Multiple-ascending Dose, Safety, Tolerability, Pharmacokinetic, and Drug-drug Interaction Study with Lasmiditan

Max Tsai, PhD

AHSAM 2020 - Oral session
Published on October 2, 2020 | NEW

3 minute listen

7 minute read

Key messages

  • Lasmiditan is a novel, highly selective, potent serotonin (5-HT)1F receptor agonist, approved in the United States for the acute treatment of adult migraine with or without aura.
  • Repeat doses of lasmiditan do not present any new safety issues and are well tolerated.
  • There is no accumulation of lasmiditan with daily dosing due to its short half-life.
  • Although in-vitro data suggested lasmiditan may induce some cytochrome P450 (CYP) enzymes, the in-vivo results have not shown this to be the case.
  • Background

    What do we already know about this topic?
  • Findings

    What does this study add?
  • Perspectives

    How does this study impact clinical practice?
  • Expert commentary

    by A. Laine Green, MSc, MD, FRCPC, FAHS

Key messages

  • Lasmiditan is a novel, highly selective, potent serotonin (5-HT)1F receptor agonist, approved in the United States for the acute treatment of adult migraine with or without aura.
  • Repeat doses of lasmiditan do not present any new safety issues and are well tolerated.
  • There is no accumulation of lasmiditan with daily dosing due to its short half-life.
  • Although in-vitro data suggested lasmiditan may induce some cytochrome P450 (CYP) enzymes, the in-vivo results have not shown this to be the case.

Background

What do we already know about this topic?

  • Single doses of lasmiditan, up to 400 mg, in healthy subjects and migraine patients is well characterized, but the safety and tolerability of multiple doses is yet to be established.
  • In-vitro data suggest multiple doses of lasmiditan may induce CYP enzyme activity but this has not previously been studied.

How was this study conducted?

  • A Phase I randomized, double-blind, placebo-controlled study on healthy adults (aged 20–63 years) that evaluated PK through serial blood samples collected at set intervals.
  • Cohort 1 patients (n=40) received probe drug cocktail (PDC) of CYP substrates (caffeine 100 mg, midazolam 2 mg, and tolbutamide 500 mg) on Day -3 and daily oral doses of lasmiditan 200 mg or placebo on Day 1 for 7 days. On Day 7, the PDC was administered with lasmiditan.
  • Cohort 2 patients (n=30) received daily oral doses of lasmiditan 400 mg or placebo for 7 days.

Findings

What does this study add?

  • Plasma concentrations peaked 2 hours post-dose following repeated 200 mg and 400 mg doses of lasmiditan, with no accumulation from daily dosing due to its 4hr half-life.
  • Daily administration of lasmiditan 200 mg for 7 days had no clinically relevant effects on the PK of caffeine, midazolam or tolbutamide.
  • In both cohorts, the most common treatment-emergent adverse advent (TEAE) was dizziness, and for subjects receiving lasmiditan, most TEAEs occurred on Day 1.
  • There was no increase in adverse events (AEs) upon administration of lasmiditan with PDC on Day 7.
  • No clinically significant changes in clinical laboratory values, vital signs and electrocardiograms were reported.

Perspectives

How does this study impact clinical practice?

  • No new safety issues were identified with multiple doses of 200 mg and 400 mg lasmiditan.
  • Lasmiditan does not appear to inhibit or induce the activities of CYP1A2, CYP2C9 or CYP3A.

Perspectives

How does this study impact clinical practice?

  • No new safety issues were identified with multiple doses of 200 mg and 400 mg lasmiditan.
  • Lasmiditan does not appear to inhibit or induce the activities of CYP1A2, CYP2C9 or CYP3A.

This is a highlights summary of an oral session given at the AHSAM 2020 Virtual Annual Scientific Meeting and presented by:

Max Tsai, PhD
Eli Lilly and Company
Indianapolis, Indiana

The content is produced by Infomedica, the official reporting partner of ASHAM 2020 Virtual Annual Scientific Meeting. The summary text was drafted by Goldcrest Medical Writing, reviewed by Marco Vercellino, MD, an independent external expert, and approved by Jessica Ailani, MD, FAHS and Mark J. Burish, MD, PhD, the scientific editors of the program.

The presenting authors of the original session had no part in the creation of this conference highlights summary.

In addition, an expert commentary on the topic has been provided by:

A. Laine Green, MSc, MD, FRCPC, FAHS
Assistant Professor and Staff Physician
Department of Neurology
Dartmouth Headache Center
Geisel School of Medicine at Dartmouth

A. Laine Green, MSc, MD, FRCPC, FAHS
Assistant Professor and Staff Physician
Department of Neurology
Dartmouth Headache Center
Geisel School of Medicine at Dartmouth

Dr. A. Laine Green is from Halifax Nova Scotia. His undergraduate degree was focused in organic chemistry. He then received a Master’s degree in synthetic (mechanistic) organic chemistry from Queen’s University. He completed his Medical School and Neurology residency training at Dalhousie University in Halifax. He completed his headache medicine fellowship with Dr. David Dodick at the Mayo Clinic in Arizona. His first year of fellowship was on the University of Arizona Campus in Tucson in the lab of Dr. Frank Porreca completing a preclinical project in medication overuse and cortical spreading depression. His second year of fellowship was the clinical based year with Dr. Dodick in Scottsdale. After fellowship Laine returned to Halifax where he was an Assistant Professor with the Division of Neurology at Dalhousie University for 5 years.  In late 2019 he moved to Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth where he is an Assistant Professor in the Department of Neurology.



Headache
Headache


Scan to open on your mobile device