THE EFFECT OF RITONAVIR ON THE PHARMACOKINETICS OF MEPERIDINE IN HIV-NEGATIVE SUB

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Human immunodeficiency virus (HIV)-infected patients may require administration of meperidine for pain control or chills and rigors associated with interleukin-2 or amphotericin B. Ritonavir (Norvir) is a protease inhibitor that is a potent inhibitor of cyto-chrome P-450, the major enzyme system involved in drug metabolism. The combination of ritonavir and meperidine could theoretically lead to increased meperidine concentrations and toxicity, and thus, their concomitant administration is contraindicated. This study will characterize the pharmacokinetics of meperidine and its major metabolite, nor- meperidine, in eight HIV-negative, healthy patients. Subjects will receive a 50 mg dose of PO meperidine on day 0 of the study. Serial samples will be drawn over 48 hours for determination of meperidine and nor-meperidine concentrations. Ritonavir will be initiated on day 2 and escalated to a dose of 500 mg BID over 5 days. After a total of 10 days of ritonavir, a 50 mg PO dose of meperidine will again be administered and samples will be collected over 72 hours while continuing ritonavir through the sampling period. Maximum blood level, time to maximum blood level, area under the curve, and clearance will be compared between the two groups. The study will provide data on meperidine disposition in patients receiving concomitant ritonavir. Currently, subject enrollment and study has been completed and data are being analyzed. Results: The AUC of meperidine decreased in all subjects by a mean of 67 ? 4 percent in the presence of RTV (p<0.005). Normeperidine mean AUC was increased 47 percent suggesting induction of hepatic metabolism. RTV exposure was similar to previous reports with 500 mg BID doses, CL/F averaged 5.6 L/h. Conclusions: Meperidine AUC is significantly reduced not increased, by concomitant RTV. Based on these findings, the risk of narcotic-related adverse effects from this combination appears to be minimal. This suggests that contraindication of meperidine is not necessary during RTV therapy. This study is terminated.