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ORIGINAL ARTICLE Potential Hepatotoxicity of Efavirenz And View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central 1 ORIGINAL ARTICLE Potential Hepatotoxicity of Efavirenz and Saquinavir/Ritonavir Coadministration in Healthy Volunteers Candice Jamois, PharmD, Myriam Riek, MSc, and Christophe Schmitt, PharmD F. Hoffmann-La Roche AG, Basel, Switzerland DOI: 10.1111/j.1753-5174.2009.00016.x 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 Cmax (maximum observed plasma concentration), tmax (time to reach t 1 β t the maximum observed plasma concentration), 2 (apparent elimination half-life), and AUC0- (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. Key Words. Drug Interaction; Efavirenz; Human Immunodeficiency Virus; Pharmacokinetics; Ritonavir; Saquinavir Reuse of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. Introduction chrome P4503A4 isoenzyme (CYP3A4) [1], the isoenzyme that metabolizes the protease inhibitor favirenz (Sustiva®; Bristol-Myers Squibb) is a antivirals. When efavirenz is coadministered with E non-nucleoside reverse transcriptase inhibi- the protease inhibitors, a profound reduction in tor, antiviral agent indicated for the treatment of protease inhibitor exposure results [1,2]. human immunodeficiency virus-1 (HIV-1) infec- Saquinavir (Invirase®; Hoffmann-La Roche) is a tion. Because of its prolonged half-life (40 to 55 potent HIV protease inhibitor with oral bioavail- hours), efavirenz can be dosed once daily [1]. ability limited by extensive first-pass metabolism Efavirenz is also a potent inducer of the cyto- mediated primarily by CYP3A4. While saquinavir © 2009, Archives of Drug Information Arch Drug Info 2009;2:1–7 2 Jamois et al. is a weak CYP3A4 inhibitor itself [3], its exposure is enrollment of 40 participants (20 for each treat- enhanced when combined with a low (subtherapeu- ment arm) was planned. The study was conducted tic) dose of ritonavir [4], a potent inhibitor of in full conformance with the principles of the Dec- CYP3A4 [5]. Thus, increasing the plasma concen- laration of Helsinki or with the laws and regula- trations of saquinavir by combining it with low- tions of the country in which the research was dose ritonavir may compensate for the acceleration conducted, whichever provided participants with of its metabolism by efavirenz. the greatest protection. Written informed consent Few studies have evaluated the pharmacoki- was obtained from all participants before any netics of saquinavir/ritonavir and efavirenz when screening procedures were performed. coadministered. In one study of healthy partici- pants, no significant differences in plasma concen- trations of saquinavir were observed following Study Participants once-daily administration of saquinavir 1,600 mg/ Healthy males or females aged 18 to 65 years with a ritonavir 200 mg when administered after a body-mass index of 18 to 30 kg/m2 were eligible if 2-week run-in period with efavirenz 600 mg or on screening they had a clinically normal physical when efavirenz was added following a 2-week examination and laboratory tests and no prior run-in period with saquinavir/ritonavir [6]. Similar history of: (i) clinically significant gastrointestinal, results were reported when efavirenz 600 mg was renal, hepatic, bronchopulmonary, neurological, added once daily after 10-day administration of cardiovascular, or endocrinologic disease; (ii) gen- saquinavir 400 mg/ritonavir 400 mg twice daily in eralized drug reaction, including severe allergic healthy volunteers [7]. asthma, regional or generalized urticaria, or ana- In an open-label efficacy study of 32 efavirenz- phylaxis of any cause; or (iii) any major illness naive, protease inhibitor-experienced, HIV-in- within 4 weeks prior to screening. Females were fected patients who received efavirenz in combina- excluded if they were pregnant, breast-feeding, or tion with a twice-daily boosted regimen (saquinavir using hormone replacement therapy. Females of 1,000 mg/ritonavir 100 mg) for 6 months, there did childbearing potential were required to use effec- not appear to be any clinically relevant