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.

Keywords: CDC7; advanced solid tumors; global; pharmacokinetics; race.

Figure 1

Relationship between covariates and TAK‐931 CL/F. Panels A–C box plots: horizontal lines comprising the box are the 25th, 50th (median), and 75th percentiles. The whisker ends denote 1.5 times the difference between the 25th and 75th percentiles. Panels D–I: black closed circles are the individual estimates of TAK‐931 apparent clearance; the blue lines show linear regressions, and gray shades are the corresponding 95% confidence intervals of linear regressions. CL/F, apparent oral clearance; HI, hepatic impairment.

Figure 2

Relationship between covariates and individual random effects (ETA) on TAK‐931 CL/F. Panels A–C box plots: horizontal lines comprising the box are the 25th, 50th (median), and 75th percentiles. The whisker ends denote 1.5 times the difference between the 25th and 75th percentiles. Panels D–I: black closed circles are the individual ETA on apparent clearance; the blue lines show linear regressions, and gray shades are corresponding 95% confidence intervals of linear regressions. CL/F, apparent oral clearance; ETA, empirical Bayes estimate of the interindividual random effect; HI, hepatic impairment.

Figure 3

Prediction‐corrected visual predictive check of the final population pharmacokinetic model stratified by study (A), renal status (B), and body weight tertiles (C) during the first 30 hours postdose. Open gray circles are individual data points. The solid black line is the median of the observed data, and the dashed black lines are the 2.5th and 97.5th percentiles of the observed data. The gray shaded area is the 95% confidence interval of the simulated median, and the lighter blue shaded areas are the 95% confidence intervals of the simulated 2.5th and 97.5th percentiles of the simulated data. Moderate renal impairment, 30 mL/min ≤ CrCL < 60 mL/min; mild renal impairment, 60 mL/min ≤ CrCL < 90 mL/min; and normal renal function, 90 mL/min ≤ CrCL. CrCL, creatinine clearance.

Figure 4

TAK‐931 median (95% prediction interval) concentration‐time profiles at 50 mg once daily for 14 days. The black solid lines are the median of simulated data and the gray shaded areas are 95% confidence intervals.

Figure 5

Forest plots of effect of renal function (normal, mild, or moderate renal impairment) and body weight on the steady‐state exposure of TAK‐931 following administration at 50 mg once daily. Black circles and associated horizontal error bars represent the median, 5th, and 95th percentiles of the normalized steady‐state AUC (typical study educated by the final model parameters). Blue shaded areas represent the 90%CI of the model predictions. Normalized AUC was derived relative to the reference patient, with a CrCL of 90.45 mL/min and a body weight of 65.95 kg. Moderate renal impairment, 30 mL/min ≤ CrCL < 60 mL/min; mild renal impairment, 60 mL/min ≤ CrCL < 90 mL/min; and normal renal function, 90 mL/min ≤ CrCL < 150 mL/min. Lower weight tertile, 37.5–62.6 kg; middle weight tertile, >62.7–79.2 kg; upper weight tertile, >79.3–127 kg. Reference patient CrCL, 90.45 mL/min; body weight, 65.95 kg. AUC, area under the plasma concentration–time curve; CI, confidence interval; CrCL, creatinine clearance.