Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships for ITMN-191 in a Phase 1 Multiple Ascending Dose Trial in Patients with Genotype 1 Chronic Hepatitis C (CHC)Infection
C. Rubino1; W. Z. Bradford2; A. Forrest1; S. Porter2; L. M. Blatt2; S. Seiwert2; S. Zeuzem3
1. ICPD/Ordway Research Institute, Inc., Albany, NY, USA.
2. Intermune, Inc, Brisbane, CA, USA.
3. J.W. Goethe Universität, Frankfurt, Germany.
ITMN-191 is a highly potent, slowly dissociating NS3/4A protease inhibitor designed to achieve high liver concentrations with only modest plasma exposure. This study examines PK-PD relationships for ITMN-191 in CHC patients.
Methods: Four cohorts of 10 naïve patients were randomized (8:2) to receive oral ITMN-191 (100 mg q12h, 100 mg q8h, 200 mg q12h, or 200 mg q8h) or placebo for 14 days. PK parameters and PK-PD relationships were assessed using non-compartmental methods and non-linear models, respectively.
Results: ITMN-191 showed potent antiviral activity with relatively low plasma concentrations. At 200 mg q8h, the mean AUC0-24, Cmax, and Cmin values were 500 ng×h/mL, 91 ng/mL and 2.78 ng/mL, respectively, and the mean max. decline in HCV RNA was 3.9 log10.The dose-exposure relationship was not uniformly proportional.Predicted Cmin values for 2, 3, and 4 log10 HCV RNA declines were 0.07, 0.19, and 2.7 ng/mL, respectively. In an inhibitory Emax model, the strongest relationship was between Day 1 Cmin and max change in HCV RNA (figure); fitted Eo, Emax and EC50 values were -0.33 log10, 3.6 log10 and 0.08 ng/mL, respectively. Conclusion: ITMN-191 achieves significant antiviral effects with substantially lower plasma exposures than reported for other NS3 inhibitors. This is consistent with the high liver:plasma concentration ratios seen in animals and likely contributes to the favorable safety and antiviral activity in patients. These data, plus in vitro evidence of synergy with peginterferon, provide a strong rationale for the ongoing triple combination study to further evaluate the PK-PD and antiviral effect of an ITMN-191.
Observed Data and Fitted PK-PD relationship for ITMN-191
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