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PBPK modeling to characterize the interplay between metabolism and
transport in the disposition of simeprevir in healthy volunteers and
HCV infected patients
Sivi Ouwerkerk-Mahadevan1 and Jan Snoeys1
1Janssen Research & Development, Beerse, Belgium
Simeprevir (SMV/TMC435)
Phase III trials of SMV+PR in HCV GT 1- and GT 4-infected treatment-naïves and relapsers showed SVR12 rates ~80%1–4
In a Phase II trial (COSMOS) of SMV + sofosbuvir ± ribavirin in HCV GT 1-infected treatment-naïves and prior null responders, the overall SVR12 rate was 92.2%5,6
Safe and well tolerated (~3800 patients treated in clinical trials to date) In development as part of IFN-free combinations
GT, genotype; IFN, interferon; PR, peginterferon-α-2a/-2b + ribavirin; SVR12, sustained virologic response 12 weeks after end of treatment
1. Jacobson I et al. Lancet In press; 2. Manns M et al. Lancet In press; 3. Forns X et al. Gastroenterology Mar 3 [Epub ahead of print];
4. Moreno C et al. HepDART 2013; 5. Lawitz E et al. EASL 2014; 6. Sukowski MS et al. EASL 2014.
O O O O N H
N H
O O
N N
N
S
MeO
(S)
(R) (R) (R) (R)
S
Once-daily capsule, HCV NS3/4A protease inhibitor
Approved in Japan, Canada, the USA, Russia and Europe
Antiviral activity in patients infected with HCV GT 1, 2, 4, 5, and 6
Substantial interpatient variability in plasma concentrations – No correlation with sustained virologic response (SVR) at therapeutic dose
More than dose-proportional increase in exposure
Increase in exposure on repeated dosing – Steady-state achieved in approximately 7 days
Difference in pharmacokinetics between healthy volunteers and patients: 2–3-fold higher exposure in patients
Ethnic differences: higher exposure in Japanese patients
Substrate of several uptake and efflux transporters
Pharmacokinetic challenges of simeprevir
Dose-normalized AUC vs dose in HCV patients
CV, coefficient of variation
Phase 2/3 studies C201, C205, C206, C208, C216, HPC3007
Dose (mg)
% CV N
25 52 18
75 79 177
100 87 196
150 111 1133
200 75 30
2000
1500
1000
500
0 0 50 100 150 200
SMV dose (mg)
SMV
dose
-nor
mal
ized
AU
C
(ng.
h/m
L/m
g)
AUC in non-Asian global phase 3 studies and in a Japanese phase 2 study
500 400
C215 Asian n=38
AUC
(µg.
h/m
L)
300 200
100
150 mg 100 mg
Non-Asian Asian
Phase 3 non-Asian
n=757
Phase 3 Asian n=14
Reason for non-linear PK
Reason for large interpatient variability
Mechanism for difference between healthy volunteers and HCV-infected patients
Ethnic differences
Drug–drug interactions in HCV-infected patients
Use of PBPK modeling to understand:
PBPK, physiologically based pharmacokinetic
PBPK model components
Drug-dependent component
System component (drug-independent)
Intestines
Lung
Oral dose
Rapidly perfused organs
Slowly perfused organs
Kidney
Liver
ADME, PK, PD, and MOA Metabolism Active transport Passive diffusion Protein binding Drug–drug interactions Receptor binding
PBPK model Dosing
Elimination
MOA, mode of action
Simeprevir parameters used for simulations
Physicochemical properties
Low solubilities at all pH
Saturation of hepatic uptake (non-linear distribution)
