A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment

Abstract

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on Cmax and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI.

Trial registration: ClinicalTrials.gov NCT02923947.

Keywords: epidermal growth factor receptors; kidney; non-small cell lung cancer; osimertinib; pharmacokinetics; renal disposition; tyrosine kinase inhibitors.

Conflict of interest statement

Karthick Vishwanathan, Marcello Marotti, and Martin Johnson are AstraZeneca employees and shareholders. Doris Weilert is an employee of IQVIA, formerly Quintiles, the contract research organization that conducted the trial. Andrew Mills is a contract employee of AstraZeneca. Inmaculada Sanchez‐Simon, Maria de Miguel‐Luken, Bhumsuk Keam, Nicolas Penel, and Alain Ravaud have nothing to disclose.

© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

Figures

FIGURE 1

Study design and patient disposition

FIGURE 2

Geometric mean plasma concentration of osimertinib by renal function group (semi‐logarithmic scale; pharmacokinetics analysis set). Geometric mean standard deviation expressed in the error bars as the exponential of (mean of the log concentration ± the standard deviation of the log concentration). Normal renal function creatinine clearance (CrCL) ≥90 mL/min; Severe renal impairment CrCL of

FIGURE 3

Osimertinib AUC as a function of renal impairment. Circles represent individual AUCss values based on population PK analysis in AURA studies; for the present study, individual AUC values are shown. AUC, area under the concentration‐time curve; AUCss, area under the plasma concentration‐time curve at steady state; PK, pharmacokinetics

FIGURE 4

Individual osimertinib AUC function of baseline creatinine clearance (CrCL) in patients across the clinical program. Circles represent individual AUC values; based on population PK analysis. AUCss, area under the plasma concentration‐time curve at steady state; CrCL, creatinine clearance; PK, pharmacokinetics; RSTS, renal impairment status