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The Effects of Once-Daily Saquinavir/Minidose Ritonavir on the Pharmacokinetics of Methadone

From the Antiviral Clinical Pharmacology Unit and Department of Medicine, University at Buffalo, Erie County Medical Center, Buffalo, New York (Dr. Shelton, Ms. Cloen, Ms. DiFrancesco, Dr. Hewitt); Department of Veteran Affairs, Western New York Healthcare System, Buffalo, New York (Dr. Berenson); Sister's Health Care System, Buffalo, New York (Dr. Esch); Roche Pharmaceuticals, Nutley, New Jersey (Dr. de Caprariis, Ms. Palic); and CEDRA Corporation, Austin, Texas (Ms. Schur, Mr. Buggé, Mr. Ljungqvist, Mr. Espinosa).

Twelve methadone-maintained HIV-negative subjects were given saquinavir/ritonavir (SQV/rtv) 1600 mg/100 mg once daily for 14 days. Pharmacokinetic evaluations of total and unbound methadone enantiomers (R and S) were conducted before and after SQV/rtv. SQV/rtv was well tolerated, with no ACTG Grade 3-4 adverse events, no evidence of sedation, and no changes in methadone dose. For R-methadone (active isomer), C_max, AUC_{0-24 h}, and C_min were unchanged, but percent unbound 4 hours after dosing was reduced by 12%. For S-methadone, no differences in pharmacokinetic parameters of total drug were seen, but unbound concentrations were reduced by 15% and 21% at 4 and 24 hours after dosing, respectively. SQV trough concentrations exceeded the anticipated EC₅₀ (50 ng/mL) in 10/12 subjects, persisting for at least 6 hours after the final dose in 4/6 subjects. Once-daily SQV/rtv in methadone-maintained subjects is safe and not associated with any clinically significant interaction with methadone during 14 days of concomitant administration.

Key Words: Methadone • saquinavir • ritonavir • pharmacokinetics

Address for reprints: Mark J. Shelton, PharmD, GlaxoSmithKline, Five Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709.

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