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Population Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Kinase Inhibitor, in Patients With Advanced Solid Tumors.

ABSTRACT: A population pharmacokinetic (PK) analysis was conducted to characterize sources of interpatient variability on the PK of TAK-931, a cell division cycle 7 kinase inhibitor, in adult patients with advanced solid tumors using data from 198 patients who received oral TAK-931 over the range of 30 to 150 mg once daily in multiple dosing schedules in 2 phase 1 and 1 phase 2 clinical studies. A 2-compartment model with 2 transit compartments describing the absorption and first-order linear elimination adequately described the PK of TAK-931. The apparent oral clearance (CL/F) of TAK-931 was estimated to be 38 L/h, and the terminal half-life was estimated to be approximately 6 hours. Creatinine clearance (CrCL) was identified as a covariate on CL/F, and body weight as a covariate on CL/F, apparent central volume of distribution, and apparent intercompartmental clearance. Simulations using the final model indicated that the effect of CrCL (≥35 mL/min) or body weight (29.8-127 kg) on TAK-931 systemic exposures was not considered clinically meaningful, suggesting that no dose adjustments were necessary to account for body weight or renal function (CrCL ≥35 mL/min). Sex, age (36-88 years), race, and mild hepatic impairment had no impact on the CL/F of TAK-931. Taken together, the population PK analysis supports the same starting dose of TAK-931 in Asian and Western cancer patients in a global setting.

SUBMITTER: Zhou X

PROVIDER: S-EPMC9297904 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeWe conducted a first-in-human, dose-escalation study, to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and activity of TAK-931, a cell division cycle 7 inhibitor, in Japanese patients with advanced solid tumors.Experimental designPatients ages ≥20 years received oral TAK-931: once daily for 14 days in 21-day cycles (schedule A; from 30 mg); once daily or twice daily for 7 days on, 7 days off in 28-day cycles (schedule B; from 60 mg); continuous once daily (schedule D; from 20 mg); or once daily for 2 days on, 5 days off (schedule E; from 100 mg) in 21-day cycles.ResultsOf the 80 patients enrolled, all had prior systemic treatment and 86% had stage IV disease. In schedule A, 2 patients experienced dose-limiting toxicities (DLTs) of grade 4 neutropenia and the maximum tolerated dose (MTD) was 50 mg. In schedule B, 4 patients experienced DLTs of grade 3 febrile neutropenia (n = 3) or grade 4 neutropenia (n = 1); the MTD was 100 mg. Schedules D and E were discontinued before MTD determination. The most common adverse events were nausea (60%) and neutropenia (56%). Time to maximum plasma concentration of TAK-931 was approximately 1-4 hours postdose; systemic exposure was approximately dose proportional. Posttreatment pharmacodynamic effects correlating to drug exposure were observed. Overall, 5 patients achieved a partial response.ConclusionsTAK-931 was tolerable with a manageable safety profile. TAK-931 50 mg once daily days 1-14 in 21-day cycles was selected as a recommended phase II dose and achieved proof of mechanism.Trial registration idNCT02699749.SignificanceThis was the first-in-human study of the CDC7 inhibitor, TAK-931, in patients with solid tumors. TAK-931 was generally tolerable with a manageable safety profile. The recommend phase II dose was determined to be TAK-931 50 mg administered once daily on days 1-14 of each 21-day cycle. A phase II study is ongoing to confirm the safety, tolerability, and antitumor activity of TAK-931 in patients with metastatic solid tumors.

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Population Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Kinase Inhibitor, in Patients With Advanced Solid Tumors.

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