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 HIVnegative 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 (Ն 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.

Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

“…These safety findings were attributed to efavirenz, a CYP3A inducer, as coadministration of the 3D regimen with emtricitabine and tenofovir DF was well tolerated in healthy volunteers. Similar safety findings were observed when the CYP3A inducer rifampin or efavirenz was coadministered with ritonavir-boosted protease inhibitors such as lopinavir and saquinavir in healthy volunteers (28)(29)(30). Patients treated with these therapy combinations reported AEs consistent with our observations, including abdominal symptoms and transaminase elevations.…”

Pharmacokinetic Interaction Study of Ritonavir-Boosted Saquinavir in Combination with Rifabutin in Healthy Subjects

“…This complication can in principle be obviated by regimens involving the concomitant administration of ritonavir, an inhibitor of CYP3A4. While the most straightforward candidate for triple therapy regimens is rifampin, this combination is contraindicated owing to the elevation of hepatic transaminases (15). The present study was undertaken to assess the utility of rifabutin as a component of combined treatment with saquinavir and ritonavir.…”

“…In principle, ritonavir thus would be expected to minimize the impact of the induction of CYP3A by the rifamycin antimycobacterials. This question was examined in a recent study involving triple therapy with saquinavir, ritonavir, and rifampin that was terminated owing to an unexpected elevation of liver transaminases (15). The possibility remains, however, that triple therapy using another member of the rifamycin group, such as rifabutin, could provide a successful treatment for both HIV and tuberculosis.…”

Clinical management of tuberculosis and HIV-1 co-infection

“…The interaction between darunavir and rifampicin has not been investigated but based on pharmacokinetic properties it should not be co-administered with rifampicin [189][190][191][192][193][194][195][196].…”