title: In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity.
abstract: Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 µM, 1.6-2.9 µM, 0.044-0.15 µM, and 5.4-5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Johan
authors: J
authors: Monbaliu
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Martha
authors: M
authors: Gonzalez
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Apexa
authors: A
authors: Bernard
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: James
authors: J
authors: Jiao
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Carlo
authors: C
authors: Sensenhauser
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Jan
authors: J
authors: Snoeys
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Hans
authors: H
authors: Stieltjes
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Inneke
authors: I
authors: Wynant
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey.
authors: Johan W
authors: JW
authors: Smit
authors: Janssen Research & Development, Preclinical Project Development (J.M.), Bioanalysis (H.St.), Pharmacokinetics, Dynamics and Metabolism (J.S, I.W.), and Clinical Pharmacology, (H.Sm.), Beerse, Belgium; Janssen Research & Development, Clinical Pharmacology (M.G., A.B.) and Biometrics and Reporting (J.J.), Raritan, New Jersey; Janssen Research & Development, Pharmacokinetics, Dynamics and Metabolism (C.S.), Spring House, Pennsylvania; Janssen Research & Development, Clinical Pharmacology (C.C.), Titusville, New Jersey CCHIEN@its.jnj.com.
authors: Caly
authors: C
authors: Chien
mesh_terms: D000069501:Abiraterone Acetate / Q000378:metabolism*; D065727:Cytochrome P-450 CYP2C8 / Q000187:drug effects*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000069501:Abiraterone Acetate