title: Dose selection for the investigational anticancer agent alisertib (MLN8237): Pharmacokinetics, pharmacodynamics, and exposure-safety relationships.
abstract: We report population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses to support phase II/III dose/regimen selection of alisertib, a selective Aurora A kinase (AAK) inhibitor. Phase I studies in adult cancer patients evaluated dosing on Days 1-7 in 21-day cycles or Days 1-21 in 35-day cycles, with corresponding maximum tolerated doses of 50 mg twice daily (BID) and 50 mg QD, respectively. Population pharmacokinetic analyses supported dose- and time-linear pharmacokinetics without identification of clinically meaningful covariates. Exposure-related increases in skin mitotic index and decreases in chromosomal alignment/spindle bipolarity in tumor mitotic cells confirmed AAK inhibition. Exposures in the 7-day schedule at or near 50 mg BID are expected to result in tumor AAK inhibition based on pharmacodynamic assessment in patient tumors. Exposure-safety analyses of data from patients receiving doses of 5-200 mg/day in the 7-day schedule support a low (∼7%) predicted incidence of dose-limiting toxicity at 50 mg BID. Taken together, these analyses support a pharmacologically active and acceptably tolerated dose range of alisertib for future clinical development.
authors.affiliation: Department of Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.affiliation: Department of Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Translational Medicine, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.affiliation: Projections Research Inc., Phoenixville, PA, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.affiliation: Department of Biostatistics, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Translational Medicine, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Hadi
authors.initials: H
authors.lastname: Danaee
authors.affiliation: Department of Clinical Research, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Fingert
authors.affiliation: Department of Drug Development Management, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleinfield
authors.affiliation: Department of Clinical Pharmacology, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Milton
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D006801:Humans; D020714:Maximum Tolerated Dose; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: Aurora A kinase; MLN8237; alisertib; dose; oncology