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

ABSTRACT The effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC0-12), maximum observed concentration of drug in plasma (C max), and minimum observed concentration of drug in plasma at the end of the dosing interval (C min) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC0-12, C max, and C min were observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 (n = 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC0-72 and C max of the active moiety (rifabutin plus 25-O-desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC0-72 and by 86% for C max. In group 3 (n = 13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC0-96 and C max of the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC0-96 of rifabutin was not affected, and C max increased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.