Unexpected Hepatotoxicity of Rifampin and Saquinavir/Ritonavir in Healthy Male Volunteers

Abstract

OBJECTIVES: Rifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers. METHODS: In an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIV-negative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured. RESULTS: In arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (>/= grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations. CONCLUSIONS: Although not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.

Figure 1

Study design.

Figure 3

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations for all nine participants in study arm 2 who commenced rifampin (600 mg once daily) + saquinavir/ritonavir (1000/100 mg twice daily) after 14 days of rifampin alone. Falling levels are post-discontinuation. Numbers indicated are participant identifiers. (a) ALT; (b) AST.

Figure 2

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels for two participants in study arm 1 who developed significant (grades 2 and 3) elevations in ALT following concomitant dosing of rifampin (600 mg once daily) with saquinavir/ritonavir (1000/100 mg twice daily). Participants took saquinavir/ritonavir alone for days 1 to 14. Falling levels are postdiscontinuation. Numbers indicated are participant identifiers.

Figure 4

Sparse concentration–time points following initiation of the triple combination in arm 1 (○) and in arm 2 () participants compared to the full pharmacokinetic profiles obtained on day 14 (arm 2; rifampin alone). (a) rifampin; (b) desacetyl-rifampin.