Negligible systemic absorption of topical isotretinoin cream: implications for teratogenicity.

The objective of the study was to assess the extent of systemic exposure of retinoic acid metabolites after excessive application of 0.1% isotretinoin cream in patients with photodamaged skin. This was a single-center, open-label, noncomparative, multiple-dose study of isotretinoin cream. Eighteen female patients with photodamaged skin received a 10 g topical application of isotretinoin cream once daily to a surface area of approximately 2,300 cm2 for 42 days. The patients were not allowed to have high vitamin A-containing foods, vitamin A supplements, or concomitant medications during the entire study period. Plasma levels of four retinoic acids (isotretinoin, tretinoin, 4-oxo-isotretinoin, and 4-oxo-tretinoin) were evaluated after 42 days of isotretinoin application and compared with baseline (pretreatment) levels. The mean area under the curve (AUC) in plasma increased by 48% (+/-SE 9.2) and 77% (+/-13) from the 24-hour pretreatment baseline level for isotretinoin and 4-oxo-isotretinoin, respectively, after treatment with excessive amounts of isotretinoin cream, suggesting systemic absorption of isotretinoin cream. This increase in systemic exposure of retinoic acids was less than that reported earlier after the U.S. recommended daily allowance of 5,000 i.u. of vitamin A supplementation (isotretinoin 141 +/- 19% and 4-oxo-isotretinoin 171 +/- 27%). The minimal systemic availability of isotretinoin cream compared with the U.S. recommended daily allowance for vitamin A supplements provides reasonable evidence for lack of its potential teratogenic risk.

Pharmacokinetics of retinoids in women after meal consumption or vitamin A supplementation.

These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4-oxo-tretinoin, and 4-oxo-isotretinoin in samples collected during the studies were analyzed using a high-performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model-independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4-oxo-tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration-time curve (AUC) for isotretinoin and 4-oxo-isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 +/- 53% and 171 +/- 77% from baseline in the 24-hour AUCs of isotretinoin and 4-oxo-isotretinoin, respectively. Dose-related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.