Investigation of the Effect of Lasmiditan on the Pharmacokinetics of P‐Glycoprotein and Breast Cancer Resistance Protein Substrates

Abstract

Lasmiditan is an in vitro inhibitor of P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically‐based pharmacokinetic models of lasmiditan and assess the safety and tolerability of rosuvastatin and dabigatran co‐administered with lasmiditan. In this open‐label, post‐marketing drug‐drug interaction phase 1 clinical trial, eligible participants were adults 21–70 years old with body mass index 18.5–35.0 kg/m2. Part 1 (P‐gp: 150 mg dabigatran etexilate with 200 mg lasmiditan) and Part 2 (BCRP: 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: single dose of probe substrate administered Day −2 with pharmacokinetic evaluation; 1‐week washout; lasmiditan administered Days 8 and 9 alone; lasmiditan co‐administered with single dose of probe substrate Day 10 with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty‐six participants were included in Part 1 and 30 in Part 2. Following dabigatran co‐administration with lasmiditan vs. dabigatran alone, 90% confidence intervals for geometric least squares (LS) mean ratios of AUC[0‐∞] and Cmax were not contained within non‐effect boundaries (0.80–1.25). Dabigatran AUC[0‐∞] increased by 25% and Cmax by 22%. Median tmax for dabigatran was 2.0–3.0 hours. Following rosuvastatin co‐administration with lasmiditan vs. rosuvastatin alone, 90% CIs for geometric LS mean ratios of AUC[0‐∞] and Cmax were contained within non‐effect boundaries (0.80–1.25). Rosuvastatin AUC[0‐∞] increased by 15% and Cmax by 7%. Median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P‐gp substrates and no clinically relevant effect on BCRP substrates.This article is protected by copyright. All rights reserved