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

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

Br J Clin Pharmacol

Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.

Published: November 2019

AI Article Synopsis

  • A population pharmacokinetic analysis was performed to understand how personal factors and other medications affect the pharmacokinetics (PK) of pevonedistat in cancer patients.* -
  • Data from 335 patients were analyzed, revealing a linear 2-compartment model best fit to describe pevonedistat's PK, with body surface area (BSA) significantly impacting clearance and distribution, while other factors like race and age showed no effect.* -
  • The study concluded that BSA-based dosing could help standardize drug exposure among diverse patients, emphasizing that coadministering carboplatin + paclitaxel significantly reduces pevonedistat clearance, but other medications did not have a notable impact.*

Article 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 m ) 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848912PMC
http://dx.doi.org/10.1111/bcp.14078DOI Listing

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