CLINICAL PHARMACOLOGY
Mechanism Of Action
Lasmiditan binds with high affinity to the 5-HT1F receptor. Lasmiditan presumably exerts its therapeutic effects in the
treatment of migraine through agonist effects at the 5-HT1F receptor; however, the precise mechanism is unknown.
Pharmacodynamics
Cardiac Electrophysiology
At a dose two times the maximum recommended daily dose, REYVOW does not prolong the QTc interval to any clinically
relevant extent.
Pharmacokinetics
Absorption
Following oral administration, lasmiditan is rapidly absorbed with a median tmax of 1.8 hours. In patients with migraine, the
absorption or pharmacokinetics of lasmiditan was not different during a migraine attack versus during the interictal period.
Effect of Food
Coadministration of lasmiditan with a high-fat meal increased the mean lasmiditan Cmax and AUC values by 22% and
19%, respectively, and delayed the median tmax by 1 hour. This difference in exposure is not expected to be clinically
significant [see DOSAGE AND ADMINISTRATION]. Lasmiditan was administered without regard to food in clinical efficacy
studies.
Distribution
The human plasma protein binding of lasmiditan is approximately 55% to 60% and independent of concentration between
15 and 500 ng/mL.
Elimination
Lasmiditan was eliminated with a geometric mean t½ value of approximately 5.7 hours. No accumulation of lasmiditan was
observed with daily dosing. Lasmiditan is primarily eliminated via metabolism, with ketone reduction representing the
major pathway. Renal excretion is a minor route of lasmiditan clearance.
Metabolism
Lasmiditan undergoes hepatic and extrahepatic metabolism primarily by non-CYP enzymes. The following enzymes are
not involved in metabolism of lasmiditan: MAO-A, MAO-B, flavin monooxygenase 3, CYP450 reductase, xanthine oxidase,
alcohol dehydrogenase, aldehyde dehydrogenase, and aldo-keto reductases. Lasmiditan is also metabolized to M7
(oxidation on piperidine ring) and M18 (combination of M7 and M8 pathways). These metabolites are considered
pharmacologically inactive.
Excretion
Recovery of unchanged lasmiditan in urine was low and accounted for approximately 3% of the dose. Metabolite S-M8
represented approximately 66% of the dose in urine, with the majority of recovery within 48 hours postdose.
Specific Populations
Age, Sex, Race/Ethnicity, And Body Weight
Based on a population pharmacokinetic (PK) analysis, age, sex, race/ethnicity, and body weight did not have a significant
effect on the PK (Cmax and AUC) of lasmiditan. Therefore, no dose adjustments are warranted based on age, sex,
race/ethnicity, or body weight.
Geriatric Use
In a clinical pharmacology study, administration of lasmiditan to subjects 65 years of age or older demonstrated 26%
greater exposure in AUC(0-∞) and 21% higher Cmax, compared to subjects 45 years of age or less. This difference in
exposure is not expected to be clinically significant [see Use In Specific Populations].
Renal Impairment
In a clinical pharmacology study, administration of lasmiditan to subjects with severe renal impairment (eGFR
<30 mL/min/1.73 m2) demonstrated 18% greater exposure in AUC(0-∞) and 13% higher Cmax, compared to subjects with
normal renal function. No dose adjustment is required based on renal function.
Hepatic Impairment
In a clinical pharmacology study, subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B,
respectively) demonstrated 11% and 35%, respectively, greater exposure [AUC(0-∞)] to lasmiditan, compared to subjects
with normal hepatic function. The Cmax were higher by 19% and 33%, respectively, for subjects with mild and moderate
hepatic impairment. This difference in exposure is not expected to be clinically significant. The use of lasmiditan has not
been studied in subjects with severe hepatic impairment [see Use In Specific Populations].
Drug Interaction Studies
Potential For Lasmiditan To Affect Other Drugs
Drug Metabolizing Enzymes
Lasmiditan is an in-vitro inhibitor of CYP2D6 but did not significantly inhibit the activity of other CYP450 enzymes.
Modeling and simulation of the impact of lasmiditan on the exposure of dextromethorphan, a recognized sensitive
CYP2D6 substrate, indicate that lasmiditan is unlikely to exert clinically significant inhibition of CYP2D6. Lasmiditan, M7,
S-M8, and [S,R]-M18 are not reversible or time-dependent inhibitors of monoamine oxidase A (MAO-A).
Daily dosing of lasmiditan did not alter the PK of midazolam, caffeine, or tolbutamide, which are substrates of CYP3A,
CYP1A2, and CYP2C9, respectively. Coadministration of lasmiditan with sumatriptan, propranolol, or topiramate resulted
in no clinically meaningful changes in exposure of these medicinal products.
Drug Transporters
Lasmiditan inhibits P-gp and BCRP in-vitro [see DRUG INTERACTIONS].
Lasmiditan inhibits OCT1 in-vitro. However, in a drug-drug interaction study with lasmiditan and sumatriptan (OCT1
substrate), no change in sumatriptan PK was observed. Lasmiditan inhibits renal efflux transporters, MATE1 and MATE2-
K, in-vitro.
Potential For Other Drugs To Affect Lasmiditan
Drug Metabolizing Enzymes
Lasmiditan undergoes hepatic and extrahepatic metabolism primarily by non-CYP enzymes. Therefore, it is unlikely that
CYP inhibitors or inducers will affect lasmiditan pharmacokinetics. Clinical studies of lasmiditan with sumatriptan,
propranolol, or topiramate did not show any significant drug interaction potential.
