Pharmacokinetics and Metabolism of All-trans-and 13-cis-Retinoic Acid in Pulmonary Emphysema Patients

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers—all‐trans‐retinoic acid (ATRA) and 13‐cis‐retinoic acid (13‐cRA)—in subjects with emphysema, evaluated strategies to overcome self‐induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low‐dose ATRA (1 mg/kg/day, n = 21), or high‐dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13‐cRA (1 mg/kg/day, n = 40). High‐dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow‐up, plasma ATRA Cmax was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13‐cRA produced lower plasma ATRA Cmax (