Predicting Nonlinear Pharmacokinetics of Omeprazole
Enantiomers and Racemic Drug Using Physiologically Based
Pharmacokinetic Modeling and Simulation: Application to Predict
Drug/Genetic Interactions
Fang Wu1, Lu Gaohua2, Ping Zhao1, Masoud Jamei2, Shiew-Mei Huang1, Edward D
Bashaw1, Sue-Chih Lee*1
1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug
Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993 USA
2. Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield, UK
Running title: PBPK model predicting nonlinear PK of omeprazole
*Corresponding author
Sue-Chih Lee, Ph.D.
Office of Clinical Pharmacology
Office of Translational Sciences
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave
Building 51, Room 2142
Silver Spring, MD 20993
Tel: 301-796-1563
Fax: 301-847-8719
Email: suechih.lee@fda.hhs.gov
Disclaimer: The views presented in this manuscript are those of authors and do not
necessarily reflect the official view of the FDA.
1
SUPPLEMENTARY METHODS
1. Modification of initial PBPK model of esomeprazole by integrating timedependent CYP2C19 inhibition
V
.Enz
(t )
max, H ,2C19
H , 2C19
CLu
(t ) 
 CLu
int, H
int, H ,3 A4
C
fup
Liver
K

.
mu,2C19 BP Kp
/ BP
Liver
V
.Enz
(t )
max, G,2C19
G, 2C19
CLu
(t ) 
 CLu
int, G
int, G,3 A4
K
 fu
.C
mu,2C19
Gut PV
(1)
(2)
Where CLuint,H(t) and CLuint,G(t) are the time variant intrinsic metabolic clearances of
esomeprazole in the whole liver and gut, respectively; Vmax,H,2C19 and Vmax,G,2C19 are the
maximum metabolic reaction velocities for CYP2C19- and CYP3A4-mediated
metabolism of esomeprazole in the whole liver and gut, respectively; Kmu,2C19 is the
Michaelis-Menten constant (corrected for non-specific binding) for CYP2C19-mediated
metabolism of esomeprazole; CLuint,H,3A4 and CLuint,G,3A4 are the whole liver and gut
intrinsic metabolic clearances by CYP3A4-mediated metabolism of esomeprazole,
respectively. fup is the fraction unbound in plasma, fuGut is the fraction unbound in
enterocyte, KpLiver is the liver to plasma concentration ratio, BP is the blood to plasma
concentration ratio, CLiver is the liver concentration and CPV is the portal vein
concentration of esomeprazole. Enz(t) signifies the level of relevant active enzyme at the
site of metabolism which are calculated as described in the literature (1).
2
Initial model (Model E1) during the first round of model development has a fixed
CLuint,2C19 value of (16.2 L/min/pmol of isoform) at enzyme level obtained from the
back calculation using retrograde function based on the i.v. clearance after single dose of
IV infusion of 20 mg esomeprazole. While in Model E2 during second round of model
development, because of TDI, the intrinsic clearance may be more than the fixed value
used in Model E1. To determine the possible higher CYP2C19 metabolism expected from
the observed nonlinear PK at 20 mg to 40 mg i.v., the value of CLu,int,2C19 was manually
increased to 150% or 200% of the initial value. At the same time, kinact and KI values
were estimated based on the literature data (2) using sensitivity analysis, which was
conducted to assess the effect of a range of kinact (1-10/h) and KI (0.1-1 μM) on the AUC
and Cmax values after single i.v. dosing of two doses (20 and 40 mg q.d.) of
esomeprazole. For the second round of model development, model E2-1 was selected
based on the best matching of the predicted parameters with the observed values as
shown in supplementary Table S1. Furthermore, because of the TDI effect of
esomeprazole on CYP2C19, the original fm describing metabolism contribution by
different enzymes may not be concrete. The CLuint, 2C19 may be larger than the value that
was back-calculated from retrograde function of SimCYP. Similarly, CLuint,3A4 could be
less than the back-calculated value. Thus, for the third round of model development (E3
round), we used the CLuint,2C19 with 150% or 200% of the initial value and decrease the
CLuint,3A4 to 60% and 40% of the initial value.
3
Model E3-II with CLuint,2C19 of 24.3 and CLuint,3A4 of 0.36 μL/min/pmol of P450 was
selected as the “best” model during the third round because using Model E3-II can get a
good prediction for esomeprazole PK data after i.v. administration, indicating these
intrinsic clearance values for CYP2C19 and CYP3A4 are plausible. Therefore, these
values were also used in Model E3-II for esomeprazole after p.o. administration. The KI
and kinact obtained from IV data analysis were verified by comparing the predicted AUC
and Cmax to the observed values for each dose after single and multiple p.o.
administration. If there was any discrepancy, sensitivity analysis was performed to assess
the effect of kinact (1-10/h) and KI (0.1-1 μM) on AUC96-120 for 20 mg and 40 mg dosing
(q.d., 5 days) and on AUC144-168 for 15 mg (q.d., 7 days). Also KI and kinact were adjusted
by sensitivity analysis on i.v. data until reaching a compatible value for the p.o. data
analysis, which is similar to a simultaneous fitting process to get estimation for K I and
kinact.
2. Modification of R-omeprazole PBPK model by integrating CYP2C19 inhibition
mechanisms
Based on the observed evidence of decreased clearance when multiple doses (40 mg)
were given (3), a TDI may exist. To account for higher CYP2C19 metabolism expected
from the observed nonlinear PK at 15 mg p.o. compared to 40 mg p.o., auto competitive
inhibition and time dependent inhibition effects on the CYP2C19 are taken into account
to develop Model R2. The value of CLu,int,2C19 was varied in a range of 100-140% of the
4
initial value in the sensitivity analyses for KI and kinact. The ki value was obtained from
literature (2), estimated as IC50/2.
At each CLu,int,2C19 level, KI and kinact values were obtained by doing sensitivity analysis
conducted to assess the effect of a range of KI (0.3-3 μM) and kinact (2-20/h) on the AUC
and Cmax values after 5 days dosing of two doses (20 and 40 mg q.d.) and 7 days dosing
of 15 mg q.d. of R-omeprazole. Optimized combination of CLu,int,2C19,, KI and kinact were
obtained and incorporated in Model R2, based on the similarity of predicted AUC and
Cmax to the observed values for each dose. Both Model R1 and Model R2 were qualified
by visually comparing simulated R-omeprazole plasma PK profiles with those from
clinical studies (3;4) and the similarities of PK parameters such as AUC, Cmax and
clearance/F between the simulated and observed results.
3. Differential equations used in the PBPK model
Differential equations describing the kinetics of esomeprazole or R-omeprazole in the
PBPK model were shown as follows:
dCPV
1

