Abstract
All-trans retinoic acid (atRA) is a front-line treatment of acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed. Of these, ketoconazole and liarozole have shown some benefits, but their usage is limited by side effects and low potency toward the cytochrome P450 26A1 isoform (CYP26A1), the main atRA hydroxylase. We determined the pharmacokinetic basis of therapy resistance to atRA and tested whether the complex disposition kinetics of atRA could be predicted in healthy subjects and in cancer patients in the presence and absence of inhibitors of atRA metabolism using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of atRA disposition was developed and verified in healthy individuals and in cancer patients. The population-based PBPK model of atRA disposition incorporated saturable metabolic clearance of atRA, induction of CYP26A1 by atRA, and the absorption and distribution kinetics of atRA. It accurately predicted the changes in atRA exposure after continuous dosing and when coadministered with ketoconazole and liarozole. The developed model will be useful in interpretation of atRA disposition and efficacy, design of novel dosing strategies, and development of next-generation atRA metabolism inhibitors.