variable results were obtained using urine data corrected for voiding time (1.55+-0.67h) and breath data corrected for mucous membrane desorption (1.40+-0.38 h).

Answer: accept

Blood

data

gave

a

half

life

of

h

Comparable

but

slightly

more

variable

results

were

obtained

using

urine

data

corrected

for

voiding

time

h

and

breath

data

corrected

for

mucous

membrane

desorption

h


The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 95.38% to 105.94% (point estimate: 100.52%) for AUC(0-last), 94.01% to 103.47% (point estimate: 98.63%) for AUC(0-infinity) and 92.34% to 103.97% (point estimate: 97.98%) for Cmax, being within the acceptance criteria for bioequivalence (80%-125%).

Answer: accept

The

parametric

confidence

intervals

of

the

geometric

mean

values

of

the

test

reference

ratios

were

to

point

estimate

for

AUC

last

to

point

estimate

for

AUC

infinity

and

to

point

estimate

for

Cmax

being

within

the

acceptance

criteria

for

bioequivalence


Results and discussion
Metabolic stability

The in vitro intrinsic clearance values of NP046 in human and mouse liver microsomes were 118.7 μl/min/mg and 656.8 μl/min/mg, respectively, which are considered high and require a metabolism SAR optimization of NP046 to improve its metabolic stability.

Answer: accept

The

in

vitro

intrinsic

clearance

values

of

NP

in

human

and

mouse

liver

microsomes

were

μ

l

min

mg

and

μ

l

min

mg

respectively

which

are

considered

high

and

require

a

metabolism

SAR

optimization

of

NP

to

improve

its

metabolic

stability


In human liver microsomal incubation studies, the formation of 2-hydroxychlorpropamide (2-OH-chlorpropamide), a major chlorpropamide metabolite in human, has been best described by a one-enzyme model with estimated K(m) and V(max) of 121.7 +- 19.9 microm and 16.1 +- 5.0 pmol min(-1) mg(-1) protein, respectively.

Answer: accept

In

human

liver

microsomal

incubation

studies

the

formation

of

hydroxychlorpropamide

OH

chlorpropamide

a

major

chlorpropamide

metabolite

in

human

has

been

best

described

by

a

one

enzyme

model

with

estimated

K

m

and

V

max

of

microm

and

pmol

min

mg

protein

respectively


As shown in Fig. 1, compared with separate injections, mixing the two insulins significantly shifted the time action curve to the right, with significantly lower GIR values after the mixed injections between 60 and 190 min and significantly higher values between 270 and 300 min.

Answer: accept

As

shown

in

Fig

compared

with

separate

injections

mixing

the

two

insulins

significantly

shifted

the

time

action

curve

to

the

right

with

significantly

lower

GIR

values

after

the

mixed

injections

between

and

min

and

significantly

higher

values

between

and

min


The concentration-time curve of scutellarin can be fitted to a three-compartment model with the main pharmacokinetic parameters as follows: T1/2 gamma, T1/2 alpha and T1/2 beta were (1.1 +- 0.8) min, (7.0 +- 2.8) min and (52 +- 29) min, respectively, Vc was (880 +- 508) mL, CL was (190 +- 54) mL.min-1, AUC0-90 and AUC0-infinity were (574 +- 134) mg.min.L-1 and (559 +/- 132) mg.min.L-1 respectively.

Answer: accept

The

concentration

time

curve

of

scutellarin

can

be

fitted

to

a

three

compartment

model

with

the

main

pharmacokinetic

parameters

as

follows

T

gamma

T

alpha

and

T

beta

were

min

min

and

min

respectively

Vc

was

mL

CL

was

mL

min

AUC

and

AUC

infinity

were

mg

min

L

and

mg

min

L

respectively


After a single intravenous administration of 10 mg of DHMP A per kg, its half-life in serum in mice was about 0.5 h and in dogs it was 5.5 h. A single oral administration to dogs of 12.5 mg/kg gave a peak of 5.0 micrograms/ml at 3 h.

Answer: accept

After

a

single

intravenous

administration

of

mg

of

DHMP

A

per

kg

its

half

life

in

serum

in

mice

was

about

h

and

in

dogs

it

was

h

A

single

oral

administration

to

dogs

of

mg

kg

gave

a

peak

of

micrograms

ml

at

h


Results
Pharmacokinetic analyses using NCA

Inter‐subject variability of obinutuzumab exposure appeared to be slightly higher for patients with CLL (CV% estimated to be <43% for AUC and <33% for Cmax for both cycles) than for patients with DLBCL or FL (CV% estimated to be <38% for AUC and <29% for Cmax for both cycles).

Answer: accept

Inter

subject

variability

of

obinutuzumab

exposure

appeared

to

be

slightly

higher

for

patients

with

CLL

CV

estimated

to

be

for

AUC

and

for

Cmax

for

both

cycles

than

for

patients

with

DLBCL

or

FL

CV

estimated

to

be

for

AUC

and

for

Cmax

for

both

cycles


Addition of FFM as a covariate on Q and/or V2 was also tested and led to a significant decrease of the OFV when added to V2 (dOFV = − 16.7).

Answer: accept

Addition

of

FFM

as

a

covariate

on

Q

and

or

V

was

also

tested

and

led

to

a

significant

decrease

of

the

OFV

when

added

to

V

dOFV


Results
Pharmacokinetic Results
Part 1: Multiple-Dose Component

The BI 425809 gMean terminal half-life after the first dose and the terminal half-life at steady state were similar across treatment groups (QD and BID, 34.2–59.3 h), and the fraction eliminated from urine ranged from 1.77 to 2.71% (after single-dose administration) and from 3.90 to 7.10% (after multiple dosing).

Answer: accept

The

BI

gMean

terminal

half

life

after

the

first

dose

and

the

terminal

half

life

at

steady

state

were

similar

across

treatment

groups

QD

and

BID

h

and

the

fraction

eliminated

from

urine

ranged

from

to

after

single

dose

administration

and

from

to

after

multiple

dosing


In the skin, the median Tmax under fed conditions was 7.0 h, compared with 5.0 h in fasting subjects.

Answer: accept

In

the

skin

the

median

Tmax

under

fed

conditions

was

h

compared

with

h

in

fasting

subjects


The area under the curve of concentration changes in patients with stomach cancer was smaller by 47%, and the maximum concentration--by 60%.

