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

• Published in: Journal of clinical pharmacology Vol. 64; no. 1; p. 94
• Main Authors: Luffer-Atlas, Debra, Wilbraham, Darren, Posada, Maria M, Landry, John, Tsai, Max, Pearlman, Eric M
• Format: Journal Article
• Language: English
• Published: England 01.01.2024
• Subjects: pharmacokinetics; drug-drug interactions; migraine; lasmiditan
• DOI: 10.1002/jcph.2328

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 aged 21-70 years with a body mass index of 18.5-35.0 kg/m . 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: a single dose of probe substrate administered on day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC ) and maximum observed drug concentration (C ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC increased by 25% and C increased by 22%. The median time of maximum observed drug concentration (t ) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC and C were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC increased by 15% and C increased by 7%. The median t 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.