Saturation of liver and gut CYP3A4 (non-linear clearance)
Clinical pharmacokinetics in healthy volunteers
Not included: – Active efflux in gastro-intestinal tract via, for example, P-gp; not
considered to play a major role, confirmed by data from drug-drug interaction with cyclosporine and data from single dose ritonavir
Model verification: Simulating the known – single dose studies
Simulation of healthy Caucasians (N=50) Observed data
Minimal change in half-life despite pronounced non-linear increase in exposure with dose – Saturable gut and liver CYP3A4 metabolism, and saturation of active uptake
Simultaneous decrease in both Vd and Cl, therefore t1/2 remains constant
100000
10000
1000
100
10
1.0
0.1 8 0 16 24 32 40 48 56 64 72
Time (h)
600 mg 450 mg 300 mg 200 mg
150 mg 100 mg 50 mg
Plas
ma
conc
entra
tion
(mg/
mL)
100000
10000
1000
100
10
1 0 12 24 36 48 60 72
Time (h)
600 mg 450 mg 300 mg 200 mg
100 mg 50 mg
Plas
ma
conc
entra
tion
(ng/
mL)
Model verification: Simulating the known – single dose studies
AUC dose normalized versus the 50 mg SMV dose. Simulations performed in 54 healthy Caucasian male volunteers. Observed data in 6 patients except for 150 mg SMV dose in 24 patients
Simulated average (±SD) and observed average SMV plasma AUC0–72h after single dose administration D
ose
norm
aliz
ed A
UC
(ng/
mL)
SMV dose (mg)
35000
0 0 50 100 150 200 250 300 350 400 450 500 550 600
5000
10000
15000
20000
25000
30000
Simulated Observed
Model verification: Simulating the known – multiple dose studies
Dose and time-dependant PK is explained by saturable clearance and saturable distribution – Lack of time-dependent inhibition was also confirmed from midazolam DDI studies
100000
10000
1000
100
10
1.0
0 24 0 48 72 96 120 144 168
Time (h)
350 mg QD 200 mg QD 150 mg QD 100 mg QD
Plas
ma
conc
entra
tion
(ng/
mL)
140000
120000
80000
60000
20000
0 50 100 150 200 250 300 350
SMV dose
Dos
e no
rmal
ized
mea
n SM
V AU
C
(ng/
ml.h
)
40000
100000
Simulated Observed
Simulation of the following interactions, and comparison with clinical DDI studies in healthy volunteers: – CYP3A4 interaction without impact on hepatic uptake
● Ritonavir (100 mg QD/BID) and erythromycin (500 mg TID) inhibit intestinal and hepatic CYP3A4 and intestinal P-gp but not hepatic OATPs
– OATP interaction without impact on metabolic clearance ● Cyclosporine (100 mg) inhibits intestinal P-gp and hepatic OATPs
– Combined OATP and CYP3A4 interactions ● Rifampicin (600 mg QD) inhibits OATP and induces liver and intestinal
CYP3A. Also inhibits hepatic MRP2 and induces intestinal P-gp
Model verification: DDI studies
MRP, multidrug resistance-associated protein; P-gp, P-glycoprotein
Efavirenz 600 mg QD – modification of published model by Rekic et al. fugut was reduced to remove
intestinal CYP3A4 induction
Ritonavir 100 mg QD and BID – modified to include CYP3A4 inactivation kinetic parameters so that complete
inhibition of gut and liver CYP3A4 is achieved (Ernest et al., Mathias et al.)
Rifampicin 600 mg QD – Model by Xu et al. was used. Induction of CYP3A4 on Day 1 was removed.
OATP1B1/3 Ki modified based on published statin interactions (Maeda et al.)
