Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer

Abstract

Background and objective: Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers.

Methods: A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks.

Results: A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics.

Conclusions: The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model.

Clinical trial registration: NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

Fig. 1

Goodness-of-fit plots for the final tucatinib population pharmacokinetic model. Dots are individual data points, and red solid lines are smoothed LOESS lines. Dashed lines represent lines of identity in the observations versus predictions plots and y = 0 in the conditional weighted residual plots. GOF goodness of fit, LOESS locally estimated scatterplot smoothing

Fig. 2

Prediction-corrected visual predictive check of the final tucatinib population pharmacokinetic model (linear). Black circles represent observed data points. The black solid line is the observed median, and the black dashed lines are the observed 5th and 95th percentiles. The blue line and blue-shaded region represent the simulated median and corresponding 95% confidence interval, respectively. The red lines represent the simulated 5th and 95th percentiles, which are the lower and upper bounds, respectively, of the simulated PI. The red-shaded areas are the 95% confidence intervals of the simulated 5th and 95th percentiles. PI prediction interval

Fig. 3

Tucatinib clearance stratified by tumor type. GM geometric mean, N number of participants