Potential Hepatotoxicity of Efavirenz and Saquinavir/Ritonavir Coadministration in Healthy Volunteers

Abstract

OBJECTIVE: This study was designed to investigate the pharmacokinetic effects of coadministration of saquinavir/ritonavir with efavirenz at steady state. METHODS: Healthy volunteers in this open-label, two-arm, one-sequence, two-period crossover study (planned enrollment of 40 participants) were randomized to one of two treatment arms: those in Arm 1 were scheduled to receive saquinavir/ritonavir 1,000/100 mg orally twice daily for 29 days and efavirenz 600 mg orally once daily starting on day 15 and continuing through day 29; participants randomized to Arm 2 were to receive efavirenz once daily for 29 days and saquinavir/ritonavir 1,000/100 mg twice daily starting on day 15 through day 29. Assessments included vital signs, laboratory analyses, electrocardiography, and blood levels of total saquinavir, ritonavir, and efavirenz. Pharmacokinetic parameters included C(max) (maximum observed plasma concentration), t(max) (time to reach the maximum observed plasma concentration), (apparent elimination half-life), and AUC(0-tau) (area-under-the-plasma-concentration-time curve over one dosing interval). RESULTS: Eight participants (four in each arm) were enrolled; only two (one from each treatment arm) reached day 15 of the study and received the concurrent initial doses of saquinavir/ritonavir and efavirenz. The study was terminated prematurely after these two participants experienced nonserious adverse events. The participant in Arm 1 experienced mild abdominal discomfort, diarrhea, sleep disorder, and headache and the participant in Arm 2 experienced moderate-intensity abdominal pain and mild vomiting with leukocytosis accompanied by elevated pancreatic and hepatic enzymes (aspartate aminotransferase and alanine aminotransferase values of 2-fold and 3.5-fold the upper limit of normal, respectively). Both participants recovered completely following treatment discontinuation. Only limited pharmacokinetic data were generated on these two participants. CONCLUSIONS: The early termination of this study precluded drawing any definitive conclusions regarding the pharmacokinetics at steady state of coadministered saquinavir/ritonavir and efavirenz.

Figure 1

Study design and patient disposition. ^aSaquinavir/ritonavir 1,000/100 mg doses every 12 hours (±1 hour). On Day 15, only the evening dose was administered. ^bEfavirenz 600 mg every 24 hours at bedtime.

Figure 2

(a) Plasma concentration-time curves for participant 2, Arm 1. Saquinavir/ritonavir trough concentrations on days 11 to 13 and full pharmacokinetic (PK) profile on day 14 (312 to 336 hours). Sparse plasma concentrations from samples taken after initiation of triple-combination therapy are also shown. (b) Plasma concentration-time curves for participant 1, Arm 2. Efavirenz trough concentrations on days 11 to 13 and full PK profile on day 14 (312 to 336 hours). Sparse plasma concentrations from samples taken after initiation of triple-combination therapy are also shown.