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

Abstract

Summary The pharmacokinetics of 1 3-cis-retinoic acid (1 3cisRA) and its effects on retinol plasma levels were investigated after the first and the last doses in melanoma patients, who participated in a study run to assess tolerance over a long period of a treatment schedule of 1 3cisRA associated with recombinant interferon cu2a . Melanoma patients with regional node metastases after radical surgery were randomized to be treated for 3 months with rlFN-ca2a, 3 x 106 IU s.c. every other day, associated with oral 13cisRA at doses of 20 mg day-' (five patients) or 40 mg every other day (seven patients). Maximum 13cisRA blood concentrations usually occurred 4 h after drug administration, with average values of 406 and 633 ng ml-' (i.e. 1.3 and 2.1 gM) after the 20 and 40 mg dose respectively. The average halflife (t1,2) was approximately 30 h. The maximum concentration, the t,12 and the area under the concentration-time curves from 0 to 48 h (AUCOQ48) of 13cisRA did not change after multiple dosing, whereas the AUCO 48 of its major blood metabolite, 4-oxo-13-cis-retinoic acid, increased. Immediately after 1 3cisRA treatment, retinol plasma levels started to decline and they reached the lowest values (approximately 20% reduction) shortly after the time of maximum 13cisRA concentrations (i.e. 4-12 h after drug intake). Afterwards, values returned to baseline. The amount of retinol reduction in time was correlated with 1 3cisRA maximum concentrations.

The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone

“…Substantial variability was observed in isotretinoin and metabolite concentrations in our study, similar to another study by the research sponsor (Roche Protocol NR15805, data on file). Our results differed, however, from other reports, primarily in terms of half‐life, because other investigators report an isotretinoin half‐life ranging from 15 to 29 hours compared with our mean of 11 hours 10 , 34 , 35 , 36 , 37 . Methodologic differences could account for some of the half‐life differences, because our observations were limited to the duration of the 12‐hour isotretinoin dosing interval, whereas other studies followed the elimination much longer and were influenced by enterohepatic circulation.…”

Induction of cell cycle arrest and apoptosis by a combined treatment with 13‐cis‐retinoic acid, interferon‐α2a, and α‐tocopherol in squamous cell carcinoma of the head and neck

“…Their concentrations were as follows: 1 μ M 13‐cRA, 200 U/mL IFN‐α2a, and 15 μ M α‐TF. These selected concentrations are very close to the peak plasma levels achieved when the therapeutic doses of these 3 drugs were administered to the patients 32–34. At the fixed concentrations, each single agent achieved only minimal cell growth inhibition.…”