Combination Therapy with Simeprevir and TMC647055/Low Dose Ritonavir: Dose Anticipation Using PBPK Modeling and Dose Optimization in Healthy Subjects
Combination therapy with simeprevir and TMC647055/low dose ritonavir: dose anticipation using PBPK modeling and dose optimization in healthy subjects
MC. Rouan, J. Snoeys, S. Ouwerkerk-Mahadevan, R. Verloes, K. Marien, L. Vijgen, A. Vandebosch, P. Van Remoortere, P. De Doncker and K. Simmen Janssen Infectious Diseases, Beerse, Belgium and Titusville, USA
8th International Workshop on Clinical Pharmacology of Hepatitis Therapy Cambridge MA, USA
26-27 June 2013 Background-1
Simeprevir TMC647055 a potent hepatitis C virus a potent novel HCV non- (HCV) NS3/4A protease non-nucleoside NS5B inhibitor in Phase 3 polymerase inhibitor co- development administered with ritonavir in phase 2 studies
Janssen Research & Development 2 Background-2 Simeprevir 150 mg qd + TMC647055 1000 mg bid have been co-administered to HCV genotype 1 infected patients for 10 days1 . The combination was safe and well tolerated . A potent antiviral activity was observed . TMC647055 exposure was increased by simeprevir (AUC ↑ about 2-fold ) . Exposure decreased with repeated dosing for both compounds
1. Bourgeois S, et al. EASL, Amsterdam, 2013
Janssen Research & Development 3 Why is TMC647055 administered with ritonavir?
. TMC647055 . Substrate for CYP3A4 and P-gp . Inducer of CYP3A4 (4β-hydroxy cholesterol plasma concentrations indicated TMC647055 dose dependent induction) . Reduces its exposure and that of simeprevir (substrate for CYP3A4) upon repeated dosing . Ritonavir (low dose < 100 mg qd) . Strong inhibitor of CYP3A4-mediated metabolism1,2,3 . Inhibitor of P-gp transport (clinical significance P-gp << CYP3A4 )3
⇒ CYP3A4 induction by TMC647055 offset with ritonavir low dose <100 mg?
1. Mathias AA, et al. Clin Pharmacol Ther. 2009 Jan;85(1):64-70 2. Eichbaum C, et al. Eur J Clin Pharmacol. Published online: 09 June 2013 3. Ieiri I, et al. J Clin Pharmacol. 2013 Jun;53(6):654-61
Janssen Research & Development 4 Doses anticipation using PBPK modeling
. PBPK modeling to predict dose levels . Building PBPK models* for the three components (simeprevir, TMC647055, ritonavir) . DDI# PBPK prediction considering CYP3A4-mediated interactions in the gut and the liver . Target exposures for the combination simeprevir + TMC647055/r . Simeprevir: exposure at 150 mg qd alone (current phase 3 trials) . TMC647055: exposure at 1000 mg bid alone (monotherapy data) . Clinical DDI study in healthy subjects to refine the doses to be given in a 12-week study in HCV-infected patients
*: Physiologically Based Pharmacokinetic models (Simcyp simulator) # : Drug Drug Interaction
Janssen Research & Development 5 Simulating the past: simeprevir
CYP3A4 inhibition CYP3A4 induction Simeprevir-ritonavir DDI Simeprevir-efavirenz DDI in healthy subjects1 in healthy subjects2 simeprevir 200 mg qd alone or with simeprevir 150 mg qd alone or with ritonavir 100 mg bid for 7 days efavirenz 600 mg qd for 14 days
Effect of ritonavir on simeprevir Effect of efavirenz on simeprevir
Ratio Observed Predicted* Ratio Observed Predicted* with/without (PBPK) with/without (PBPK)
C ↑ 4.7 ↑ 4.3 max Cmax ↓ 0.49 ↓ 0.60
AUC ↑ 7.2 ↑ 5.9 AUC ↓ 0.29 ↓ 0.30 0-24h 0-24h
