STEADY-STATE PHARMACOKINETICS OF ISOTRETINOIN AND ITS 4-OXO METABOLITE - IMPLICATIONS FOR FETAL SAFETY

Isotretinoin is the most potent human teratogen on the market. Women f or whom contraception fails may conceive during or soon after disconti nuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isot retinoin and its major 4-oxo metabolite were studied in 16 adult patie nts treated fro acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of i sotretinoin in women of childbearing age (n = 11). The clinical effica cy and tolerability of isotretinoin was investigated, and the correlat ion between these data and steady-state serum concentrations of isotre tinoin was tested. The concentration-time data best fitted a two-compa rtment open model with linear elimination. There was no correlation be tween efficacy and tolerability of isotretinoin and steady-state serum concentrations. There rr as no correlation between dose of isotretino in and steady-state concentration, due to the large variability in app arent clearance. Values for elimination half-life (t(1/2)) of isotreti noin and its metabolite were 29 +/- 40 hours and 22 +/- 10 hours, resp ectively. These data suggest a longer elimination t(1/2) of the parent drug than previously reported. This is probably due to the longer sam pling time used in this study (as long as 28 days). This study suggest s that a greater variability exists in the safe time after discontinua tion of the drug for onset of conception.