TY - JOUR
T1 - Pharmacokinetic study of osimertinib in cancer patients with mild or moderate hepatic impairment
AU - Grande, Enrique
AU - Donald Harvey, R.
AU - You, Benoit
AU - Batlle, Jaime Feliu
AU - Galbraith, Hal
AU - Sarantopoulos, John
AU - Ramalingam, Suresh S.
AU - Mann, Helen
AU - So, Karen
AU - Johnson, Martin
AU - Vishwanathan, Karthick
N1 - Publisher Copyright:
Copyright ª 2019 by The American Society for Pharmacology and Experimental Therapeutics
PY - 2019/5
Y1 - 2019/5
N2 - 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): Cmax 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.
AB - 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): Cmax 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.
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U2 - 10.1124/jpet.118.255919
DO - 10.1124/jpet.118.255919
M3 - Article
C2 - 30872388
AN - SCOPUS:85065011696
SN - 0022-3565
VL - 369
SP - 291
EP - 299
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -