Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer
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ORIGINAL RESEARCH ARTICLE
Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer Neeraj Gupta1 · Xiaohui Wang2 · Elliot Offman2 · Marita Prohn3 · Narayana Narasimhan4,5 · David Kerstein4,6 · Michael J. Hanley1 · Karthik Venkatakrishnan1,7
© The Author(s) 2020
Abstract Background and objectives Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. Methods Plasma concentration–time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). Results Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. Conclusions Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.
1 Introduction Narayana Narasimhan and David Kerstein were employees of ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, at the time the study was conducted. Karthik Venkatakrishnan was an employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, at the time the study was conducted. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00929-4) contains supplementary material, which is available to authorized users. * Neeraj Gupta [email protected] 1
Quantitative Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA 02139, USA
2
Certara, Princeton, NJ, USA
3
qPharmetra, Nijmegen, The Netherlands
Brigatinib is an inhibitor of oncogenic variants of the anaplastic lymphoma kinase gene, ALK, including the ALK fusions (e.g., EML4-ALK) that are found in non-small cell lung cancer (NSCLC) [1–3]. An accelerated approval of brigatinib was granted in the USA in 2017, followed by approval in the European Union and Canada in 2018,
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