Answer: accept

The

area

under

the

curve

of

concentration

changes

in

patients

with

stomach

cancer

was

smaller

by

and

the

maximum

concentration

by


RESULTS
Pharmacokinetic and covariate model.

Residual error was described as Y = F × (1 + ε1), where Y is the observed NVP concentration, F is the predicted concentration, and ε1 is the proportional random effects, assumed to have a mean of zero and variance of σ12.

Answer: accept

Residual

error

was

described

as

Y

F

ε

where

Y

is

the

observed

NVP

concentration

F

is

the

predicted

concentration

and

ε

is

the

proportional

random

effects

assumed

to

have

a

mean

of

zero

and

variance

of

σ


The mean values (+-SD) for elimination half-life, CL/F, and Vd/F after a single dose were 12.9 +- 3.34 h, 11.8 +- 4.96 L h-1, and 233 +- 126 L, respectively.

Answer: accept

The

mean

values

SD

for

elimination

half

life

CL

F

and

Vd

F

after

a

single

dose

were

h

L

h

and

L

respectively


The Cmax of both M5 and M7 occurred 2 h post-exposure at both doses, indicating that both metabolites were rapidly produced after administration of canagliflozin.

Answer: accept

The

Cmax

of

both

M

and

M

occurred

h

post

exposure

at

both

doses

indicating

that

both

metabolites

were

rapidly

produced

after

administration

of

canagliflozin


Results and discussion
Pharmacokinetic study of the five AAs

The ratios (AUC(0-∞)/dose) of AA I and AA II were higher than those of the other AAs, and thet1/2zvalues were in the following order from large to small: AA I, AA II, 7-OH AA I, AA D and AA C.

Answer: accept

The

ratios

AUC

dose

of

AA

I

and

AA

II

were

higher

than

those

of

the

other

AAs

and

thet

zvalues

were

in

the

following

order

from

large

to

small

AA

I

AA

II

OH

AA

I

AA

D

and

AA

C


Mean residence time (MRT) and elimination half-life (T½β) were statistically different (P < 0.05) in doxy-FOLA group as compared to doxy-ref group (MRT: 26 h and 5.2 h; and T½β: 18 h vs 3 h, on the first day for doxy-FOLA and doxy-ref, respectively).

Answer: accept

Mean

residence

time

MRT

and

elimination

half

life

T

½

β

were

statistically

different

P

in

doxy

FOLA

group

as

compared

to

doxy

ref

group

MRT

h

and

h

and

T

½

β

h

vs

h

on

the

first

day

for

doxy

FOLA

and

doxy

ref

respectively


The variation in the paired AUC of VM26 was 50%.

Answer: accept

The

variation

in

the

paired

AUC

of

VM

was


Kidney exposure to GA was further linked to an Imax model in the 11β-HSD 2 module of the PD model to predict the urinary excretion of cortisol and cortisone.

Answer: accept

Kidney

exposure

to

GA

was

further

linked

to

an

Imax

model

in

the

β

HSD

module

of

the

PD

model

to

predict

the

urinary

excretion

of

cortisol

and

cortisone


At 30 and 40 mg (Figure 2), the daily oral dosing of vinorelbine provided a continuous blood exposure, as median trough concentrations were all >1 ng/mL.

Answer: accept

At

and

mg

Figure

the

daily

oral

dosing

of

vinorelbine

provided

a

continuous

blood

exposure

as

median

trough

concentrations

were

all

ng

mL


Results
Tissue distribution of [14C] DHA

In contrast, the radioactivity lasted much less in the contents of stomach, small intestine, and large intestine with half-lives of 16.75, 28.73, and 37.20 hours, respectively.

Answer: accept

In

contrast

the

radioactivity

lasted

much

less

in

the

contents

of

stomach

small

intestine

and

large

intestine

with

half

lives

of

and

hours

respectively


If we adjusted AUC by dose, it was, respectively, 2.5 times, 1.7 times and 2.3 times greater in the high-dose group than in the low-dose group.

Answer: accept

If

we

adjusted

AUC

by

dose

it

was

respectively

times

times

and

times

greater

in

the

high

dose

group

than

in

the

low

dose

group


Results
Pharmacokinetics of Levobupivacaine

The Cmax of Levo-Bupi, used alone, (142.45 ± 13.04 ng/ml) did not significantly differ from that in LL-1 (p = 0.114).

Answer: accept

The

Cmax

of

Levo

Bupi

used

alone

ng

ml

did

not

significantly

differ

from

that

in

LL

p


Bioavailability was determined by measuring 72 h urinary recovery of unchanged drug.

Answer: accept

Bioavailability

was

determined

by

measuring

h

urinary

recovery

of

unchanged

drug


As shown in Table2, Emax values for EDL, gastro, and quad muscles ranged between 23% and 30% and Cave50 range was estimated to be 47–72 nM. In order to determine whether the increase in skeletal muscle mass caused by MYO‐029 treatment is due to hypertrophy or hyperplasia, morphometric analysis (data not shown) was performed on EDL muscles after 4 weeks of treatment in the 10 mg/kg/week dose group.

Answer: accept

As

shown

in

Table

Emax

values

for

EDL

gastro

and

quad

muscles

ranged

between

and

and

Cave

range

was

estimated

to

be

nM

In

order

to

determine

whether

the

increase

in

skeletal

muscle

mass

caused

by

MYO

treatment

is

due

to

hypertrophy

or

hyperplasia

morphometric

analysis

data

not

shown

was

performed

on

EDL

muscles

after

weeks

of

treatment

in

the

mg

kg

week

dose

group


Free PTH demonstrated an effective half-life of approximately 60 hours and a dose-dependent, sustained exposure with an infusion-like profile within the calculated physiologic range for active PTH at steady-state.

Answer: accept

Free

PTH

demonstrated

an

effective

half

life

of

approximately

hours

and

a

dose

dependent

sustained

exposure

with

an

infusion

like

profile

within

the

calculated

physiologic

range

for

active

PTH

at

steady

state


Blank LNCs showed in vitro cytotoxicity (IC50 63.4 µg/mL), which was significantly increased by the incorporation of OA and MFS (IC50 43.4±1.1 µg/mL).