*: Virtual trial in healthy subjects 1. Sekar V, et al. EASL, Vienna, 2010 2. Ouwerkerk-Mahadevan S, et al. CROI, Seattle, Washington, 2012
Janssen Research & Development 6 Simulating the past: dual combination 150 mg qd simeprevir + 1000 mg bid TMC647055 in HCV-infected patients for 10 days Simulated average plasma concentration-time profiles
Simeprevir TMC647055
Mean parameters (CV%) observed and predicted on Day 10 Simeprevir Observed Predicted* TMC647055 Observed Predicted*
Cmax 1600 1300 Cmax 11000 8200 (ng/ml) (37) (79) (ng/ml) (40) (48)
AUC0-24h 13000 15000 AUC0-12h 46000 54000 (ng.h/ml) (46) (97) (ng.h/ml) (45) (62) *: Virtual trial in HCV-infected patients. TMC647055 PBPK predictions were adjusted for the effect of simeprevir not incorporated in the current model (2-fold increase in exposure)
Janssen Research & Development 7 Simulating the unknown
50 mg qd simeprevir, 300 mg qd TMC647055, 20 mg qd ritonavir is predicted to result in exposures close to targets
Simulated average plasma concentration-time profiles*
Simeprevir TMC647055
*: Virtual trial in healthy subjects. TMC647055 PBPK predictions were adjusted for the effect of simeprevir not incorporated in the current model (2-fold increase in exposure)
Janssen Research & Development 8 Clinical study in healthy subjects: study design
Period 1 Period 2 Period 3 Simeprevir 150 mg Simeprevir 50 mg Simeprevir 100 mg TMC647055 300 mg TMC647055 600 mg Ritonavir 20 mg Ritonavir 30 mg 7-day washout 21-day washout 14 days 14 days 14 days
qd administration of the three compounds after breakfast. Blood PK sampling on Day 14
. Open-label, sequential study design consisting of 3 treatment periods separated by a washout period (n = 10 adult healthy subjects) . Compare exposure of simeprevir and TMC647055 when administered together with ritonavir at doses predicted using PBPK (Period 2) and at doses defined after interim analysis of previous study data (Period 3) to the target exposures (simeprevir: 150 mg qd alone, Period 1; TMC647055: 1000 mg bid alone, historical data) . Assess the safety and tolerability of multiple doses of simeprevir +TMC647055/r
Janssen Research & Development Results: TMC647055 pharmacokinetics
Mean TMC647055 plasma profiles and PK parameters • at 300 mg qd with 50 mg qd simeprevir + 20 mg qd ritonavir • at 1000 mg bid alone (historical data)
Alone Combo Mean 1000 mg bid 300 mg qd (CV%) historical data Day 14 Day 6
Cmax 6570 5220 ng/ml (60) (27)
AUC24h 52200 40100 ng.h/ml (56) (33)
Cmin* 210 160 ng/ml (86) (42)
*: C12h for bid dosing and C24h for qd dosing
Janssen Research & Development 10 Results: simeprevir pharmacokinetics
Mean simeprevir plasma profiles on Day 14 • at 150 mg qd alone • at 50 mg with 300 mg qd TMC647055 + 20 mg ritonavir • at 100 mg with 600 mg qd TMC647055 + 30 mg ritonavir
Janssen Research & Development 11 Conclusions
. PBPK predictions allowed informed selection of appropriate doses to be tested in healthy volunteers . The CYP3A4 inducing effect of TMC647055 was counteracted by low-dose ritonavir. This enabled qd dosing of TMC647055 . Co-administration of simeprevir and TMC647055/r was safe and well tolerated in healthy subjects . A trial in HCV-infected patients is ongoing with 12-week co-administration of simeprevir and TMC647055/r at doses derived from the exposures obtained in healthy subjects
Janssen Research & Development 12