Physiologically Based Pharmacokinetic Model of All- trans -Retinoic Acid with Application to Cancer Populations and Drug Interactions.

All- trans retinoic acid ( at RA) 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 at RA has been limited by at RA inducing its own metabolism during therapy, resulting in a decrease of at RA exposure during continuous dosing. Frequent relapse occurs in patients receiving at RA monotherapy. In an attempt to combat therapy resistance, inhibitors of at RA 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 at RA hydroxylase. We determined the pharmacokinetic basis of therapy resistance to at RA and tested whether the complex disposition kinetics of at RA could be predicted in healthy subjects and in cancer patients in the presence and absence of inhibitors of at RA metabolism using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of at RA disposition was developed and verified in healthy individuals and in cancer patients. The population-based PBPK model of at RA disposition incorporated saturable metabolic clearance of at RA, induction of CYP26A1 by at RA, and the absorption and distribution kinetics of at RA. It accurately predicted the changes in at RA exposure after continuous dosing and when coadministered with ketoconazole and liarozole. The developed model will be useful in interpretation of at RA disposition and efficacy, design of novel dosing strategies, and development of next-generation at RA metabolism inhibitors.