Answer: accept

Blank

LNCs

showed

in

vitro

cytotoxicity

IC

µ

g

mL

which

was

significantly

increased

by

the

incorporation

of

OA

and

MFS

IC

µ

g

mL


Previous studies showed a DDFP blood half-life of <2 min yet therapeutic effects lasted >90 min after injection.

Answer: accept

Previous

studies

showed

a

DDFP

blood

half

life

of

min

yet

therapeutic

effects

lasted

min

after

injection


Paliperidone exposure approached the exposure at steady state from the second injection onwards, with the steady-state levels reached after about 8 to 9 months (Figure 2).

Answer: accept

Paliperidone

exposure

approached

the

exposure

at

steady

state

from

the

second

injection

onwards

with

the

steady

state

levels

reached

after

about

to

months

Figure


In contrast, the SUVmean underestimated the concentration in blood (17.9±6.1%ID/l; P=0.007) (Table 3).

Answer: accept

In

contrast

the

SUVmean

underestimated

the

concentration

in

blood

ID

l

P

Table


Results
In vivo NIR Optical Imaging
Affibody clearance

Affibody-DyLight750 conjugate clearance rate was estimated by scanning the contralateral area of the animal and showed that fluorescence intensity decreased exponentially following ZHER2-DyLight-750 injection with an estimated half-life of 37.5±2.8 min.

Answer: accept

Affibody

DyLight

conjugate

clearance

rate

was

estimated

by

scanning

the

contralateral

area

of

the

animal

and

showed

that

fluorescence

intensity

decreased

exponentially

following

ZHER

DyLight

injection

with

an

estimated

half

life

of

min


The PK studies revealed a half-life of 47.7 ± 7.4 h. VSW1198 was present in all tested tissues with the highest levels in the liver.

Answer: accept

The

PK

studies

revealed

a

half

life

of

h

VSW

was

present

in

all

tested

tissues

with

the

highest

levels

in

the

liver


The parameters AUC24 h/MIC in serum for bacteriostatic, bactericidal, and elimination activities were calculated as 18.91, 29.13, and 34.03 h based on the inhibitory sigmoid Emax modeling.

Answer: accept

The

parameters

AUC

h

MIC

in

serum

for

bacteriostatic

bactericidal

and

elimination

activities

were

calculated

as

and

h

based

on

the

inhibitory

sigmoid

Emax

modeling


In the sensitivity analysis (subject 20 excluded), maximum serum concentration for IAsp in IDegAsp was 305 pmol/L in the elderly subjects and 221 pmol/L in the younger adults.

Answer: accept

In

the

sensitivity

analysis

subject

excluded

maximum

serum

concentration

for

IAsp

in

IDegAsp

was

pmol

L

in

the

elderly

subjects

and

pmol

L

in

the

younger

adults


Population pharmacokinetic modeling with exploratory covariate analysis

The between-subject variability (BSV) for each parameter was 31 % to 34 %, except for ka (82 %).

Answer: accept

The

between

subject

variability

BSV

for

each

parameter

was

to

except

for

ka


No change was seen after 0.5 days in the hexobarbital (HB) sleeping time and in its half-life in blood plasma.

Answer: accept

No

change

was

seen

after

days

in

the

hexobarbital

HB

sleeping

time

and

in

its

half

life

in

blood

plasma


Increased carboplatin doses administered on successive courses of treatment reflected a greater than twofold increase in drug clearance, from 3.4-7.1 ml/min over a 7-week period.

Answer: accept

Increased

carboplatin

doses

administered

on

successive

courses

of

treatment

reflected

a

greater

than

twofold

increase

in

drug

clearance

from

ml

min

over

a

week

period


After intranasal administration of metoclopramide, (5 mg in 0.5 ml sterile water) the maximum plasma concentration of 13.5 +- 7.3 (mean +- s.d.) ng ml-1 was achieved.

Answer: accept

After

intranasal

administration

of

metoclopramide

mg

in

ml

sterile

water

the

maximum

plasma

concentration

of

mean

s

d

ng

ml

was

achieved


Clozapine, an atypical antipsychotic, depends mainly on cytochrome P4501A2 (CYP1A2) for its metabolic clearance.

Answer: accept

Clozapine

an

atypical

antipsychotic

depends

mainly

on

cytochrome

P

A

CYP

A

for

its

metabolic

clearance


Comparison of AUE values between NKTR-181 and oxycodone yielded patterns similar to those for Drug Liking Emax (Table 2).

Answer: accept

Comparison

of

AUE

values

between

NKTR

and

oxycodone

yielded

patterns

similar

to

those

for

Drug

Liking

Emax

Table


Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution.

Answer: accept

Compared

with

intravenous

administration

the

absolute

bioavailability

of

oral

cisapride

was

in

rats

and

in

the

dog

for

the

drug

given

in

solution


Geometric mean ratios of C(max) and AUC(0-48) of efavirenz before and after co-administration of 14 successive daily doses of AP were compared.

Answer: accept

Geometric

mean

ratios

of

C

max

and

AUC

of

efavirenz

before

and

after

co

administration

of

successive

daily

doses

of

AP

were

compared


After i.v. administration, both drugs had high systemic serum clearance, averaging 24 ml/min/kg.

Answer: accept

After

i

v

administration

both

drugs

had

high

systemic

serum

clearance

averaging

ml

min

kg


Results
Adequacy of therapeutic drug monitoring

A mean of 1.87 and 1.75 AUC was obtained for EC-MPS- and MMF-treated kidney transplant recipients, respectively.

Answer: accept

A

mean

of

and

AUC

was

obtained

for

EC

MPS

and

MMF

treated

kidney

transplant

recipients

respectively


In the viremic group, substitutions in HIV protease were detected most frequently in the following positions in subjects on indinavir (IDV): L10I/V (35.7%), M46I/L (35.7%), A71T/V (35.7%), V82A (42.9%); and for subjects on nelfinavir (NFV): D30N (50.0%), V77I (56.3%), N88D (37.5%).

Answer: accept

In

the

viremic

group

substitutions

in

HIV

protease

were

detected

most

frequently

in

the

following

positions

in

subjects

on

indinavir

IDV

L

I

V

M

I

L

A

T

V

V

A

and

for

subjects

on

nelfinavir

NFV

D

N

V

I

N

D


The bioavailability and pharmacokinetics of dilevalol following oral and intravenous administration were investigated in 12 healthy male volunteers.

