Lasmiditan

Lasmiditan binds with high affinity to the 5-HT_1F receptor. Lasmiditan presumably exerts its therapeutic effects in the treatment of migraine through agonist effects at the 5-HT_1F receptor; however, the precise mechanism is unknown.

Cardiac Electrophysiology

At a dose two times the maximum recommended daily dose, lasmiditan does not prolong the QTc interval to any clinically relevant extent.

Absorption

Following oral administration, lasmiditan is rapidly absorbed with a median t_max 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 C_max and AUC values by 22% and 19%, respectively, and delayed the median t_max by 1 hour. This difference in exposure is not expected to be clinically significant. 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 t_½ 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 (C_max 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 and 21% higher C_max, compared to subjects 45 years of age or less. This difference in exposure is not expected to be clinically significant.

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 and 13% higher C_max, 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] to lasmiditan, compared to subjects with normal hepatic function. The C_max 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.

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.

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.