Mechanisms of Pharmacokinetic and Pharmacodynamic Drug Interactions Associated with Ritonavir‐Enhanced Tipranavir

Abstract

Tipranavir is a nonpeptidic protease inhibitor that has activity against human immunodeficiency virus strains resistant to multiple protease inhibitors. Tipranavir 500 mg is coadministered with ritonavir 200 mg. Tipranavir is metabolized by cytochrome P450 (CYP) 3A and, when combined with ritonavir in vitro, causes inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in addition to induction of glucuronidase and the drug transporter P-glycoprotein. As a result, drug-drug interactions between tipranavir-ritonavir and other coadministered drugs are a concern. In addition to interactions with other antiretrovirals, tipranavir-ritonavir interactions with antifungals, antimycobacterials, oral contraceptives, statins, and antidiarrheals have been specifically evaluated. For other drugs such as antiarrhythmics, antihistamines, ergot derivatives, selective serotonin receptor agonists (or triptans), gastrointestinal motility agents, erectile dysfunction agents, and calcium channel blockers, interactions can be predicted based on studies with other ritonavir-boosted protease inhibitors and what is known about tipranavir-ritonavir CYP and P-glycoprotein utilization. The highly complex nature of drug interactions dictates that cautious prescribing should occur with narrow-therapeutic-index drugs that have not been specifically studied. Thus, the known interaction potential of tipranavir-ritonavir is reported, and in vitro and in vivo data are provided to assist clinicians in predicting interactions not yet studied. As more clinical interaction data are generated, better insight will be gained into the specific mechanisms of interactions with tipranavir-ritonavir.