Answer: accept

The

bioavailability

and

pharmacokinetics

of

dilevalol

following

oral

and

intravenous

administration

were

investigated

in

healthy

male

volunteers


Comparison of the exposure for the 30 mg/kg oral dose to the 10-minute IV infusion of the same dose showed that ST-246 had approximately 41% bioavailability for that dose.

Answer: accept

Comparison

of

the

exposure

for

the

mg

kg

oral

dose

to

the

minute

IV

infusion

of

the

same

dose

showed

that

ST

had

approximately

bioavailability

for

that

dose


When inspected visually (Fig 3), the apparent concentration in the spinal cord was very low relative to the concentration in the neighboring CSF and meninges, suggesting that the calculated values in the spinal cord may have been overestimated.

Answer: accept

When

inspected

visually

Fig

the

apparent

concentration

in

the

spinal

cord

was

very

low

relative

to

the

concentration

in

the

neighboring

CSF

and

meninges

suggesting

that

the

calculated

values

in

the

spinal

cord

may

have

been

overestimated


The plasma concentration curves showed a fast distribution phase with a mean half‐life of 5 hours and a slow elimination phase with a mean half‐life of 70 hours (range 50‐300 hours) and were well described by a 2‐compartment model.

Answer: accept

The

plasma

concentration

curves

showed

a

fast

distribution

phase

with

a

mean

half

life

of

hours

and

a

slow

elimination

phase

with

a

mean

half

life

of

hours

range

hours

and

were

well

described

by

a

compartment

model


Cenicriviroc CCR2/CCR5 antagonist activity

Higher CCL2 levels correlated with higher cenicriviroc median Cmax (r = 0.39; P < 0.05).

Answer: accept

Higher

CCL

levels

correlated

with

higher

cenicriviroc

median

Cmax

r

P


The best formulation (F4) consisting of hypromellose, sodium bicarbonate, polyethylene oxide, docusate sodium, mannitol, crosscarmellose sodium, and magnesium stearate, gave floating lag time of 56 ± 4.16 s and good matrix integrity with in vitro dissolution of 98.2% in 12 h. After stability studies, no significant change was observed in stability, solubility, floating lag time, total floating duration, matrix integrity, and sustained drug release rates, as confirmed by DSC and powder X-ray diffraction studies.

Answer: accept

The

best

formulation

F

consisting

of

hypromellose

sodium

bicarbonate

polyethylene

oxide

docusate

sodium

mannitol

crosscarmellose

sodium

and

magnesium

stearate

gave

floating

lag

time

of

s

and

good

matrix

integrity

with

in

vitro

dissolution

of

in

h

After

stability

studies

no

significant

change

was

observed

in

stability

solubility

floating

lag

time

total

floating

duration

matrix

integrity

and

sustained

drug

release

rates

as

confirmed

by

DSC

and

powder

X

ray

diffraction

studies


However, compound 22e inhibited hERG with an IC50 value of 2.5 μM (Table 4).

Answer: accept

However

compound

e

inhibited

hERG

with

an

IC

value

of

μ

M

Table


The bioavailability of 5PDTT following administration of 5PDTT/SBE7-beta-CD complex was estimated to 41% while it was close to zero when 5PDTT was given as a micronized powder.

Answer: accept

The

bioavailability

of

PDTT

following

administration

of

PDTT

SBE

beta

CD

complex

was

estimated

to

while

it

was

close

to

zero

when

PDTT

was

given

as

a

micronized

powder


Results
Part 2, multiple dose pharmacokinetics

The mean AUC0-4h values ranged from 22.5 to 28.5 ng·h/mL in fast acetylators and 115–168 ng·h/mL in slow acetylators across all PK sampling days.

Answer: accept

The

mean

AUC

h

values

ranged

from

to

ng

h

mL

in

fast

acetylators

and

ng

h

mL

in

slow

acetylators

across

all

PK

sampling

days


RESULTS
PPK model evaluation
PPK model application

ADA has minimal effect on nivolumab CL (<20%), and the estimated effect for ADA on CL was 114% (95% CI: 106–122%) relative to occasions when ADAs were not present.

Answer: accept

ADA

has

minimal

effect

on

nivolumab

CL

and

the

estimated

effect

for

ADA

on

CL

was

CI

relative

to

occasions

when

ADAs

were

not

present


To minimize interindividual variation, only subjects with moderate fecal isoflavone degradation rates (half-lives of daidzein and genistein were 15.7 and 8.9 h, respectively) were included.

Answer: accept

To

minimize

interindividual

variation

only

subjects

with

moderate

fecal

isoflavone

degradation

rates

half

lives

of

daidzein

and

genistein

were

and

h

respectively

were

included


After intravenous (iv) administration of [14C]cidofovir (3 or 5 mg/kg) or [14C]cyclic HPMPC (5 mg/kg), plasma concentrations of total radioactivity declined in a multiexponential manner for both drugs with terminal half-lives of 7-11 hr.

Answer: accept

After

intravenous

iv

administration

of

C

cidofovir

or

mg

kg

or

C

cyclic

HPMPC

mg

kg

plasma

concentrations

of

total

radioactivity

declined

in

a

multiexponential

manner

for

both

drugs

with

terminal

half

lives

of

hr


Median time to progression (TTP) and overall survival were 7.1 months and 13.0 months, respectively.

Answer: accept

Median

time

to

progression

TTP

and

overall

survival

were

months

and

months

respectively


The biological half-life of total plasma radioactivity in IV and orally dosed pigs (86.6 hr) was much larger than that of IVB animals (3.34 hr).

Answer: accept

The

biological

half

life

of

total

plasma

radioactivity

in

IV

and

orally

dosed

pigs

hr

was

much

larger

than

that

of

IVB

animals

hr


3.2. PKs of SSa after the Oral Administration of Pure SSa and DA-9805

The AUC and Cmax values of SSa were dose-proportional following oral administration of pure SSa and DA-9805.

