3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

PHARMACOKINETICS OF SCH 417690 ADMINISTERED ALONE OR IN COMBINATION WITH RITONAVIR OR LOPINAVIR/RITONAVIR

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuPe3.1B05

Saltzman M.¹, Rosenberg M.¹, Kraan M.², Keung A.², Boutros T.³, Sansone A.^2
1Parkway Research Center, Inc., North Miami Beach, FL, United States of America, ²Schering Plough Research Institute, Kenilworth, New Jersey, United States of America, ³Pfizer, Inc., San Diego, CA, United States of America

INTRODUCTION: Exposure to SCH 417690, a new CCR5 receptor antagonist, is significantly boosted by coadministration with ritonavir, a CYP3A4 inhibitor. This study assessed the pharmacokinetic effects of ritonavir/lopinavir (Kaletra®) versus ritonavir alone, in combination with SCH 417690.

METHODS: Healthy adult subjects were randomized to 1 of 3 open-label treatment groups: (1) SCH 417690 10 mg; (2) SCH 417690 10 mg with ritonavir 100 mg; or (3) SCH 417690 10 mg with ritonavir 100 mg/lopinavir 400 mg QD for 14 days. Samples were obtained on Days 1, 7, and 14 and on the mornings of Days 15 through 21 for determination of SCH 417690 plasma concentrations. The primary pharmacokinetic end points were C_max and AUC, analyzed using a 1-way ANOVA model with a treatment effect. Safety was assessed through adverse event (AE) reports, vital signs, physical examinations, electrocardiograms (ECG), and laboratory values.

RESULTS: Twenty-four subjects (63% men; 83% Hispanic; median age, 40 yrs) were enrolled, 8 subjects per group; all completed the study. SCH 417690 exposure on Day 1 was similar among all 3 groups. However, on Day 14, SCH 417690 exposure was boosted significantly by ritonavir, with C_max and AUC_0-24 values 2.5 and 5.4 times greater, respectively, compared with SCH 417690 exposure alone. Results were similar with ritonavir/lopinavir in Group 3, with C_max and AUC_0-24 values 2.3 and 4.2 times greater, respectively, compared with SCH 417690 exposure alone. The difference in SCH 417690 exposure between Group 2 and Group 3 was not considered clinically significant. Only 1 AE, an episode of mild diarrhea in Group 3, was considered possibly related to study medication(s). No laboratory or ECG abnormalities were observed.

CONCLUSIONS: Coadministration of SCH 417690 with ritonavir or ritonavir/lopinavir in healthy volunteers resulted in significantly higher exposure to SCH 417690, with similar effects exerted by both combinations. Both combinations were well tolerated.

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Basic | TuPe3.1B05 | Angela Sansone
PK and pharmacodynamics

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