Pharmacokinetic study of osimertinib in cancer patients with mild or moderate hepatic impairment

Enrique Grande, R. Donald Harvey, Benoit You, Jaime Feliu Batlle, Hal Galbraith, John Sarantopoulos, Suresh S. Ramalingam, Helen Mann, Karen So, Martin Johnson, Karthick Vishwanathan

Research output: Contribution to journalArticle

Abstract

Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (n 5 7) or moderate hepatic impairment (n 5 5) versus normal hepatic function (n 5 10): C max was reduced to 51% and 61%, respectively; area under the curve was reduced to 63% and 68%, respectively. PK results for the metabolites were similar. No apparent differences in the safety profile were found between patients with normal hepatic function and patients with mild or moderate hepatic impairment. Comparison of these study results with National Cancer Institute-Organ Dysfunction Working Group criteria from population PK analysis showed osimertinib exposure was not affected by hepatic impairment. No dose adjustment is required for osimertinib when treating patients with mild or moderate hepatic impairment. No apparent differences in the safety of osimertinib were found between patients with normal hepatic function and mild or moderate hepatic impairment.

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
DOIs
StatePublished - May 1 2019

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Pharmacokinetics
Liver
Neoplasms
osimertinib
Safety
National Cancer Institute (U.S.)
Population Groups
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Area Under Curve

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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Pharmacokinetic study of osimertinib in cancer patients with mild or moderate hepatic impairment. / Grande, Enrique; Donald Harvey, R.; You, Benoit; Batlle, Jaime Feliu; Galbraith, Hal; Sarantopoulos, John; Ramalingam, Suresh S.; Mann, Helen; So, Karen; Johnson, Martin; Vishwanathan, Karthick.

In: Journal of Pharmacology and Experimental Therapeutics, 01.05.2019, p. 291-299.

Research output: Contribution to journalArticle

Grande, E, Donald Harvey, R, You, B, Batlle, JF, Galbraith, H, Sarantopoulos, J, Ramalingam, SS, Mann, H, So, K, Johnson, M & Vishwanathan, K 2019, 'Pharmacokinetic study of osimertinib in cancer patients with mild or moderate hepatic impairment', Journal of Pharmacology and Experimental Therapeutics, pp. 291-299. https://doi.org/10.1124/jpet.118.255919
Grande, Enrique ; Donald Harvey, R. ; You, Benoit ; Batlle, Jaime Feliu ; Galbraith, Hal ; Sarantopoulos, John ; Ramalingam, Suresh S. ; Mann, Helen ; So, Karen ; Johnson, Martin ; Vishwanathan, Karthick. / Pharmacokinetic study of osimertinib in cancer patients with mild or moderate hepatic impairment. In: Journal of Pharmacology and Experimental Therapeutics. 2019 ; pp. 291-299.
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