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Fourteen patients with various forms of psoriasis participated in a clinical study to characterize the pharmacokinetics of etretinate before, during, and after 6 months of therapy. A single 100 mg dose was initially given, followed 2 days later by approximately 170 days of multiple dosing with 25 mg one, two, three, or four times a day depending on the subject's response and tolerance. Blood samples were drawn for 48 hours after the initial dose, for 12 hours after dosing at monthly intervals, and for up to 8 months after administration of the last dose. Blood concentrations of etretinate were determined by a specific reverse-phase gradient elution HPLC assay. Blood concentrations after the first dose declined with an apparent t1/2 of approximately 7 hours, whereas those after the last dose declined with an apparent t1/2 of approximately 120 days. The lengthening of the t1/2 during chronic dosing appears to result from the cumulation of blood concentrations in the measurable range rather than from time-related alterations in drug kinetics. This is substantiated by the fact that etretinate blood concentration--time data for the entire course of therapy were fit by a nonlinear least-squares computer program designed to accommodate changes in the dosing regimen. A single polyexponential kinetic equation described the entire 6-month course of therapy as well as the 8-month washout without the need to invoke nonlinear kinetics. Although single-dose kinetic data for etretinate may not be good predictors of steady-state blood concentrations, etretinate appears to follow linear kinetics during these dosing regimens.

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 EC(50) (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.

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