[QPV C sys Q PV C PV  f a  ka  FG (t )  D POk a t ]
dt
VPV
fu
dCliver
1
C

[QPV C PV Q HA C sys (QPV  QHA  p  CLuint,H (t ) )  liver ]
Kpliver
dt
Vliver
BP
BP
5
(3)
(4)
dCsys
dt

1
C
CL
[(QPV Q HA )  liver  (QPV Q HA ) C sys  R C sys  DIV ]
Kp
Vsys
BP
liver
BP
(5)
Where CPV, Cliver and Csys are the concentrations of drug in the portal vein, systemic
circulation and liver, respectively; VPV and Vliver are the volumes of portal vein blood and
of the liver, respectively; Vsys is the volume of distribution of drug (substrate/inhibitor) in
the blood; QPV and QHA are the blood flows in the portal vein and hepatic artery,
respectively; fup is the unbound fraction in plasma, BP is the blood to plasma
concentration ratio of the drug (CB/CP)); fa is the fraction of drug absorbed into the
enterocytes; ka is the first-order absorption rate constant of the drug; FG is the intestinal
availability of the drug; CLR is the renal clearance of the drug from plasma; Kpliver is the
partition coefficient of liver over plasma; Dpo and DIV are the orally and intravenously
administered dose of the drug; CLu,int,H(t) is the time-variant intrinsic metabolic
clearance of the drug in the liver.
4. Enzymes dynamics and inhibition
When both competitive and TDI mechanism were incorporated in the model O to
simulate the mutual and auto-inhibitory effects of both R-omeprazole and esomeprazole
on the hepatic and intestinal metabolism, the CLu,int,G(t) and CLu,int,H(t) in the PBPK
models incorporating TDI were refined by the following equations:
FG (t ) 
Qgut
(6)
Qgut  fugut  CLuint,G (t )
CLuint,G (t )  CLuint,2C19  Amt gut 2C19(t )  Actgut 2C19 (t )  CLuint,3 A4  Amt gut3 A4  Actgut3 A4
6
(7)


