Pharmacokinetics of isotretinoin during repetitive dosing to patients

Abstract

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients

“…Conversely, the AUC of the metabolite 4-oxo-13cisRA after repeated doses was greater than after the first dose. Thus, as reported in previous studies (Brazzell et al, 1983), the pharmacokinetics of 13cisRA does not change during continuous treatment.…”

“…In children with neuroblastoma treated with the maximum tolerated dose of 160 mg m-2 day-', the average 13cisRA peak levels was 7.4 gM (Villablanca et al, 1995). From all these data it is clear that after administration of the same dose of 13cisRA, there is a marked variability in maximum drug blood concentrations (Brazzell et al, 1983;Goodman et al, 1982 (Goodman et al, 1982).…”

“…In patients suffering from cystic acne and in patients with various keratinization disorders, the half-lives were 10 and 16 h respectively (Brazzell et al, 1983), and in male volunteers the half-life was 20 h (Khoo et al, 1982). The differences between 13cisRA half-life in cancer and non-cancer patients might be due to differences in age.…”

“…Maximum blood concentrations ranged from 98 to 535 ng ml-', with an average value of 262 ng ml1 (i.e. 0.9 tM) in patients with cystic acne treated with 80 mg of 13cisRA (Brazzell et al, 1983), and they ranged from 74 to 511 ng ml-l (i.e. from 0.3 to 1.7 gM) in healthy volunteers receiving a 100 mg per dose (Khoo et al, 1982).…”

“…Nothing can be said about peaks achievable with the 1 mg kg-1 dose, as only two patients were studied after this dose. It is known that gastrointestinal absorption of 13cisRA (Colbum et al, 1983), as well as that of other retinoids, is influenced by food intake and composition. All the patients analysed in the study received the 13cisRA dose after a similar light breakfast.…”