Erythromycin 500 mg TID – Simcyp Sim-file was used unmodified
Cyclosporine 100 mg – Model by Varma et al. was modified. CYP3A4 Clint added. Lag time, Fa, Ka included
in first-order absorption model, muscle Kp reduced to match observed Vd,ss. OATP inhibition, Fu, inc and CYP3A4 Ki were modified to match published DDI data
Model verification: Compound file modification to match clinical data
Model verification: Ritonavir DDI
Plasma concentration time profile for 200 mg QD. SMV administration for 7 days with and without 100 mg BID ritonavir in healthy Caucasian volunteers (study C104), and simulated data in 36 patients
Simulated GMR Observed GMR
Cmax AUC Cmax AUC
Ritonavir 5.8 10 4.7 (3.8–5.8) 7.2 (5.6–9.2)
28000
0 24
Time-substrate (h)
Plas
ma
conc
entra
tion
(ng/
mL)
24000
20000
16000
12000
8000
4000
20 16 12 8 4
CSys CSys with interaction 28000
0 0 24
Time-substrate (h)
Plas
ma
conc
entra
tion
(ng/
mL)
24000
20000
16000
12000
8000
4000
20 16 12 8 4
SMV 200 mg QD, day 7 (n=12) SMV 200 mg QD + Ritonavir 100 mg BID, Day 12 (n=12)
0
PBPK DDI summary Source: FDA clinical pharmacology review (modified)
PBPK model simulated and observed exposure changes of SMV by different enzyme and/or transport inhibitors and inducers
Inhibitor / inducer (mechanisms)
SMV dose
AUC (Cmax) ratio Explanation of observed DDI findings
Sim Obs
Ritonavir (Strong CYP3A inhibitor)
Single 2.1 (13) 1.8 (1.3) CYP3A inhibition augmented OATP saturation over time Multiple 10 (5.8) 7.2 (4.7)
Erythromycin (moderate CYP3A inhibitor)
Single 1.4 (1.1) - Erythromycin DDI study was done using lower SMV dose (150mg) than the ritonavir
study (200mg). At lower doses, stronger interaction is seen
Multiple 6.2 (3.7) 7.5 (4.5)
Cyclosporine (OATP inhibitor) Multiple 1.3
(Cmin ratio) 1.2
(Cmin ratio) OATP saturation after multiple dosing
diminished inhibitor effect
Rifampin (strong CYP3A inducer,
OATP inhibitor)
Single 2.1 (1.8) - OATP inhibition + CYP3A4 induction: Cmax and AUC of SMV Multiple 0.6 (1.1) 0.5 (1.3)
Efavirenz (moderate CYP3A inducer) Multiple 0.3 (0.6) 0.5 (0.3) CYP3A induction only, no effect on OATP
Cmax AUC
Summary
Figure reproduced with permission of John Keogh, JPK Consulting and modified
CYP3A4
Hepatocyte
Low doses
OATPs
CYP3A4
Hepatocyte
High and/or multiple doses
OATPs
Saturating
Non-linearity of SMV PK is described by Saturation of both OATP Uptake and CYP3A4 metabolism
CYP3A4
Hepatocyte
Ritonavir or Erythromycin Day 1
OATPs
CYP3A4
Hepatocyte
Ritonavir or Erythromycin Day 7
OATPs
Saturation
Saturation of OATP due to increased circulating Simprevir following inhibition of CYP3A4.
CYP3A4
Hepatocyte
Cyclosporine single dose at SS
OATPs
Near saturation of OATPs following repeat dose of victim accounts for relatively modest increase in exposure following single dose administration of a potent OATP inhibitor
CYP3A4
Hepatocyte
Rifampicin multiple dose
OATPs
CYP3A4
Hepatocyte
Efavirenz multiple dose
OATPs
Inhibition of OATPs by Rifampicin, but not by Efavirenz explains observation of increased Cmax by Rifampicin, despite decreased AUC observed for both CYP3A4 inducers
Already approaching Saturation
Cmax AUC
Changes were incorporated into the model for mild hepatic impairment Liver volume in HCV patients was 10% lower1,2 CYP3A4 abundance was decreased from 137 pmol/mg protein to
108.1 pmol/mg protein3
This resulted in 30% lower liver CYP3A4 Clint
A population of HCV patients was created
1. Lin et al Hepatogastroenterology 1998; 2. Johnson et al Clin Pharmacokinet 2010; 3. Nakai et al. DMD 2008
1 0
2 3 4 5 6 7 8
Non-HCV* F1 F2 F3
NS NS
p<0.05
CYP
3A4/
GAP
DH
1
0
2
3
4
5
6
Non-HCV* F1 F2 F3
NS p<0.05
p<0.01
OAT
P-C
/GAP
DH
Healthy volunteers
Simulating the known: Healthy volunteers and patients dosed SMV 150mg QD
