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 a potent hepatitis C virus (HCV) NS3/4A protease inhibitor in Phase 3 development TMC647055 a potent novel HCV nonnon-nucleoside NS5B polymerase inhibitor coadministered with ritonavir in phase 2 studies 2
Background-2 Simeprevir 150 mg qd + TMC647055 1000 mg bid have been co-administered to HCV genotype 1 infected patients for 10 days 1 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 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 metabolism 1,2,3 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 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 5
Simulating the past: simeprevir CYP3A4 inhibition Simeprevir-ritonavir DDI in healthy subjects 1 simeprevir 200 mg qd alone or with ritonavir 100 mg bid for 7 days CYP3A4 induction Simeprevir-efavirenz DDI in healthy subjects 2 simeprevir 150 mg qd alone or with efavirenz 600 mg qd for 14 days Effect of ritonavir on simeprevir Ratio with/without Observed Predicted* (PBPK) C max 4.7 4.3 AUC 0-24h 7.2 5.9 Effect of efavirenz on simeprevir Ratio with/without Observed Predicted* (PBPK) C max 0.49 0.60 AUC 0-24h 0.29 0.30 *: Virtual trial in healthy subjects 1. Sekar V, et al. EASL, Vienna, 2010 2. Ouwerkerk-Mahadevan S, et al. CROI, Seattle, Washington, 2012 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 Simeprevir Observed Predicted* C max (ng/ml) Mean parameters (CV%) observed and predicted on Day 10 1600 (37) 1300 (79) TMC647055 Observed Predicted* C max (ng/ml) 11000 (40) 8200 (48) AUC 0-24h (ng.h/ml) 13000 (46) 15000 (97) AUC 0-12h (ng.h/ml) 46000 (45) 54000 (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) 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) 8
Clinical study in healthy subjects: study design Period 1 Simeprevir 150 mg Period 2 Simeprevir 50 mg TMC647055 300 mg Ritonavir 20 mg 7-day washout 14 days 14 days 21-day washout Period 3 Simeprevir 100 mg TMC647055 600 mg Ritonavir 30 mg 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
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) Mean (CV%) C max ng/ml AUC 24h ng.h/ml C min * ng/ml Combo 300 mg qd Day 14 6570 (60) 52200 (56) 210 (86) Alone 1000 mg bid historical data Day 6 5220 (27) 40100 (33) 160 (42) *: C 12h for bid dosing and C 24h for qd dosing 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 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 12