Impact of Disease and Treatment Response in Drug–Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non-Small Cell Lung Cancer

• Type of Material: Article
• Authors: Karthick Vishwanathan, AstraZeneca; Mireille Cantarini, AstraZeneca; Karen So, AstraZeneca; Eric Masson, AstraZeneca; Jennifer Fetterolf, AstraZeneca; Suresh Ramalingam, Emory University; R Donald Harvey, Emory University
• Language: English
• Date: 2019-01-01
• Publisher: Wiley Open Access: Various Creative Commons Licenses
• Publication Version: Final Published Version
• Copyright Statement: © 2019 AstraZeneca. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/cts.12688
• Title of Journal or Parent Work: Clinical and Translational Science
• ISSN: 1752-8054
• Volume: 13
• Issue: 1
• Start Page: 41
• End Page: 46
• Grant/Funding Information: This study was funded by AstraZeneca.
• Keywords: osimertinib; advanced epidermal growth factor receptor; abnormal liver function; EGFR mutation; tyrosine kinase inhibitor treatment; liver metasteses; oral dose; non-small cell lung cancer; hepatic disease; simvastatin exposure
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3–32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax)) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.