A phase 1 and pharmacokinetic study using the aromatic retinoic acid analogue dichloroetretinate (Ro 12-7554)

Abstract

A phase I study was carried out with the new aromatic retinoic acid analogue DCE, all-trans-9-(2,6-dichloro-4-methoxy-m-tolyl)-3,7-dimethyl-2,4,6,8- nonatetraenacetylester. Data from preclinical studies show that DCE has a promising anti-tumor effect. Data from others investigators show that when DCE was given to patients in daily doses, the dose-limiting toxicity. This toxicity was comprising considerable muco-cutaneous toxicity, occurred at 40 mg/day. To avoid this dose-limiting toxicity, a weekly oral treatment schedule was tested for toxicity in this study. The starting dose was 40 mg/m2 body surface, and a modified Fibonacci scheme was used for the dose escalations. A total of 20 patients entered this study, and all were evaluable for toxicity. The highest dose was 300 mg/m2. In three patients, completely reversible WHO grade 1 liver toxicity was observed. In contrast to daily doses, a once-a-week schedule produced no mucocutaneous toxicity. Pharmacokinetic measurements showed that absorption was highly unpredictable and did not increase with dose increments. Given the results of the pharmacokinetic determinations, we concluded that escalating the DCE dose would not lead to a recommendable dose for further phase II studies, and the study was subsequently discontinued.

Pharmacokinetics of Parenteral 13-cis-Retinoic Acid Formulations in Rats

“…Furthermore, the absorption of retinoids from the gastrointestinal tract is highly variable, depending on the presence of food,14 and saturable. 16. 16 The latter property precludes high-dosage regimens.…”

“…16. 16 The latter property precludes high-dosage regimens. These problems hamper the adequate and precise dosing of oral retinoids.…”