alterations tive nonhormonal contraception during the study in plasma levels of saquinavir resulting from the and for at least 1 month after the last dose. Use of combination (levels of other agents were not mea- any CYP3A4 inhibitor or inducer within 4 weeks or sured), although these values ranged widely [8]. any other medication (except aspirin or acetamin- Another similarly designed study evaluated the ophen, allowed up to 48 hours of dosing) within 2 pharmacokinetics of the three agents in 42 HIV- weeks prior to the first dose of study drug or within infected patients who were switched from their six times the elimination half-life (whichever was current regimen to a once-daily boosted regimen longer) was prohibited. Participants were to abstain (saquinavir 1,200 mg/ritonavir 100 mg) plus from ingesting grapefruit/grapefruit juice within efavirenz due to adverse events [9]. As in the pre- 14 days and any herbal product containing Saint vious study, a large interpatient variability in John’s wort or garlic within 4 weeks from dosing saquinavir and efavirenz pharmacokinetics was and from using tobacco for a minimum of 6 months noted, although the plasma levels of both of these prior to the start of the study. In addition, partici- agents were adequate to maintain virologic sup- pants were excluded if they had a positive test for pression [9]. Because only limited data are available drugs of abuse in their urine or a positive alcohol to support the use of saquinavir/ritonavir with breath test at screening or baseline; had a history of efavirenz, the present study was designed to further alcohol and/or drug abuse; had a positive test for investigate the pharmacokinetic effects of coad- HIV or hepatitis B or C at screening; had partici- ministration of all three drugs at steady state. pated in a clinical study with an investigational drug within 3 months prior to dosing; and/or had Methods donated or experienced blood loss of more than 400 mL in the 3-month period prior to dosing. Study Design This open-label, randomized, two-arm, one-se- quence, two-period crossover study in healthy Study Treatment volunteers was conducted at the Roche Clinical Participants randomized to Arm 1 received sa- Pharmacology Unit in Strasbourg, France. The quinavir/ritonavir 1,000/100 mg orally twice daily overall study design is shown in Figure 1. An (morning and evening doses at 12-hour intervals) Arch Drug Info 2009;2:1–7 Efavirenz/Saquinavir/Ritonavir: Hepatotoxicity 3 ScreeningBaseline Treatment Period Follow-Up Study Day -2 evening Within 15 to Day -28 to -2 Day 1 to 14 Day 15 to 29 Day evening to Day -1 21 days after last dose Arm 1 14 days of dosing with 14 days of dosing with Day 44 to 50 saquinavira/ saquinavir/ritonavira ritonavir and efavirenzb No. participants No. receiving at least No. completing 14 No. completing 29 randomized = 4 one dose = 4 days treatment = 1 days treatment = 0 No. withdrawn No. withdrawn during 14 days during 29 days treatment = 3 treatment = 1 Total withdrawn during each treatment period = 4 A2Arm 2 Day 44 to 50 14 days of dosing 14 days of dosing with b with efavirenzb efavirenz and saquinavir/ritonavira No. participants No. receiving at least No. completing 14 No. completing 29 randomized = 4 one dose = 4 days treatment = 1 days treatment = 0 No. withdrawn No. withdrawn during 14 days during 29 days treatment = 3 treatment = 1 Total withdrawn during each treatment period = 4 Figure 1 Study design and patient disposition. aSaquinavir/ritonavir 1,000/100 mg doses every 12 hours (Ϯ1 hour). On Day 15, only the evening dose was administered. bEfavirenz 600 mg every 24 hours at bedtime. for 29 days (day 1 to day 29). Starting on day 15 Randomization numbers were generated by the and continuing through day 29, these participants sponsor and allocated by the Unit’s pharmacist also received efavirenz 600 mg orally once daily at sequentially in the order in which participants bedtime (approximately 10:00 pm). Participants were screened and enrolled. On day 15, no randomized to Arm 2 received efavirenz once morning doses of either agent were given.
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