title: Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.
abstract: The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.
authors.affiliation: Roche Innovation Center, New York, NY, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Cleary
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini
authors.affiliation: d3 Medicine, Parsippany, NJ, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: Dall
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Bogman
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Luigi
authors.initials: L
authors.lastname: De Petris
authors.affiliation: IOR Quiron Dexeus University Hospital, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Bordogna
authors.affiliation: Roche Innovation Center, New York, NY, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Phipps
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000494:pharmacology; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D012293:Rifampin / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D002227:Carbazoles; D010880:Piperidines; D014230:Triazoles; C101425:posaconazole; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib; D008874:Midazolam; D012293:Rifampin
keywords: ALK inhibitor; CYP3A; NSCLC; alectinib; drug-drug interaction