Answer: accept

The

AUC

and

Cmax

values

of

SSa

were

dose

proportional

following

oral

administration

of

pure

SSa

and

DA


There was rapid and significant absorption of drug-derived products evidenced by maximum concentrations for plasma and the majority of sampled tissues at 1 h post dose, and extensive renal clearance, with greater than 62% of dose voided in urine in 12 h. Analysis of urine revealed that the administered compound had been completely metabolised to five metabolites of which the two major products have been characterised.

Answer: accept

There

was

rapid

and

significant

absorption

of

drug

derived

products

evidenced

by

maximum

concentrations

for

plasma

and

the

majority

of

sampled

tissues

at

h

post

dose

and

extensive

renal

clearance

with

greater

than

of

dose

voided

in

urine

in

h

Analysis

of

urine

revealed

that

the

administered

compound

had

been

completely

metabolised

to

five

metabolites

of

which

the

two

major

products

have

been

characterised


A 50 U/kg dose of antithrombin had a simulated half-life 13.2 ± 6.6 hours.

Answer: accept

A

U

kg

dose

of

antithrombin

had

a

simulated

half

life

hours


Between Trials 2 and 3, acetaminophen VZ was reduced (1.14 vs 1.00 l.kg-1), t1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml.min-1.kg-1), and fractional urinary recovery of acetaminophen glucuronide reduced.

Answer: accept

Between

Trials

and

acetaminophen

VZ

was

reduced

vs

l

kg

t

prolonged

vs

h

clearance

reduced

vs

ml

min

kg

and

fractional

urinary

recovery

of

acetaminophen

glucuronide

reduced


Individual values for CL extended from 0.59 to 1.56 l h−1 kg−1, with the values for CL calculated from AUC0−t being, on average, about 10% less than the values calculated from the concentrations at steady state.

Answer: accept

Individual

values

for

CL

extended

from

to

l

h

kg

with

the

values

for

CL

calculated

from

AUC

t

being

on

average

about

less

than

the

values

calculated

from

the

concentrations

at

steady

state


QC activity in serum and CSF at predose and after PQ912 administration

For an estimate of half maximal effective concentration (EC50) in serum and CSF, changes in QC activity were plotted versus PQ912 concentrations and fitted to an Emax model (Fig. 4A and B, respectively).

Answer: accept

For

an

estimate

of

half

maximal

effective

concentration

EC

in

serum

and

CSF

changes

in

QC

activity

were

plotted

versus

PQ

concentrations

and

fitted

to

an

Emax

model

Fig

A

and

B

respectively


Consistent with these findings, the in vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein as compared to the wild-type protein.

Answer: accept

Consistent

with

these

findings

the

in

vitro

intrinsic

clearance

of

S

warfarin

was

lower

with

the

cDNA

expressed

R

H

protein

as

compared

to

the

wild

type

protein


The backward stepwise elimination retained only the geographic site as influencing the Emax parameter (the critical value corresponding to the m = 213 comparisons required to perform the stepwise addition is 13.53).

Answer: accept

The

backward

stepwise

elimination

retained

only

the

geographic

site

as

influencing

the

Emax

parameter

the

critical

value

corresponding

to

the

m

comparisons

required

to

perform

the

stepwise

addition

is


Animal and human studies have indicated that viloxazine hydrochloride, an antidepressant drug with a half-life of 3-4 h in most subjects at low dosage, is rapidly and almost completely absorbed after oral administration.

Answer: accept

Animal

and

human

studies

have

indicated

that

viloxazine

hydrochloride

an

antidepressant

drug

with

a

half

life

of

h

in

most

subjects

at

low

dosage

is

rapidly

and

almost

completely

absorbed

after

oral

administration


For single dose evaluation, Cmax was achieved in 1.83 to 3.67 hours after oral administration.

Answer: accept

For

single

dose

evaluation

Cmax

was

achieved

in

to

hours

after

oral

administration


Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin.

Answer: accept

Steady

state

EFV

plasma

concentrations

n

samples

were

measured

in

the

presence

of

rifampicin


The pharmacokinetic analysis revealed that MPT0B292 was a high extraction ratio drug with high systemic clearance, a high volume of distribution and a short half-life in rats.

Answer: accept

The

pharmacokinetic

analysis

revealed

that

MPT

B

was

a

high

extraction

ratio

drug

with

high

systemic

clearance

a

high

volume

of

distribution

and

a

short

half

life

in

rats


The point estimates (90 % CI) of the ratio of omeprazole + lacosamide coadministered versus omeprazole alone for AUC (1.098 [0.996-1.209]) and C(max) (1.105 [0.979-1.247]) fell within the acceptance range for bioequivalence.

Answer: accept

The

point

estimates

CI

of

the

ratio

of

omeprazole

lacosamide

coadministered

versus

omeprazole

alone

for

AUC

and

C

max

fell

within

the

acceptance

range

for

bioequivalence


Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P <.02) and area under the curve (AUC, P <.04) compared with prestudy values.

Answer: accept

Pharmacokinetic

parameters

of

exogenous

FVIII

infused

into

subjects

weeks

after

vector

infusion

showed

an

increased

half

life

T

P

and

area

under

the

curve

AUC

P

compared

with

prestudy

values


Icosapent ethyl 4 g/day at steady-state did not significantly change the single-dose AUC0–inf or Cmax of rosiglitazone 8 mg.

Answer: accept

Icosapent

ethyl

g

day

at

steady

state

did

not

significantly

change

the

single

dose

AUC

inf

or

Cmax

of

rosiglitazone

mg


Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2–22 mg.

Answer: accept

Median

Tmax

was

h

systemic

exposure

increased

less

than

dose

proportionally

over

the

dose

range

mg


Using the distribution ratio of nitroglycerin between red blood cells and plasma, we determined the systemic clearance of nitroglycerin in arterial blood to be about 3/4 of cardiac output.

Answer: accept

Using

the

distribution

ratio

of

nitroglycerin

between

red

blood

cells

and

plasma

we

determined

the

systemic

clearance

of

nitroglycerin

in

arterial

blood

to

be

about

of

cardiac

output


For total [(14) C] radioactivity, the mean (SD) Cmax was 15,981 (2721) ng-eq/mL, and AUC∞ 53,755 (15,587) ng-eq.h/mL.

Answer: accept

For

total

C

radioactivity

the

mean

SD

Cmax

was

ng

eq

mL

and

AUC

ng

eq

h

mL


Pharmacokinetic studies demonstrated that radiolabeled sIL-4R had a distribution half-life of 9 minutes and an elimination half-life of 2.3 hours following intravenous (IV) administration.

