Ritonavir's Role in Reducing Fentanyl Clearance and Prolonging Its Half-life

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Abstract
Background: The human immunodeficiency virus protease inhibitor ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme, and ritonavir's concomitant administration with the substrates of this enzyme may lead to dangerous drug interactions. Methods: The authors investigated possible interactions between ritonavir and intravenously administered fentanyl in a double-blind, placebo-controlled, cross-over study in two phases. Twelve healthy volunteers received orally ritonavir or placebo for 3 days; the dose of ritonavir was 200 mg three times on the first day and 300 mg three times on the second. The last dose of ritonavir 300 mg or placebo was given on the morning of the third day. On the second day, 2 h after the afternoon pretreatment dose, fentanyl 5 microg/kg was injected intravenously in 2 min with naloxone to moderate its effects, and 15 timed venous blood samples were collected for 18 h. Results: Ritonavir reduced the clearance of fentanyl by 67% from 15.6+/-8.2 to 5.2+/-2.0 ml x min(-1) x kg(-1) (P<0.01). The area under the fentanyl plasma concentration-time curve from 0 to 18 h was increased from 4.8+/-2.7 to 8.8+/-2.3 ng x ml(-1) x h(-1) by ritonavir (P<0.01). Ritonavir did not affect the initial concentrations and the steady-state volume of distribution of fentanyl. One subject discontinued participation before fentanyl administration because of severe side effects, and during the study 8 of the remaining 11 subjects reported nausea. Conclusions: Ritonavir can inhibit the metabolism of fentanyl significantly, so caution should be exercised if fentanyl is given to patients receiving ritonavir medication.