Study Examines Cardiovascular Effects of Lasmiditan, Propranolol

The combination of lasmiditan, which is approved for pain relief of acute migraine attacks, and propranolol, which is sometimes used as a migraine preventative, was investigated for cardiovascular impact, according to a recently published study.

Propranolol is known to reduce heart rate by approximately 17% to 18%, while lasmiditan is not known to induce vasoconstriction, unlike triptans. In previous lasmiditan trials, increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were seen inconsistently.

In this phase 1, single‐center study, researchers wanted to evaluate heart rate following coadministration of lasmiditan (200 mg) and propranolol (80 mg, twice daily) in healthy adults under fasting conditions, compared with propranolol alone.

Secondary and exploratory objectives included assessments of tolerability, blood pressure, and pulse rate. The pharmacokinetic effects after giving both drugs were compared with lasmiditan alone or propranolol alone.

The study included 44 healthy male (n = 32) and female (n = 12) subjects, aged 18 to 65 years. They had normal hematology, clinical chemistry, and urinalysis lab results, a body mass index of 19 to 35 kg/m², and were nonsmokers for at least 3 months.

On day 1 of the study, participants received a single dose of 200 mg lasmiditan. From day 4 through day 10 they received doses of 80 mg bid propranolol in the morning and evening, approximately 12 hours apart.

On day 9 propranolol and lasmiditan were coadministered, with the second daily dose of propranolol administered at the usual evening time. Participants were discharged on day 11 and had a follow‐up visit about 7 days after the last dose.

Data were collected via continuous 12‐lead Holter ambulatory monitoring during certain days, blood pressure readings, and ECGs.

“Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was –6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing,” the authors wrote.

Specifically, mean hourly heart rate fell after giving both from 62.4 bpm predose to the lowest value of 54.2 bpm at 1 to 2 hours postdose. Mean hourly heart rate then showed an increasing trend toward predose levels, rising from 54.5 bpm at 2 to 3 hours postdose to 63.4 bpm at 3 to 4 hours postdose, before remaining relatively stable up through 12 hours postdose (range 62.3 to 68.8 bpm).

The maximum difference between coadministration and propranolol alone was between 4 and 5 hours postdose (–6.5 bpm; 90% CI, –8.3 to –4.7). In addition, after coadministration, there was short‐lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg).

Both drugs have different metabolic pathways and exposure to either drug was not affected by coadministration, said the authors, who noted that coadministration was generally well tolerated.

The study was funded by the maker of lasmiditan, Eli Lilly.

Reference

Tsai M, Case M, Ardayfio P, Hochstetler H, Wilbraham D. Effects of lasmiditan on cardiovascular parameters and pharmacokinetics in healthy subjects receiving oral doses of propranolol. Clin Pharmacol Drug Dev. 2020; 9(5):629–638. doi:10.1002/cpdd.768