Answer: accept

Pharmacokinetic

studies

demonstrated

that

radiolabeled

sIL

R

had

a

distribution

half

life

of

minutes

and

an

elimination

half

life

of

hours

following

intravenous

IV

administration


Results
Pharmacokinetics
Single High Dose

Following a single high dose of BAT/FF, FF exposure was reduced by approximately 20% compared with FF alone (AUC(0‐t’) ratio of geometric least squares means [GLSM]: 0.79; AUC(0‐t) GLSM: 0.77; Table 2; Figure 1A).

Answer: accept

Following

a

single

high

dose

of

BAT

FF

FF

exposure

was

reduced

by

approximately

compared

with

FF

alone

AUC

t

ratio

of

geometric

least

squares

means

GLSM

AUC

t

GLSM

Table

Figure

A


Single- and Multidose Comparisons with Amantadine IR

As expected, dose-normalized Cmax was 34% lower for ADS-5102 compared with amantadine IR.

Answer: accept

As

expected

dose

normalized

Cmax

was

lower

for

ADS

compared

with

amantadine

IR


The average terminal phase elimination half-lives were 0.87 and 1.03h for ET-26-HCl and ET-26-acid respectively.

Answer: accept

The

average

terminal

phase

elimination

half

lives

were

and

h

for

ET

HCl

and

ET

acid

respectively


An age effect on Cmax and AUC∞ was not apparent; however, mean AUC∞ values were approximately 1.8–1.9-fold higher in the female cohorts than in the reference male cohort.

Answer: accept

An

age

effect

on

Cmax

and

AUC

was

not

apparent

however

mean

AUC

values

were

approximately

fold

higher

in

the

female

cohorts

than

in

the

reference

male

cohort


Although elimination half-lives were not determined for 1H-PFAs, concentrations were higher than the corresponding PFPAs 48 h after rats were dosed with PFPiAs, suggestive of slower elimination.

Answer: accept

Although

elimination

half

lives

were

not

determined

for

H

PFAs

concentrations

were

higher

than

the

corresponding

PFPAs

h

after

rats

were

dosed

with

PFPiAs

suggestive

of

slower

elimination


The apparent volume of distribution and total body clearance were 1.17 ± 0.10 l/kg and 0.45 ± 0.03 l/kg/h, respectively.

Answer: accept

The

apparent

volume

of

distribution

and

total

body

clearance

were

l

kg

and

l

kg

h

respectively


There was a statistically significant linear correlation between the self-reported drug effect and C(max) of ketamine (r = 0.55; P < 0.01).

Answer: accept

There

was

a

statistically

significant

linear

correlation

between

the

self

reported

drug

effect

and

C

max

of

ketamine

r

P


Omeprazole and 5‐OH‐Omeprazole PK: Assessment of CYP2C19 Activity

The metabolite‐to‐parent ratio (5‐OH‐omeprazole/omeprazole), based on the AUCinf, decreased with increasing ASP8477 dose from 1.053 (alone) to 0.1600 (in combination with 100 mg ASP8477 once daily).

Answer: accept

The

metabolite

to

parent

ratio

OH

omeprazole

omeprazole

based

on

the

AUCinf

decreased

with

increasing

ASP

dose

from

alone

to

in

combination

with

mg

ASP

once

daily


In particular, the AUC(0,∞) ratio (90% confidence interval) for coadministration of warfarin and lacosamide versus warfarin alone was 0.97 (0.94-1.00) for S-warfarin and 1.05 (1.02-1.09) for R-warfarin, and the AUCINR ratio was 1.04 (1.01-1.06).

Answer: accept

In

particular

the

AUC

ratio

confidence

interval

for

coadministration

of

warfarin

and

lacosamide

versus

warfarin

alone

was

for

S

warfarin

and

for

R

warfarin

and

the

AUCINR

ratio

was


The pharmacokinetic parameters in Chinese volunteers after taking flecainide were: Ka = 0.908h-1, T1/2 = 8.131h, peats time = 3.487h, AUC = 441.8ng.h/ml.

Answer: accept

The

pharmacokinetic

parameters

in

Chinese

volunteers

after

taking

flecainide

were

Ka

h

T

h

peats

time

h

AUC

ng

h

ml


These data suggest that fluconazole can be expected to interact with any drug whose clearance is dominated by P450s 2C9, 3A4, and other as yet undefined isoforms.

Answer: accept

These

data

suggest

that

fluconazole

can

be

expected

to

interact

with

any

drug

whose

clearance

is

dominated

by

P

s

C

A

and

other

as

yet

undefined

isoforms


Using an enzyme-multiplied immunoassay (EMIT) system for theophylline analysis, pharmacokinetic estimations were excellent for Css (r = 0.9103, p less than 0.01) and Cl (r = 0.9750, p less than 0.01).

Answer: accept

Using

an

enzyme

multiplied

immunoassay

EMIT

system

for

theophylline

analysis

pharmacokinetic

estimations

were

excellent

for

Css

r

p

less

than

and

Cl

r

p

less

than


After intravenous MOX, serum clearance was 10.2 +- 3.4 (R-MOX) and 10.9 +- 3.2 (S-MOX) ml/hr/kg.

Answer: accept

After

intravenous

MOX

serum

clearance

was

R

MOX

and

S

MOX

ml

hr

kg


The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +- 96 mmHg/h) was significantly greater than that for placebo (-112 +- 81 mmHg/h; P< 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 +- 95 mmHg/h) or 50 mg losartan (-144 +- 66 mmHg/h).

Answer: accept

The

area

under

the

curve

h

for

the

fall

in

mean

blood

pressure

with

mg

candesartan

cilexetil

mmHg

h

was

significantly

greater

than

that

for

placebo

mmHg

h

P

but

the

difference

was

not

statistically

significant

compared

with

either

mg

candesartan

cilexetil

mmHg

h

or

mg

losartan

mmHg

h


The first and second distribution half-lives were similar for the four groups studied, with geometric mean distribution half-lives of about 0.1 h (6 min) and 0.75 h (45 min), respectively.

