title: Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.
abstract: Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.
authors.affiliation: Celgene Corporation, 86 Morris Ave, Summit, NJ, 07901, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kasserra
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Assaf
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Liangang
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Maria
authors.initials: M
authors.lastname: Palmisano
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology; D057809:HEK293 Cells; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D013552:Swine; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D002220:Carbamazepine; D013792:Thalidomide; D003577:Cytochrome P-450 Enzyme System; C467566:pomalidomide; D016666:Fluvoxamine; D007654:Ketoconazole
keywords: P-glycoprotein; cytochrome P450; drug-drug interactions; pharmacokinetics; pomalidomide; relapsed/refractory multiple myeloma