dAmtgut 2C19
kinact
 kdeg, gut 2C19  Amt 0, gut 2C19 Amtgut 2C19  kdeg, gut 2C19 

fu
K
dt
1  mic I

fu gut I PV

1
Actgut 2C19 
fugut  I PV
1
fumic ( I )  ki
FH (t ) 






QH
QH  fub  CLuint,H (t )
(8)
(9)
(10)
CLuint,H (t )  CLuint,2C19  Amtliver 2C19(t )  Actliver 2C19 (t )  CLuint,3 A4  Amtliver3 A4  Actliver3 A4
(11)
dAmtliver 2C19
dt
Actliver 2C19 





kinact
 kdeg,liver 2C19  Amt 0,liver 2C19 Amtliver 2C19  kdeg,liver 2C19 
fu
mic ( I )  K I

1
fu p ( I )

I liver


BP ( I ) kpliver ( I )

BP ( I )

1
fu p ( I )
I liver

BP ( I ) kpliver ( I )
BP ( I )
1
fumic ( I )  ki











(12)
(13)
Where FG (t) is the intestinal availability of the drug; Qgut is a nominal flow in gut model
(L/h); fugut is the unbound fraction of drug in enterocytes; fumic(I) is the fraction of
unbound inhibitor in the in vitro microsomal incubation; Amtgut2C19 and Amtgut3A4 are the
amount of active 2C19 and 3A4 at any given time in the gut; Actgut2C19 and Actgut3A4 are
the activity of CYP2C19 and CYP3A4 at any given time in the gut; CLu,int,G (t) is the
time-variant intrinsic metabolic clearance of the drug in the gut; kdeg,gut2C19 is the first
7
order turnover rate constant of the enzyme in the gut; The SimCYP mean default value of
kdeg,gut2C19 used for the simulations is 0.03/h for the gut, Ipv is the concentration of
inhibitor in the portal vein.
CLu,int,H(t) is the time-variant intrinsic metabolic clearance of the drug in the liver;
Amtliver2C19 and Amtliver3A4 are the amount of active 2C19 and 3A4 at any given time in
the liver; Actliver2C19 and Actliver3A4 are the activity of CYP2C19 and CYP3A4 at any
given time in the liver; Amt0,liver2C19 is the basal amount of 2C19 in the liver. kdeg,liver2C19 is
the first order turnover rate constant of the enzyme in the liver; The SimCYP mean
default values of kdeg,liver2C19 used for the simulations is 0.0267/h for the liver; In the
absence of inhibitor, the enzyme content in the gut is at steady state and the degradation
rate is equal to the synthesis rate, which was assumed to be unaffected by inhibitors.
CLu,int,2C19 and CLu,int,3A4 are the time-variant intrinsic metabolic clearance of the drug
by CYP2C19 and CYP3A4, respectively; ki is the CYP2C19 competitive inhibition
constant of R-omeprazole; kinact and KI are the maximum rate of inactivation and the
concentration of inhibitor (R-omeprazole or esomeprazole) that supports half maximal
inhibition interaction between the enzyme and inhibitor, respectively; fup(I) is the
unbound fraction in plasma, BP(I) is the blood to plasma concentration ratio of the
inhibitor(CB/CP); fumic(I) is the fraction of unbound inhibitor in the in vitro microsomal
incubation. Kp,liver(I) is the partition coefficient of liver over plasma for the inhibitor; Iliver
is the concentration of inhibitor in the liver.
8
SUPPLEMENTARY RESULTS
1. Performance of esomeprazole models (Model E1, Model E2 and E3) and Romeprazole model (Model R1 and Model R2) after IV or oral administration
Supplementary Table S1 and S2 show that Model E3-II, relative to Model E1,
significantly improved the prediction of clearance after i.v. and oral administration of
esomeprazole.
Supplementary Table S3 shows that optimized Model R2, relative to Model R1,
significantly improved the prediction of clearance after oral administration of Romeprazole.
2. Sensitivity analysis of the impact of TDI parameters (KI and kinact) of CYP2C19
on the CL/F (Dose/AUC) of esomeprazole after oral administration
Supplementary Figure S1 shows a representative result for the impact of KI and kinact on
