title: Physiologically Based Pharmacokinetic Model of All-trans-Retinoic Acid with Application to Cancer Populations and Drug Interactions.
abstract: All-transretinoic 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 ofatRA has been limited byatRA inducing its own metabolism during therapy, resulting in a decrease ofatRA exposure during continuous dosing. Frequent relapse occurs in patients receivingatRA monotherapy. In an attempt to combat therapy resistance, inhibitors ofatRA 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 mainatRA hydroxylase. We determined the pharmacokinetic basis of therapy resistance toatRA and tested whether the complex disposition kinetics ofatRA could be predicted in healthy subjects and in cancer patients in the presence and absence of inhibitors ofatRA metabolism using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model ofatRA disposition was developed and verified in healthy individuals and in cancer patients. The population-based PBPK model ofatRA disposition incorporated saturable metabolic clearance ofatRA, induction of CYP26A1 byatRA, and the absorption and distribution kinetics ofatRA. It accurately predicted the changes inatRA exposure after continuous dosing and when coadministered with ketoconazole and liarozole. The developed model will be useful in interpretation ofatRA disposition and efficacy, design of novel dosing strategies, and development of next-generationatRA metabolism inhibitors.
authors.affiliation: Department of Pharmaceutics (J.J., C.N., Y.S., N.I.), Department of Medicine (J.A.), and Department of Comparative Medicine (J.P.), University of Washington, Seattle, Washington.
authors.forename: Jing
authors.initials: J
authors.lastname: Jing
authors.affiliation: Department of Pharmaceutics (J.J., C.N., Y.S., N.I.), Department of Medicine (J.A.), and Department of Comparative Medicine (J.P.), University of Washington, Seattle, Washington.
authors.forename: Cara
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Department of Pharmaceutics (J.J., C.N., Y.S., N.I.), Department of Medicine (J.A.), and Department of Comparative Medicine (J.P.), University of Washington, Seattle, Washington.
authors.forename: Jisun
authors.initials: J
authors.lastname: Paik
authors.affiliation: Department of Pharmaceutics (J.J., C.N., Y.S., N.I.), Department of Medicine (J.A.), and Department of Comparative Medicine (J.P.), University of Washington, Seattle, Washington.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.affiliation: Department of Pharmaceutics (J.J., C.N., Y.S., N.I.), Department of Medicine (J.A.), and Department of Comparative Medicine (J.P.), University of Washington, Seattle, Washington.
authors.forename: John K
authors.initials: JK
authors.lastname: Amory
authors.affiliation: Department of Pharmaceutics (J.J., C.N., Y.S., N.I.), Department of Medicine (J.A.), and Department of Comparative Medicine (J.P.), University of Washington, Seattle, Washington ni2@uw.edu.
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001702:Biopharmaceutics / Q000379:methods; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase / Q000378:metabolism*; D014018:Tissue Distribution; D014212:Tretinoin / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D014212:Tretinoin; D000072516:Retinoic Acid 4-Hydroxylase