lm exhibits linear pharmacokinetics and exposure increases proportionally with doses between 1 and600 mg.
A loading dose of 240 mg achieved the serum galcanezumab-gnlm steady-state concentration after the first dose. Thetime to maximum concentration is 5 days, and the elimination half-life is 27 days.
There was no difference in pharmacokinetic parameters between healthy volunteers and patients with episodic or chronicmigraine.
Absorption
Following a subcutaneous dose of galcanezumab-gnlm, the time to maximum concentration was about 5 days.
Injection site location did not significantly influence the absorption of galcanezumab-gnlm.
Distribution
The apparent volume of distribution (V/F) of galcanezumab-gnlm was 7.3 L (34% Inter Individual Variability [IIV]).
Metabolism and EliminationGalcanezumab-gnlm is expected to be degraded into small peptides and amino acids via catabolic pathways in the samemanner as endogenous IgG.
The apparent clearance (CL/F) of galcanezumab-gnlm was 0.008 L/h and the elimination half-life of galcanezumab wasapproximately 27 days.
Specific Populations
Age, Sex, Weight, Race, Ethnicity
The pharmacokinetics of galcanezumab-gnlm were not affected by age, sex, race, or subtypes of migraine spectrum(episodic or chronic migraine), based on a population pharmacokinetics analysis. Body weight has no clinically relevanteffect on the pharmacokinetics of galcanezumab-gnlm.
Patients with Renal or Hepatic Impairment
Renal and hepatic impairment are not expected to affect the pharmacokinetics of galcanezumab-gnlm. Populationpharmacokinetic analysis of integrated data from the galcanezumab-gnlm clinical studies revealed that creatinineclearance did not affect the pharmacokinetics of galcanezumab-gnlm in patients with mild or moderate renal impairment.
Patients with severe renal impairment (creatinine clearance <30 mL/min) have not been studied. Based on a populationPK analysis, bilirubin concentration did not significantly influence the CL/F of galcanezumab-gnlm.
No dedicated clinical studies were conducted to eva luate the effect of hepatic impairment or renal impairment on thepharmacokinetics of galcanezumab-gnlm.
Drug Interaction Studies
P450 Enzymes
Galcanezumab-gnlm is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant
medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of galcanezumab-gnlm has not been assessed.
Mutagenesis
Genetic toxicology studies of galcanezumab-gnlm have not been conducted.
Impairment of Fertility
When galcanezumab-gnlm (0, 30, or 250 mg/kg) was administered to male rats by subcutaneous injection prior to andduring mating, no adverse effects on fertility was observed. The higher dose tested was associated with a plasmaexposure (Cave, ss) 8 times that in humans at the recommended human dose (RHD) of 120 mg. When galcanezumab-gnlmwas administered to female rats by subcutaneous injection in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior toand during mating and continuing throughout organogenesis, no adverse effects on fertility were observed. The highestdose tested (250 mg/kg) was associated with a plasma Cave, ss 38 times that in humans at the RHD.
14 CLINIC |
