Assess cardiovascular effects of coadministration of lasmiditan with propranolol in healthy subjects.

Lasmiditan is a selective serotonin 5-HT_1F receptor agonist developed for acute treatment of migraine. Based on previous clinical data, lasmiditan has been associated with maximum mean decreases in pulse rate of 5 to 10 bpm. In clinical practice, lasmiditan may potentially be coadministered with propranolol, a non-selective β-adrenergic receptor antagonist (known to decrease heart rate [HR]) used for migraine prophylaxis.

This open-label, fixed-sequence study enrolled 44 healthy subjects (aged 21-63 years), receiving single oral doses of 200mg lasmiditan on Day 1 (lasmiditan alone) and Day 9 (lasmiditan at propranolol steady-state concentrations), and twice-daily oral doses of propranolol (80mg, mornings and evenings) on Days 4-10. Vital signs were assessed frequently on Days -1, 1, 8, and 9. HR effects were assessed by Holter ambulatory monitoring and triplicate 12-lead electrocardiogram. Safety and PK were also assessed.

While coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, the maximum magnitude of this effect was 6.5 bpm and recovered to predose levels by 3-4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mmHg) and diastolic blood pressure (6.4 mmHg) were observed following coadministration. The most commonly occurring (frequency ≥3) treatment-emergent events (TEAEs) related to study treatment were dizziness, fatigue, paraesthesia, somnolence, discomfort, and nausea. No CV TEAEs were reported. Coadministration resulted in no clinically meaningful changes in exposure to either drug; 90% CIs for geometric LS means for all C_max and AUC parameters were within 0.8 and 1.25.

Lasmiditan added to the heart rate-lowering effect of propranolol with minimal effects on BP. There were no clinically relevant PK interactions that would preclude the coadministration of lasmiditan and propranolol.