0 31 62 93 124 155 186 217 248 279 310 0 31 62 93 124 155 186 217 248 279 310 0
1,000
2,000
3,000
4,000
5,000
Plas
ma
conc
entra
tion
(ng/
mL)
Time (h)
4,500
3,500
2,500
1,500
500
Patients
tmax
(h) Cmax
(ng/mL) AUC
(ng/mL.h)
3.90 2129 26951
Plas
ma
conc
entra
tion
(ng/
mL)
Time (h)
tmax
(h) Cmax
(ng/mL) AUC
(ng/mL.h)
4.52 4385 71316
0
1,000
2,000
3,000
4,000
5,000 4,500
3,500
2,500
1,500
500
Liver volume in Chinese patients is >30% smaller than in Caucasian patients Hepatic CYP3A4 abundance per mg protein is slightly lower in Chinese patients vs
Caucasian patients Lower OATP1B1 hepatic uptake transporter expression levels in Japanese patient
CYP3A abundance in Caucasian vs Chinese patients
Barter et al. Clin Pharmacokinet 2013; Tomita et al. Clin Pharmacol Ther 2013
Gut CYP3A Hepatic CYP3A
Caucasian Chinese
CYP
abu
ndan
ce (n
mol
)
0
500
1000
1500
2000
Live
r vol
ume
(mL)
Caucasian Chinese
Liver volume
137
116 120
99
020406080
100120140160
CPY3A4 CYP3A5
66
25
58
22
0
10
20
30
40
50
60
70
CPY3A4 CYP3A5
CYP
abu
ndan
ce (n
mol
)
Simulations: Chinese vs Caucasian healthy volunteers
Chinese patients (N=40)
Incorporating differences in liver volume and CYP3A4 expression into the model gives plasma exposures in Chinese patients 2-fold higher than in Caucasian patients at 100 mg
0 12 24 36 48 60 72 84 96 108 120 24 36 48 60 72 84 96 108 120 Time (h)
Upper CI
0 12
1,000 1,500 2,000 2,500 3,000 3,500 4,000 4,500
Plas
ma
conc
entra
tion
(ng/
mL)
Mean Lower CI
Cmax (ng/mL)
AUC (ng/mL.h)
2071 38292
Cmax (ng/mL)
AUC (ng/mL.h)
1098 17895
0 500
Time (h)
1,000 1,500 2,000 2,500 3,000 3,500 4,000 4,500
Plas
ma
conc
entra
tion
(ng/
mL)
0 500
Caucasian patients (N=40)
5,000 5,000
Simulating the unknown: Liver concentrations of SMV in Japanese and Caucasian patients
Physiological factors incorporated into the model: Japanese patients have 15% lower liver volume, lower CYP3A4 abundance, and intrinsically lower OATP1B1 baseline activity
Liver 150 mg Caucasian patients Liver 100 mg Japanese patients Plasma 150 mg Caucasian patients Plasma 100 mg Japanese patients
80000 SM
V co
ncen
tratio
n (n
g/m
l) 70000
60000
50000
40000
30000
20000
10000
0 460 456 464 468 472 476 480
Time (h)
Simulating the unknown: DDI in patients
AUC ratio healthy
volunteers
AUC ratio HCV patients
CYP 3A inhibitors
Ritonavir 100 mg BID 10 5.1
Erythromycin 6.2 4.9
CYP 3A inducers
Efavirenz 0.3 0.23
Rifampicin 0.54 0.32
OATP substrate
Rosuvastatin 2.9 2.8
Regulatory feedback FDA PBPK modeling review memo online
Questions addressed by the submitted PBPK modeling report and additional information requested by the Office of Clinical Pharmacology include: – What are the major mechanisms contributing to non-linear PK
of SMV? – Can DDI with SMV be predicted?
In addition, sponsor simulated PK of SMV in various specific populations and projected liver concentrations of SMV in Caucasian and Asian HCV patients
Regulatory feedback FDA PBPK modeling review memo online
Conclusion Sponsor’s PBPK modeling and simulation reasonably captured
non-linear PK of SMV Saturation of OATP transporter mediated drug distribution into
the liver and saturation of CYP3A4 metabolism together appear to be the plausible mechanisms contributing to the non-linear PK and differential effects of CYP3A4 and/or OATP modulators observed in the DDI studies
The model can be used to predict other untested DDI situations and to evaluate the effect of various intrinsic factors (eg. ethnicity, liver disease) on SMV exposure
Acknowledgements
The authors would like to thank the volunteers and:
– Jan Snoeys – Maarten Huisman – Anne Brochot – Maria Beumont-Mauviel – Alex Simion
Medical writing support was provided by Martin Goulding on behalf of Complete Medical Communications, funded by Janssen