the simulated CL/F for esomeprazole after multiple dosing (40 mg q.d.) for 5 days. TDI
parameters KI and kinact appear to play an important role in the changes of CL/F, which
decreases with both the increase of kinact within the range of 1-10/h and the decrease of KI
within the range of 0.1-1 µM.
3. Simulations of active CYP2C19 percentage changes
Supplementary Figure S2 shows a representative simulation result for the percentage of
active CYP2C19 changes after multiple dosing of omeprazole (40 mg, q.d.) and
esomeprazole (40 mg, q.d.) for 5 days. For both omeprazole and esomeprazole, the
9
percentage of active CYP2C19 decreases dramatically during the first 24 hours and then
slowly goes down until getting to the steady state at around 48 hours (omeprazole) or 24
hours (esomeprazole). The lowest percentage of active CYP2C19 reaches around 14.1%
and 6.2% of original abundance for omeprazole and esomeprazole, respectively.
4. Prediction of Drug-drug Interaction between Omeprazole and Fluconazole:
Effect of Concomitant Fluconazole on Omeprazole PK
The effect of concomitant fluconazole on omeprazole PK in healthy volunteers with
various ethnic groups was predicted using the developed omeprazole PBPK model
(combination of esomeprazole model E3-II and R-omeprazole model R2) and fluconazole
PBPK model taken from the SimCYP Inhibitor Library. Simulations were conducted
according to the trial design reported in the paper by Kang et al (5). In the simulation, a
single p.o. dose of 20 mg omeprazole (solution), with fluconazole 100 mg (solution), was
administered to male healthy volunteers (n=180, 10 trials and 18 subjects per trial) on day
5 after p.o. dose of 100 mg fluconazole q.d. for 4 days. AUC and Cmax ratios
(with/without fluconazole) were calculated using the simulated mean AUC or Cmax
values and compared with the observed ratios. The observed and predicted omeprazole
AUC ratios (with/without fluconazole) are shown in Supplementary Table S4. Because
the study was conducted in Korean population, which is not available in the SimCYP
Population Library, we used Japanese, Chinese and Caucasian populations. Compared to
the values observed by Kang et al, both predicted AUC and Cmax ratio in Chinese (4.8
and 1.9) and in Caucasian (6.9 and 2.1) populations are comparable to those observed in
10
the Korean population (6.3 and 2.4). Note that we have not considered any possible effect
due to formulation differences (solution was used in our simulations while capsule was
used in the clinical study).
SUPPLEMENTARY DISCUSSION
The selection of distribution model of R- and S-omeprazole
In this study, minimal PBPK model using SimCYP software was developed to predict
drug concentrations in plasma, portal vein and liver compartments as the tissue
distribution of R- and S-omeprazole is low with a Vss of 0.1 and 0.2 L/kg which are less
than body water (0.7 L/kg) (6). Full PBPK model with TDI inhibition using SimCYP
software was also adopted to predict the pharmacokinetic profile after i.v. infusion of 40
mg esomeprazole, however, the simulated results did not capture the observed data,
especially it missed the terminal phase (data not shown). For the simplicity of the models
and not introducing more unknown parameters such as kps, minimal PBPK model was
selected for predicting R- and S-omeprazole pharmacokinetic profiles.
Reference List
1. Rowland YK, Jamei M, Yang J, Tucker GT, Rostami-Hodjegan A.
Physiologically based mechanistic modelling to predict complex drug-drug