Answer: accept

The

first

and

second

distribution

half

lives

were

similar

for

the

four

groups

studied

with

geometric

mean

distribution

half

lives

of

about

h

min

and

h

min

respectively


3.3. Pharmacokinetic Analyses of the Tongshu Suppository

This observation was also confirmed by the data processing results, where the Tmax was 34.87 min in the Tongshu suppository group, which was longer than the peak time of gavage of the Aceclofenac suspension alone.

Answer: accept

This

observation

was

also

confirmed

by

the

data

processing

results

where

the

Tmax

was

min

in

the

Tongshu

suppository

group

which

was

longer

than

the

peak

time

of

gavage

of

the

Aceclofenac

suspension

alone


Concurrent medications potentially interfering with voriconazole metabolism given on this date included pantoprazole 40 mg IV every 12 h and ciprofloxacin 400 mg IV every 8 h. Notably, the systemic clearance of voriconazole increased nearly three-fold while the weight-adjusted volume of distribution more than doubled (Table 1).

Answer: accept

Concurrent

medications

potentially

interfering

with

voriconazole

metabolism

given

on

this

date

included

pantoprazole

mg

IV

every

h

and

ciprofloxacin

mg

IV

every

h

Notably

the

systemic

clearance

of

voriconazole

increased

nearly

three

fold

while

the

weight

adjusted

volume

of

distribution

more

than

doubled

Table


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

IgG1 showed the slowest extravasation into tissue (peaks at 24 h) and also has a tissue half-life >100 h.

Answer: accept

IgG

showed

the

slowest

extravasation

into

tissue

peaks

at

h

and

also

has

a

tissue

half

life

h


When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal administration as compared to intravenous administration (P < 0.0001).

Answer: accept

When

oxaliplatin

was

delivered

at

mg

kg

the

area

under

the

curve

AUC

of

the

peritoneal

fluid

was

fold

higher

with

intraperitoneal

administration

as

compared

to

intravenous

administration

P


Making two mutations in the putative FcRn binding region of ssCH2D reduced the elimination phase half-life from 9.9 h to 3.9 h.

Answer: accept

Making

two

mutations

in

the

putative

FcRn

binding

region

of

ssCH

D

reduced

the

elimination

phase

half

life

from

h

to

h


The absolute bioavailability varied between 3.6 and 22.2%.

Answer: accept

The

absolute

bioavailability

varied

between

and


The group with normal renal function had values of 37.41% and 22.64% for inter-individual and residual variability of vancomycin clearance, respectively.

Answer: accept

The

group

with

normal

renal

function

had

values

of

and

for

inter

individual

and

residual

variability

of

vancomycin

clearance

respectively


At a dose of 100 microg/kg body weight, the absolute bioavailabilities of PCP across soils ranged from 36% to 65%, and the relative bioavailabilities ranged from 48% to 82%.

Answer: accept

At

a

dose

of

microg

kg

body

weight

the

absolute

bioavailabilities

of

PCP

across

soils

ranged

from

to

and

the

relative

bioavailabilities

ranged

from

to


It was predicted that humans would have a higher BA and a longer half-life in the plasma compared with the animals by a simple calculation using intrinsic hepatic clearance in monkeys, which correlates well with human values for CYP3A4 substrates, and Fa * Fg in rats, which correlates relatively well with human values.

Answer: accept

It

was

predicted

that

humans

would

have

a

higher

BA

and

a

longer

half

life

in

the

plasma

compared

with

the

animals

by

a

simple

calculation

using

intrinsic

hepatic

clearance

in

monkeys

which

correlates

well

with

human

values

for

CYP

A

substrates

and

Fa

Fg

in

rats

which

correlates

relatively

well

with

human

values


The oral bioavailability of griseofulvin (GF) formulated as a fast disintegrating lyophilized dry emulsion (LDE) tablet was studied and compared to the commercially available immediate release (IR) tablet, as a reference, in both the fasted and fed states in nine healthy volunteers after a single oral dose (125 mg) in a crossover design.

Answer: accept

The

oral

bioavailability

of

griseofulvin

GF

formulated

as

a

fast

disintegrating

lyophilized

dry

emulsion

LDE

tablet

was

studied

and

compared

to

the

commercially

available

immediate

release

IR

tablet

as

a

reference

in

both

the

fasted

and

fed

states

in

nine

healthy

volunteers

after

a

single

oral

dose

mg

in

a

crossover

design


Estimated absolute bioavailability and clearance were 60% and 2l h(-1), respectively.

Answer: accept

Estimated

absolute

bioavailability

and

clearance

were

and

l

h

respectively


Population PK model and internal model evaluation

The cosine function on bioavailability has a relative amplitude of 14.7% with a peak at 12:14, while the cosine function on clearance has a relative amplitude of 7.2% and a peak at 18:50.

Answer: accept

The

cosine

function

on

bioavailability

has

a

relative

amplitude

of

with

a

peak

at

while

the

cosine

function

on

clearance

has

a

relative

amplitude

of

and

a

peak

at


Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin.

Answer: accept

Steady

state

concentration

elimination

half

life

and

the

total

body

clearance

of

esmolol

were

not

changed

significantly

P

greater

than

by

digoxin


Results and discussion
Bioavailability studies

In the same way, area under the curve0–48 for D-PNPs (10.63 ± 3.77 h μg/mL) and D-CNPs (16.90 ± 6.93 h μg/mL) was five- and eight-fold higher than that of daidzein suspension (1.91 ± 0.81 h μg/mL).

Answer: accept

In

the

same

way

area

under

the

curve

for

D

PNPs

h

μ

g

mL

and

D

CNPs

h

μ

g

mL

was

five

and

eight

fold

higher

than

that

of

daidzein

suspension

h

μ

g

mL


The t(1/2) of OR-1855 was 61 +- 5 hours in healthy subjects and 82 +- 3 hours (P < .01) in subjects with hepatic impairment.

Answer: accept

The

t

of

OR

was

hours

in

healthy

subjects

and

hours

P

in

subjects

with

hepatic

impairment


The crystal structure of 5 shows a planar molecule with the F atom displaced from the mean plane by 1.005 Å (mean plane deviation for the molecule except F = 0.048 Å).