Drug Transporters
Lasmiditan is a substrate for P-gp in-vitro.
Clinical Studies
Migraine
The efficacy of REYVOW in the acute treatment of migraine was demonstrated in two randomized, double-blind, placebocontrolled
trials [Study 1 (NCT02439320) and Study 2 (NCT02605174)]. These studies enrolled patients with a history of
migraine with and without aura according to the International Classification of Headache Disorders (ICHD-II) diagnostic
criteria. Patients were predominantly female (84%), and White (78%), with a mean age of 42 years (range 18-81). Twentytwo
percent of patients were taking preventive medication for migraine at baseline. Study 1 randomized patients to
REYVOW 100 mg (n=744), or 200 mg (n=745) or placebo (n=742) and Study 2 randomized patients to REYVOW 50 mg
(n=750), 100 mg (n=754), or 200 mg (n=750) or placebo (n=751). Patients were allowed to take a rescue medication
2 hours after taking study drug; however, opioids, barbiturates, triptans, and ergots were not allowed within 24 hours of
study drug administration.
The primary efficacy analyses were conducted in patients that treated a migraine with moderate to severe pain within
4 hours of the onset of the attack. The efficacy of REYVOW was established by an effect on pain freedom at 2 hours and
Most Bothersome Symptom (MBS) freedom at 2 hours compared to placebo for Studies 1 and 2. Pain freedom was
defined as a reduction of moderate or severe headache pain to no pain, and MBS freedom was defined as the absence of
the self-identified MBS (photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most
commonly selected MBS was photophobia (54%), followed by nausea (24%), and phonophobia (22%).
In both studies, the percentage of patients achieving pain freedom and MBS freedom 2 hours after treatment was
significantly greater among patients receiving REYVOW at all doses compared to those receiving placebo (see Table 2).
Table 2: Migraine Efficacy Endpoints after Treatment for Studies 1 and 2
|
Study 1 |
Study 2 |
REYVOW
100 mg |
REYVOW
200 mg |
Placebo |
REYVOW
50 mg |
REYVOW
100 mg |
REYVOW
200 mg |
Placebo |
Pain Free at 2 hours |
N |
498 |
503 |
515 |
544 |
523 |
521 |
534 |
% Responders |
28.3 |
31.8 |
15.3 |
28.3 |
31.4 |
38.8 |
21.0 |
Difference from placebo (%) |
13 |
16.5 |
|
7.3 |
10.4 |
17.8 |
|
p-value |
<0.001 |
<0.001 |
|
0.006 |
<0.001 |
<0.001 |
|
MBS Free at 2 hours |
N |
464 |
467 |
480 |
502 |
491 |
478 |
509 |
% Responders |
41.2 |
40.7 |
29.6 |
40.8 |
44.0 |
48.7 |
33.2 |
Difference from placebo (%) |
11.6 |
11.1 |
|
7.6 |
10.8 |
15.5 |
|
p-value |
<0.001 |
<0.001 |
|
0.014 |
<0.001 |
<0.001 |
|
Pain relief at 2 hours, defined as a reduction in migraine pain from moderate or severe to mild or none, was also
evaluated (see Table 3).
Table 3: Additional Migraine Efficacy Endpoint after Treatment for Studies 1 and 2
|
Study 1 |
Study 2 |
REYVOW
100 mg |
REYVOW
200 mg |
Placebo |
REYVOW
50 mg |
REYVOW
100 mg |
REYVOW
200 mg |
Placebo |
Pain Relief at 2 hoursa |
N |
498 |
503 |
515 |
544 |
523 |
521 |
534 |
% Responders |
54.0 |
55.3 |
40.0 |
55.9 |
61.4 |
61.0 |
45.1 |
Difference from placebo (%) |
14.0 |
15.3 |
|
10.8 |
16.3 |
15.9 |
|
a The analysis of pain relief was descriptive and was not controlled for Type I error. |
Figure 1 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in
Studies 1 and 2.
Figure 1: Percentage of Patients Achieving Migraine Pain Freedom within 2 Hours in Pooled Studies 1 and 2
 |
a The 50 mg arm was only included in Study 2. |
Figure 2 presents the percentage of patients achieving MBS freedom within 2 hours in Studies 1 and 2.
Figure 2: Percentage of Patients Achieving MBS Freedom within 2 Hours in Pooled Studies 1 and 2
 |
a The 50 mg arm was only included in Study 2. |
Effects On Driving
Driving performance was assessed at 90 minutes after administration of REYVOW 50 mg, 100 mg, 200 mg, alprazolam
1 mg, and placebo in a randomized, double-blind, placebo- and active-controlled, five-period crossover study in 90 healthy
volunteers (mean age 34.9 years) using a computer-based driving simulation. Driving performance was evaluated using a
validated threshold established in a population with blood alcohol concentration of 0.05%. The primary outcome measure
was the difference from placebo in the Standard Deviation of Lateral Position (SDLP), a measure of driving performance.
A dose-dependent impairment of computer-based simulated driving performance was seen with all doses of REYVOW at
90 minutes after administration.
Driving performance was also assessed at 8, 12, and 24 hours after administration of REYVOW 100 mg or 200 mg, in a
separate randomized, double-blind, placebo- and active-controlled, four-period crossover study in 67 healthy volunteers
(mean age 32.8 years) evaluating computer-based simulated driving performance using SDLP as the primary endpoint.
Diphenhydramine 50 mg was used as a positive control. The mean SDLP did not reach the threshold for driving
impairment at 8 hours or later after administration of REYVOW 100 or 200 mg.