Assessment of ritonavir effects on hepatic and first‐pass CYP3A activity and methadone disposition using noninvasive pupillometry

Purpose Ritonavir (RIT) decreases methadone (M) conc. & causes withdrawal. M metabolism is attributed mainly to CYP3A. Acute & chronic RIT are said to cause CYP3A inhibition & induction, respectively. We tested whether acute & chronic RIT would inhibit & induce M elimination, due to commensurate changes in CYP3A. Alfentanil (ALF) was the CYP3A probe. Methods Volunteers (12) were studied in a nonrandomized crossover. On 3 consecutive days they received ALF 15 íg/kg IV, ALF 43 μg/kg PO, & M‐HCl (11 mg PO + 6 mg IV). They then took RIT, 200 mg po TID × 1d, 300 mg BID x 6d, then 400 mg BID x 13d. Subjects received ALF 4.3 μg/kg PO on RIT day 2, M (11 mg PO + 6 mg IV) on RIT day 3, & ALF 4.3 μg/kg PO, ALF 5 μg/kg IV, & M on RIT days 15,16, 17. Dark‐adapted pupil diameters were measured after opioid dosing. Results Average dose‐normalized AUC for IV ALF miosis was increased from 6 to 24 mm‐hr/mg by acute RIT. Average dose‐normalized AUC for PO ALF miosis was increased from 2.1 to 37 and 19 mm‐hr/mg by acute and chronic RIT, respectively. Average AUC for M miosis was increased from 89 to 115 mm‐hr by acute RIT, but returned to 78 after chronic RIT. Conclusions Miosis was a utilitarian method to measure M & ALF disposition. RIT was a profound (first‐pass≫ hepatic) CYP3A inhibitor. Acute & chronic RIT inhibited & mildly increased M elimination, but the latter was not due to CYP3A induction. M may be metabolized by P450s in addition to CYP3A, which are induced by RIT. Clinical Pharmacology & Therapeutics (2004) 75 , P96–P96; doi: 10.1016/j.clpt.2003.11.368