Session Title: Category 5h. VIRAL HEPATITIS: h. HEPATITIS C - DRUG DEVELOPMENT
Presentation Date: Apr 16, 2010
IMPACT OF LOW DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF RG7227 (ITMN-191), A HIGHLY POTENT AND SELECTIVE INHIBITOR OF THE HCV NS3/4A PROTEASE
J.Ö. Haznedar1*, J. Fretland2, G. Leong3, S. Blotner4, T. Hill5, P. Smith1, J.Q. Tran1
1Clinical Pharmacology, Roche, South San Francisco, CA, 2Department of Drug Metabolism and Pharmacokinetics, Hoffmann-La Roche Inc., Nutley, NJ, 3Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto LLC, Palo Alto, CA, 4Pharma Development Innovation Biomathematics, 5Clinical Research & Exploratory Development Operations, Hoffmann-La Roche Inc., Nutley, NJ, USA. *email@example.com
Background and aims: Low dose ritonavir (RTV), a potent CYP3A inhibitor, is being used to “boost” the pharmacokinetics (PK) of HIV protease inhibitors (PIs) which are CYP3A substrates, enabling regimen simplification while improving treatment response. RG7227, an HCV NS3/4A PI, is a CYP3A substrate and RTV has a potential to enhance its PK. This Phase 1 study investigated the effects of low dose RTV on the single-dose PK of RG7227.
Material and methods: A single-center, open-label Phase 1 study in 14 healthy males and females between 18 and 45 years of age. Subjects received RTV 100 mg twice-daily (BID) for 10 days. Single oral doses of RG7227 100 mg were administered on 3 separate occasions: alone (2 days before ritonavir dosing), with the first dose of RTV, and on the last day of RTV dosing. Serial PK blood samples for the measurement of RG7227 were collected at pre-dose and up to 48 hours post-dose.
Results: Twelve subjects completed the study. Single doses of RTV 100 mg increased RG7227 AUC0-inf, Cmax and C12h by 5.69-fold (90% CI: 4.06, 7.96), 3.14-fold (90% CI: 1.87, 5.25) and 50.6-fold (90% CI: 25.6, 100), respectively. Multiple doses of RTV 100 mg BID for 10 days had similar effects on RG7227 AUC0-inf (5.46-fold; 90% CI: 4.03, 7.40) and Cmax (3.19-fold; 90% CI: 2.09, 4.85). The multiple-dose effect of ritonavir on RG7227 C12h was less pronounced than the single-dose ritonavir effect (26.9-fold; 90% CI: 17.7, 41.0). This is likely due to the mixed inhibition and induction effects of ritonavir on CYP enzymes. No new safety findings were observed.
Conclusion: Low dose RTV significantly enhances RG7227 Cmin, which appears to be the key parameter driving efficacy and prevention of resistance. Less of an effect was observed on AUC and Cmax, which are parameters often attributed to safety. RG7227 dose and dosing frequency may be reduced when co-administered with RTV, to achieve a high Cmin while providing similar or lower AUC and Cmax compared to an unboosted regimen. A Phase 1b study of RTV-boosted RG7227 QD and BID regimens in combination with SOC in HCV-infected patients is being conducted.