Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies

Abstract

Aims: A population pharmacokinetic (PK) analysis was conducted to quantify the impact of patient-specific and concurrent medication factors on pevonedistat PK.

Methods: Data were pooled from 6 clinical studies consisting of 335 patients with solid tumours or haematological malignancies administered pevonedistat alone or in combination with azacitidine, docetaxel, carboplatin + paclitaxel, or gemcitabine. Model development and covariate analysis followed standard methods. Parameters and bootstrap 95% confidence intervals were estimated using nonlinear mixed-effects modelling. The final model was evaluated using visual predictive checks and other goodness-of-fit criteria.

Results: A linear 2-compartment model best described pevonedistat PK. The final model included the effect of body surface area (BSA) on clearance (CL and Q) and volume of distribution of pevonedistat, effect of concomitantly administered carboplatin + paclitaxel on CL, and effect of albumin on Q. Race, sex, age, tumour type (haematological vs solid), mild or moderate renal impairment (creatinine clearance ≥30 mL/min), or mild hepatic impairment, had no impact on pevonedistat PK.

Conclusions: The clinical PK profile of pevonedistat is comparable in patients with solid tumours or haematological malignancies. All PK parameters exhibited ≥20% change over the observed BSA range (1.38-3 m2 ) with CL ranging from 75.5 to 208% of the reference value, with simulations supporting BSA-based dosing to minimize interindividual variability in drug exposures. Concurrent administration of carboplatin + paclitaxel decreased pevonedistat CL by approximately 44%, while coadministration with azacitidine, gemcitabine or docetaxel did not alter pevonedistat CL. No other factors were identified as influencing pevonedistat PK.

Trial registration: ClinicalTrials.gov NCT00677170 NCT00722488 NCT00911066 NCT01011530 NCT01814826 NCT01862328.

Keywords: anticancer drugs; pharmacokinetics; population analysis.

Conflict of interest statement

H.M.F., X.Z., D.V.F., F.S. and K.V. are employees of Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. D.R.M is a consultant for Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1

Visual predictive checks results for final model—observed and simulated pevonedistat dose‐normalized concentrations vs time after dose—all data. Blue open circles are the observed data; solid red line is the median of the observed data; red dashed lines are the 5th and 95th percentiles of the observed data; black solid line is the median of the simulated data; black dashed lines are the 5th and 95th percentiles of the simulated data; grey shaded areas are the 95% confidence intervals associated with the simulated lower and upper percentiles. The confidence intervals (CIs) are not computed beyond 60 hours as the number of observations is insufficient to determine confidence intervals

Figure 2

Visual predictive checks of dose‐normalized concentration–time data of pevonedistat coadministered with azacitidine (A) or carboplatin plus paclitaxel (B). Blue open circles are the observed data; solid red line is the median of the observed data; red dashed lines are the 5th and 95th percentiles of the observed data; black solid line is the median of the simulated data; black dashed lines are the 5th and 95th percentiles of the simulated data; grey shaded areas are the 95% confidence intervals associated with the simulated lower and upper percentiles

Figure 3

Pevonedistat clearance by patient covariates. 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 and the symbols beyond the whiskers are the outliers

Figure 4

Pevonedistat concentration vs time with and without concomitant administration of carboplatin + paclitaxel

Figure 5

Simulated pevonedistat exposures following fixed (mg) vs BSA based dosing (mg/m2). AUC, area under the concentration–time curve; BSA, body surface area

Figure 6

Simulated pevonedistat concentration–time profiles at the recommended clinical dose of 20 mg/m2 administered on days 1, 3 and 5. Note: Black solid line is the median simulated concentration; black dashed lines are the lower 5th and upper 95th percentiles of the simulated data; grey shaded areas are the 95% confidence intervals for each percentile