interactions involving simultaneous competitive and time-dependent enzyme
inhibition by parent compound and its metabolite in both liver and gut - the effect
11
of diltiazem on the time-course of exposure to triazolam. Eur J Pharm Sci 2010;
39(5):298-309.
2. Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A, Paris BL et
al. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole,
is
a
metabolism-dependent
inhibitor
of
CYP2C19:
implications
for
coadministration with clopidogrel. Drug Metab Dispos 2011; 39(11):2020-33.
3. Hassan-Alin M, Andersson T, Niazi M, Rohss K. A pharmacokinetic study
comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its
two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy
subjects. Eur J Clin Pharmacol 2005; 60(11):779-84.
4. Andersson T, Weidolf L. Stereoselective disposition of proton pump inhibitors.
Clin Drug Investig 2008; 28(5):263-79.
5. Kang BC, Yang CQ, Cho HK, Suh OK, Shin WG. Influence of fluconazole on the
pharmacokinetics of omeprazole in healthy volunteers. Biopharm Drug Dispos
2002; 23(2):77-81.
6. Chen Y, Jin JY, Mukadam S, Malhi V, Kenny JR. Application of IVIVE and
PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy
and approach during the drug discovery phase with four case studies. Biopharm
Drug Dispos 2012; 33(2):85-98.
12
7. Hassan-Alin M, Andersson T, Bredberg E, Rohss K. Pharmacokinetics of
esomeprazole after oral and intravenous administration of single and repeated
doses to healthy subjects. Eur J Clin Pharmacol 2000; 56(9-10):665-70.
8. Andersson T, Hassan-Alin M, Hasselgren G, Rohss K, Weidolf L.
Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin
Pharmacokinet 2001; 40(6):411-26.
13
Supplementary Table S1. Observed vs. predicted clearance, AUC and Cmax after i.v.
single (s.d., Day 1, 0-24 h) ascending doses of esomeprazole solution in population
representatives
Predicted
PK
Dose
Observeda
parameters
(mg)
Initial model
Modified
Modified
Modified
Modified
E1
model
model
model
model
E2- I
E3- I
E3-II
E3-III
(Cluint,2C19
(Cluint,2C19
(Cluint,2C19
(Cluint,2C19
(Cluint,2C19
16.2
16.2
16.2
24.3
32.4
Cluint,3A4
Cluint,3A4
Cluint,3A4 0.36
Cluint,3A4 0.36
Cluint,3A4 0.36
0.612
0.612
µL/min/pmol
µL/min/pmol
µL/min/pmol
µL/min/pmol
µL/min/pmol
of isoform )
of isoform )
of isoform )
of isoform )
of isoform )
Without
KI 0.4
KI 0.8
KI 0.3
KI 0.3
applying
umol/L,
umol/L,
umol/L,
umol/L,
TDI
kinact 6/h
kinact 8/h
kinact 5/h
kinact 8/h
CL(Dose/AUC,
20
22.2
21.1
17.9
16.9
19.8
21.5
40
15.8
19.9
14.0
12.8
14.3
13.1
20
2.60
2.75
3.24
3.42
2.93
2.69
40
7.32
5.81
8.28
9.03
8.07
8.83
20
2.62
2.80
2.83
2.89
2.83
2.69
40
5.70
5.92
6.06
6.17
6.06
5.81
L/h)
AUC (µM*h)
Cmax (µM)
a: observed values from Hassen-Alin et al, 2000 (7). The PK parameters such as AUC, Cmax were
recalculated using Phoenix WinNonlin based on the digitized data.
14
Supplemental Table S2. Observed vs. predicted clearance after oral single (s.d., Day 1,
0-24 h) and multiple ascending doses (q.d. for 5 days of 20/40 mg esomeprazole solution
or 7 days of 15 mg esomeprazole solution) in population representatives
PK
parameters
CL/F
(Dose/AUC,
L/h)
AUC
(µM*h)
Cmax
(µM)
Dose(mg)
15
20
40
15
20
40
15
20
40
Observeda
s.d.
(day1)
67.8
32.9
23.9
0.64
1.76
4.84
0.85
1.33
3.27
m.d.
(day5/7)
31.9
18.7
11.0
1.36
3.10
10.5
1.55
1.88
4.73
Predicted
Model E1
Model E3-II
based on the above
Based on the above
initial model
modified model E3-II
Cluint,2C19=16.2 and
Cluint,3A4 =0.612
Cluint,2C19=24.3 and
µL/min/pmol of
Cluint,3A4 =0.36
isoform
