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HIV/AIDS

Induction Effects of Ritonavir: Implications for Drug Interactions

HIV Clinical Pharmacist, Northern Alberta HIV Program & Regional Pharmacy Services, Capital Health Authority, Edmonton, Alberta, Canada

Erin M Yakiwchuk, BSP ACPR

Pharmacist, Regional Pharmacy Services, Capital Health Authority, Edmonton, Alberta

Christine A Hughes, PharmD

Associate Professor, Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta; HIV Clinical Pharmacist, Northern Alberta HIV Program & Regional Pharmacy Services, Capital Health Authority, Edmonton, Alberta

Reprints: Dr. Foisy, Northern Alberta HIV Program & Regional Pharmacy Services, Royal Alexandra Hospital, 10240 Kingsway Ave., CSC 243, Edmonton, Alberta T5H 3V9, Canada, fax 780/735-4866, Michelle.Foisy{at}capitalhealth.ca

OBJECTIVE: To review the literature on the induction effects of ritonavir on the cytochrome P450 enzyme system and glucuronyl transferase and identify resultant established and potential drug interactions.

DATA SOURCES: Primary literature was identified from MEDLINE (1950–April 2008), EMBASE (1988–April 2008) and International Pharmaceutical Abstracts (1970–April 2008) using the search terms ritonavir, cytochrome P450 enzyme system, enzyme induction, glucuronyl transferase, and drug interactions. Additionally, relevant conference abstracts and references of relevant articles were reviewed.

STUDY SELECTION AND DATA ABSTRACTION: All English-language articles and abstracts identified were reviewed.

DATA SYNTHESIS: Ritonavir is a well-known inhibitor of the metabolism of numerous medications that are substrates of the CYP3A and CYP2D6 pathways. It also exhibits a biphasic, time-dependent effect on P-glycoprotein of inhibition followed by induction. Numerous pharmacokinetic studies suggested that ritonavir induces cytochrome P450 enzymes 3A, 1A2, 2B6, 2C9, and 2C19, as well as glucuronyl transferase. Additionally, several case reports described clinically significant subtherapeutic effects of drugs metabolized by these isoenzymes when coadministered with ritonavir. Both therapeutic and boosting doses of ritonavir appear to induce these enzymes; however, most of the studies of low-dose ritonavir involved a second protease inhibitor such as lopinavir, darunavir, or tipranavir. It is, therefore, difficult to distinguish the relative effects of additional medications unless well-designed, 3-way studies are conducted.

CONCLUSIONS: At both therapeutic and boosting doses, ritonavir exhibits a clinically relevant induction effect on numerous drug-metabolizing enzymes. A decrease or loss of therapeutic effect may be observed when ritonavir is coadministered with medications that are substrates for these enzymes. It is important for clinicians to be aware of drugs potentially impacted by ritonavir therapy to identify and manage these interactions.

Key Words: cytochrome P450 enzyme system, drug interactions, enzyme induction, P-glycoprotein, protease inhibitors, ritonavir, uridine diphosphate–glucuronosyltransferase enzymes

Published Online, June 24, 2008. www.theannals.com, DOI 10.1345/aph.1K615