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

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.

Effect of Statins on Lung Cancer Molecular Pathways: A Possible Therapeutic Role

“…Chemotherapy may improve liver function, thus reducing the levels of statin in the blood. Physicians should be aware of this possibility [ 128 ].…”

Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

“…Since the main scope of this review is to focus on discrepancies between published data and FDA and EMA guidelines, their results were not further explored here. Moreover, as OATP1B1 and OATP1B3 substrates used in the retrieved data have complex pharmacokinetic profiles involving drug-metabolizing enzymes and other transporters, the results of such case reports should be carefully analyzed to decide on the importance of each part of the pathway [48][49][50][51][52][53][54][55][56][57][58][59].…”