Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development

Abstract

The BCR-ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model-based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration-time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed-effects modeling. Ponatinib pharmacokinetics were described by a 2-compartment model with first-order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19-85 years), race, body weight (40.7-152.0 kg), total bilirubin (0.1-3.16 mg/dL), alanine aminotransferase (6-188 U/L), albumin (23.0-52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady-state average concentrations that are in the pharmacological range for BCR-ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805.

Keywords: BCR-ABL; Philadelphia chromosome; acute lymphoblastic leukemia; chronic myeloid leukemia; pediatric; pharmacokinetics; ponatinib; tyrosine kinase inhibitors.

Conflict of interest statement

M.H. is an employee of Takeda Pharmaceutical Company Limited. P.D. is an employee of Certara and consultant to Takeda Pharmaceutical Company Limited. N.N. is a previous employee of ARIAD Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. S.S. is a previous employee of Takeda Pharmaceutical Company Limited. N.G. is an employee of Takeda Pharmaceutical Company Limited. K.V. is a previous employee of Takeda Pharmaceutical Company Limited.

© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Structural model describing the pharmacokinetics of ponatinib. ALAG2, absorption lag time from the second absorption compartment; CL/F, apparent oral clearance; D, dose; F1, fraction of absorbed dose entering in the central compartment via the first absorption compartment; F2, fraction of absorbed dose entering in the central compartment via the second absorption compartment; Ka1, first‐order absorption rate constant via the F1 route; Ka2, first‐order absorption rate constant via the F2 route; Ktr, transit rate constants from the first absorption compartment to the central compartment (identical to Ka1); K34 and K43, distributional rate constants between the central and peripheral compartments; K30, elimination rate constant from the central compartment; Q/F, apparent distributional clearance; V3/F, apparent central volume of distribution; V4/F, apparent peripheral volume of distribution.

Figure 2

Diagnostic plots. (A) Goodness‐of‐fit plots of the final model based on population‐predicted vs observed plasma ponatinib concentrations (left) and individual‐predicted vs observed plasma ponatinib concentrations (right). Circles represent individual data, black solid lines represent the identity line, and blue solid lines are LOESS curves. The gray shaded areas represent the 95%CI of the LOESS curves. (B) Conditional weighted residuals vs time since first dose. (C) Conditional weighted residuals vs predicted plasma ponatinib concentration. In (B) and (C), circles represent individual data, and the blue solid line with a gray‐shaded area shows a linear regression with 95%CI. (D) VPC of the final model for the overall analysis population. Black circles (whiskers) represent the median (90% range) of observed plasma ponatinib concentrations, and the colored shaded regions represent the 95%CIs of predicted 50th (blue), 5th (red), and 95th percentile (green) concentrations. CI, confidence interval; LOESS, locally estimated scatterplot smoothing; VPC, visual predictive check.

Figure 3

(A‐F). Individual predicted ponatinib steady‐state exposures (45 mg once daily) vs continuous covariates: age (A), body weight (B), serum albumin (C), bilirubin (D), CrCL (E), and ALT (F). Small black circles represent individual ponatinib exposures; black line (gray‐shaded area) represents a linear regression (95%CI) of individual exposures vs covariate; numbers [ranges] at the top of the plots are changes in percent [95%CI] in ponatinib exposure predicted by the linear regression at the 5th or 95th percentile of individual covariate values (large black circles) relative to the predicted AUC at the median of individual covariate values (red circle and horizontal line). (G‐I) Individual predicted exposures vs categorical covariates: sex (G), disease status (H), and race (I). Boxplots represent distributions of individual ponatinib exposures vs covariates; numbers [ranges] at the top of the plots are changes in percent [95%CI] in ponatinib mean exposure at categorical covariate values (large black circles) relative to the predicted AUC in the most common covariate category (red circle and horizontal line); numbers below each box represent the sample size within each category. ALT, alanine aminotransferase; AUC, area under the plasma concentration–time curve; CI, confidence interval; CrCL, creatinine clearance; HV, healthy volunteers; Pts, patients.

Figure 3

(A‐F). Individual predicted ponatinib steady‐state exposures (45 mg once daily) vs continuous covariates: age (A), body weight (B), serum albumin (C), bilirubin (D), CrCL (E), and ALT (F). Small black circles represent individual ponatinib exposures; black line (gray‐shaded area) represents a linear regression (95%CI) of individual exposures vs covariate; numbers [ranges] at the top of the plots are changes in percent [95%CI] in ponatinib exposure predicted by the linear regression at the 5th or 95th percentile of individual covariate values (large black circles) relative to the predicted AUC at the median of individual covariate values (red circle and horizontal line). (G‐I) Individual predicted exposures vs categorical covariates: sex (G), disease status (H), and race (I). Boxplots represent distributions of individual ponatinib exposures vs covariates; numbers [ranges] at the top of the plots are changes in percent [95%CI] in ponatinib mean exposure at categorical covariate values (large black circles) relative to the predicted AUC in the most common covariate category (red circle and horizontal line); numbers below each box represent the sample size within each category. ALT, alanine aminotransferase; AUC, area under the plasma concentration–time curve; CI, confidence interval; CrCL, creatinine clearance; HV, healthy volunteers; Pts, patients.

Figure 4

Magnitude of covariate effects relative to the overall population on individual predicted estimates of ponatinib exposure. The horizontal blue bar shows the 5th to 95th percentile range of ponatinib exposures relative to the median of individual predicted exposures. Red circles (error bars) show exposures (95%CI) at the 5th and 95th percentile of a covariate compared with exposure at the median (continuous covariates) or exposures for a covariate category relative to the reference (most common) category. ALT, alanine aminotransferase; CI, confidence interval; CrCL, creatinine clearance; HV, healthy volunteers; Pts, patients.

Figure 5

Simulated ponatinib concentrations vs time in the first week (left panels) and over the day 28 dosing interval (right panels) of once‐daily dosing with 15 mg, 30 mg, or 45 mg. Solid black lines show the ponatinib plasma concentration–time profile predicted for the typical patient; shaded areas show the 5th to 95th percentiles of concentration‐time profiles predicted for 1000 virtual patients; horizontal dashed lines represent concentrations of ponatinib associated with inhibition of BCR‐ABL1 (10.7 ng/mL) and T315I mutants (21.3 ng/mL) in cell‐based assays.

Figure 6

Predicted pediatric exposures of ponatinib in patients receiving 30 mg (body weight ≥45 kg), 20 mg (≥30 and