µL/min/pmol of isoform
(Without applying TDI (KI=0.3 μM, kinact=5/h,
ka=10/h, fugut=0.03, ka=10/h,
fugut=0.03,
Vss=0.2
L/kg, Vss=0.2 L/kg, fumic=1)
fumic=1)
s.d.
(day1)
38.4
37.8
37.7
1.13
1.53
3.07
1.20
1.60
3.21
m.d.
(day5/7)
37.7
37.8
37.8
1.15
1.53
3.06
1.20
1.61
3.21
s.d.
(day1)
39.8
37.4
29.2
1.09
1.55
4.23
1.11
1.5
3.10
m.d.
(day5/7)
24.8
20.7
12.5
1.75
2.80
9.24
1.37
1.91
4.29
a. Observed data from Hassan-Alin et al, 2005 and Andersson 2001 (3;8). The PK parameters such as
AUC, Cmax were recalculated using Phoenix WinNonlin based on the digitized data.
15
Supplementary Table S3. Observed vs. predicted pharmacokinetic parameters after oral
single (s.d., Day 1, 0-24 h) and multiple (m.d., Day 5, 96-120 h or m.d., Day 7, 144-168
h) ascending doses of R-omeprazole solution using population representatives.
Predicted
PK parameters
CL/F(Dose/AUC,
L/h)
AUC (µM*h)
Cmax (µM)
Dose (mg)
15
20
40
15
20
40
15
20
40
Observeda
s.d.
(day1)
127.65
72.38
70.61
0.34
0.8
1.64
0.55
0.8
1.87
m.d.
(day5/7)
140.00
65.80
48.25
0.31
0.88
2.4
0.47
0.82
2.34
Initial model
(Model R1)
Cluint,2C19=29.9
Modified model
(Model R2)
Cluint,2C19=29.9
µL/min/pmol isoform
µL/min/pmol isoform
(Without
applying
TDI, ki=4.05µM
(ki=4.05µM,
KI
=1.6 µM, kinact=4/h,
Vss=0.1 L/kg
ka=2/h, fugut=0.04,
fumic=1)
s.d.
m.d.
(day1)
(day5/7)
70.00
64.78
68.93
62.93
66.17
54.62
0.62
0.67
0.84
0.92
1.75
2.12
0.64
0.68
0.86
0.93
1.75
2.02
ka=2/h, fugut=0.04,
fumic=1)
s.d.
m.d.
(day1)
(day5/7)
71.15
71.15
71.48
71.48
71.48
71.48
0.61
0.61
0.81
0.81
1.62
1.62
0.64
0.64
0.85
0.85
1.70
1.70
a. Observed data from Hassan-Alin et al, 2005 and Andersson 2001 (3;8). The PK parameters such as
AUC, Cmax were recalculated using Phoenix WinNonlin based on the digitized data.
16
Supplementary Table S4. Observed vs. predicted omeprazole AUC and Cmax ratios
(with/without fluconazole 100mg q.d. from Day 1 to Day 5) following single oral dose of
omeprazole 20 mg administered on Day 5 in healthy volunteers
Parameters
Predicteda in
Japanese pop.
Predicteda in
Chinese pop.
Predicteda in
Caucasian pop.
Observedb in
Korean pop.
(omeprazole
solution)
(omeprazole
solution)
(omeprazole
solution)
(omeprazole
capsules)
Omeprazole AUC
ratioc
2.5
4.8
6.9
6.3
Omeprazole Cmax
ratioc
1.3
1.9
2.1
2.4
(omeprazole+
fluconazole
/omeprazole
alone)
a. Predicted from simulations using virtual population of 10 trials of healthy subjects with various races
(n=18 per trial);
b. Observed data from Kang et al, 2002 (5).
c. Omeprazole AUC ratio = AUCwith fluconzole / AUCwithout fluconazole; Cmax ratio was calculated in a similar
manner.
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Legends to Supplementary Figures
Supplementary Figure S1. Changes in esomeprazole CL/F (Dose/AUC) as a function of
TDI parameters (KI and kinact) of CYP2C19 pathway, when sensitivity analysis was
performed using modified model E3-II in Supplementary Table S2 for esomeprazole after
p.o. multiple dosing (40 mg q.d. for 5 days).
Supplementary Figure S2. Final model predicted CYP2C19 activity changes in the liver
following oral dosing of esomeprazole (A) and omeprazole (B) with TDI effect (dosing
regimen: PO-40 mg q.d. for 5 days)
Supplemental Figure S3. Simulated (lines) and observed (circles) mean plasma
concentration-time profile of R-omeprazole using initial model (model R1) and modified
model (model R2) incorporating TDI of CYP2C19 after multiple oral administration of
R-omeprazole (A) with 20 mg q.d. dosing for 5 days and (B) with 40 mg q.d. dosing for 5
days in healthy subjects.
18