Answer: accept

The

crystal

structure

of

shows

a

planar

molecule

with

the

F

atom

displaced

from

the

mean

plane

by

Å

mean

plane

deviation

for

the

molecule

except

F

Å


The time to peak concentration was significantly less with exercise than without, 2.9 +- 2.1 and 13.7 +- 5.4 min, respectively (p less than 0.005).

Answer: accept

The

time

to

peak

concentration

was

significantly

less

with

exercise

than

without

and

min

respectively

p

less

than


A mean peak plasma concentration of 454 pg/ml was measured an average of 50 min following a 2 mg rectal dose.

Answer: accept

A

mean

peak

plasma

concentration

of

pg

ml

was

measured

an

average

of

min

following

a

mg

rectal

dose


The terminal elimination half-life (mean = 1.35 +- 0.3 hours) was found to be shorter than that reported for normotensive volunteers or nonpregnant hypertensive women (mean, 3.4 +- 0.4 hours).

Answer: accept

The

terminal

elimination

half

life

mean

hours

was

found

to

be

shorter

than

that

reported

for

normotensive

volunteers

or

nonpregnant

hypertensive

women

mean

hours


True Ke on day 0 could not be estimated because of protocol design, thus t1/2, Vss, and CL on day 0 were calculated based on the 0–24-h serum concentration versus time profile.

Answer: accept

True

Ke

on

day

could

not

be

estimated

because

of

protocol

design

thus

t

Vss

and

CL

on

day

were

calculated

based

on

the

h

serum

concentration

versus

time

profile


Ticagrelor pharmacokinetic parameters (Study 2)

When ticagrelor was released into the ascending colon, absorption (tmax) of ticagrelor was delayed (mean 3.8 h) and the t½ (9.7 h) was longer, compared with the administration of the orally administered suspension or release in the proximal and distal small bowel (mean tmax = 1.42–1.51 h; t½ = 7.19–7.56).

Answer: accept

When

ticagrelor

was

released

into

the

ascending

colon

absorption

tmax

of

ticagrelor

was

delayed

mean

h

and

the

t

½

h

was

longer

compared

with

the

administration

of

the

orally

administered

suspension

or

release

in

the

proximal

and

distal

small

bowel

mean

tmax

h

t

½


Effect of different doses of SCE on the pharmacokinetics of CsA

The time to reach the maximum (Tmax) was delayed from 6.33±1.50 hours to 6.8±1.10 hours, 8.67±1.63 hours, and 13.5±7.55 hours when CsA was administered with 54 mg/kg, 108 mg/kg, and 216 mg/kg of SCE, respectively.

Answer: accept

The

time

to

reach

the

maximum

Tmax

was

delayed

from

hours

to

hours

hours

and

hours

when

CsA

was

administered

with

mg

kg

mg

kg

and

mg

kg

of

SCE

respectively


The mean (+- SD) for alpha half-life was 1.2 +- 1.3 hours, and that for the beta half-life was 9.8 +- 5.9 hours.

Answer: accept

The

mean

SD

for

alpha

half

life

was

hours

and

that

for

the

beta

half

life

was

hours


Pheroid vesicles and Pheroid microsponges increased the C(max) values of sCT to 262.64+-17.1 pg/ml and 202.66+-28.6 pg/ml, respectively.

Answer: accept

Pheroid

vesicles

and

Pheroid

microsponges

increased

the

C

max

values

of

sCT

to

pg

ml

and

pg

ml

respectively


The area under curve (AUC) was 0.907.

Answer: accept

The

area

under

curve

AUC

was


Estimates of CL, V1, Q, and V2 were 7.37 mL/minute/kg, 134 mL/kg, 7.75 mL/minute/kg, and 275 mL/kg, respectively.

Answer: accept

Estimates

of

CL

V

Q

and

V

were

mL

minute

kg

mL

kg

mL

minute

kg

and

mL

kg

respectively


Radical curative effects of tafenoquine at various doses alone and in combination with chloroquine (Cohort 1)

Similar transient increases were observed prior to eventual clearance in some of the monkeys treated with chloroquine and 0.2 or 0.06 mg/kg/day of tafenoquine for three days.

Answer: accept

Similar

transient

increases

were

observed

prior

to

eventual

clearance

in

some

of

the

monkeys

treated

with

chloroquine

and

or

mg

kg

day

of

tafenoquine

for

three

days


The respective values for T1/2z (terminal elimination half-life) for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h.

Answer: accept

The

respective

values

for

T

z

terminal

elimination

half

life

for

Re

liposome

in

blood

and

plasma

are

h

and

h


Renal clearance values of S-STL were significantly reduced from 33.7 +- 6.0 to 28.9 +- 5.6 ml min-1 kg-1 for administration as racemate and pure enantiomer, respectively.

Answer: accept

Renal

clearance

values

of

S

STL

were

significantly

reduced

from

to

ml

min

kg

for

administration

as

racemate

and

pure

enantiomer

respectively


The ratios of model-predicted to observed Cmax, AUCinf and AUCτ values on Day 1 and Day 7 at 100 mg were 0.7-1.0.

Answer: accept

The

ratios

of

model

predicted

to

observed

Cmax

AUCinf

and

AUC

τ

values

on

Day

and

Day

at

mg

were


In vivo systemic exposure and joint retention of PRX after IA injection in rats

The Cmax values of PRX following conventional and E30-NP injection were 2.3 and 2.2 μg/mL, respectively, which are 62% (P<0.05) and 59% (P<0.05) that of the drug solution.

Answer: accept

The

Cmax

values

of

PRX

following

conventional

and

E

NP

injection

were

and

μ

g

mL

respectively

which

are

P

and

P

that

of

the

drug

solution


In contrast, multiple pretreatments of CuE (200 μg kg-1 d-1, 3 d, i.p.) significantly decreased tolbutamide clearance (CL) by 25% and prolonged plasma half-time (T 1/2) by 37%.

Answer: accept

In

contrast

multiple

pretreatments

of

CuE

μ

g

kg

d

d

i

p

significantly

decreased

tolbutamide

clearance

CL

by

and

prolonged

plasma

half

time

T

by


Plasma (0-24 h; rat and dog), urine (0-72 h; rat and dog) and fecal (0-72 h; rat and dog) samples were collected and analyzed.

Answer: accept

Plasma

h

rat

and

dog

urine

h

rat

and

dog

and

fecal

h

rat

and

dog

samples

were

collected

and

analyzed