[TuPe3.1B06] Similar Increase in SCH 417690 Plasma Exposure with Coadministration of Varying Doses of Ritonavir in Healthy Volunteers

3rd International AIDS Society Conference on HIV Pathogenesis and Treatment

Rio de Janeiro - July 24 - 27, 2005

SIMILAR INCREASE IN SCH 417690 PLASMA EXPOSURE WITH COADMINISTRATION OF VARYING DOSES OF RITONAVIR IN HEALTHY VOLUNTEERS

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuPe3.1B06

Seiberling M.¹, Kraan M.², Keung A.², Martinho M.², Sansone A.²
¹Swiss Pharma Contract, Ltd., Allschwil, Switzerland, ²Schering Plough Research Institute, Kenilworth, New Jersey, United States of America

INTRODUCTION: SCH 417690 is a novel CCR5 receptor antagonist metabolized by CYP3A4. This study assessed the effect of ritonavir, a potent CYP3A4 inhibitor, on SCH 417690 pharmacokinetics.

METHODS: In an open-label, parallel-group study, healthy volunteers were randomized (n=9/group) to receive SCH 417690 10 mg BID alone (A) or in combination with 1 of 4 ritonavir regimens: 100 mg QD (B), 100 mg BID (C), 200 mg BID (D), or titrated to 400 mg BID (E) for 14 days. Blood samples for pharmacokinetic analysis of SCH 417690 were drawn before and at multiple time points after dosing on Days 1 and 14. Primary end points included AUC_0-12h and C_max with log-transformed data for Day 14 analyzed using a 1-way ANOVA. Safety was assessed by adverse events (AEs), vital signs, electrocardiograms (ECG), and laboratory values.

RESULTS: Forty-five of 46 subjects enrolled completed the study. Ritonavir (100–800 mg/day) coadministered with SCH 417690 significantly increased SCH 417690 AUC_0-12h and C_max by approximately 500% (469%–585%) and approximately 350% (301%–395%), respectively, regardless of ritonavir dose. An earlier study (N=28) evaluating treatments A and E for 7 days demonstrated the same findings, with increases in AUC_0-12h and C_max of 612% and 355%, respectively. Eighty-three percent of subjects reported ≥1 AE. One subject in Group D discontinued due to pruritus/rash on the lower legs. The most commonly reported AEs included mild or moderate diarrhea, headache, abdominal pain, nausea, taste perversion, and flatulence. In Group A (SCH 417690 alone), only headache was reported in ≥1 subject. Vital signs, ECGs, and laboratory tests were unremarkable.

CONCLUSIONS: Coadministration of ritonavir (100–800 mg/day) with SCH 417690 resulted in boosting of SCH 417690 exposure by approximately 500%, irrespective of the ritonavir dose. There was no significant safety risk associated with SCH 417690 alone or in combination with ritonavir treatment.

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Basic | TuPe3.1B06 | Angela Sansone
PK and pharmacodynamics

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