Galcanezumab is a humanised IgG4 monoclonal antibody that binds calcitonin gene-related peptide (CGRP) thus preventing its biological activity. Elevated blood concentrations of CGRP have been associated with migraine attacks. Galcanezumab binds to CGRP with high affinity (KD = 31 pM) and high specificity (>10,000-fold vs related peptides adrenomedullin, amylin, calcitonin and intermedin).
Based on a population pharmacokinetic (PK) analysis, following a loading dose of 240 mg the maximum serum concentration (Cmax) of galcanezumab was approximately 30 μg/mL (27% coefficient of variation, (CV)) and the time to Cmax was 5 days postdose.
Monthly doses of 120 mg or 240 mg achieved a steady-state Cmax (Cmax,ss) of approximately 28 μg/mL (35% CV) or 54 μg/mL (31% CV), respectively. The galcanezumab Cmax,ss at monthly doses of 120 mg is achieved after the 240 mg loading dose.
Injection site location (abdomen, thigh, buttocks and arm) did not significantly influence the absorption of galcanezumab.
Based on a population PK analysis, the apparent volume of distribution of galcanezumab was 7.3 L.
As a humanised IgG4 monoclonal antibody, galcanezumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Based on a population PK analysis, the apparent clearance of galcanezumab was approximately 0.008 L/hour and the half life of galcanezumab was 27 days.
Galcanezumab exposure increases proportionally with dose. Based on a population PK analysis that included doses ranging from 5–300 mg, the rate of absorption, apparent clearance and apparent volume of distribution was independent of dose.
No dose adjustment is needed on the basis of age (18 to 65 years), sex, weight, race or ethnicity as there was no clinically meaningful effect of these factors on the apparent clearance or apparent volume of distribution of galcanezumab.
Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepatic impairment on the PK of galcanezumab have not been conducted. Renal elimination of IgG monoclonal antibody is low. Similarly, IgG monoclonal antibodies are mainly eliminated via intracellular catabolism and hepatic impairment is not expected to influence the clearance of galcanezumab. Based on a population PK analysis, bilirubin concentration or Cockcroft-Gault creatinine clearance (range: 24 to 308 mL/min) did not significantly influence the apparent clearance of galcanezumab.
Non-clinical data revealed no special hazards for humans based on repeat-dose toxicity studies conducted in rats and cynomolgus monkeys and safety pharmacology evaluations conducted in cynomolgus monkeys at exposures approximately 10 to 80 times higher than clinical exposures in patients receiving 240 mg.
Nonclinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of galcanezumab. There is no evidence to suggest that chronic treatment with galcanezumab would increase the risk of carcinogenesis based on data from pharmacology and chronic toxicology studies with galcanezumab, as well as an assessment of the literature regarding CGRP.
No effects on fertility parameters such as oestrous cycle, sperm analysis, or mating and reproductive performance were observed in rats that were administered galcanezumab (exposures approximately 4 to 20 times the human exposure at 240 mg). In male fertility study, right testis weight was significantly reduced at exposures to 4 times the human exposure at 240 mg.
At Gestational Day 20, an increase in the number of foetuses and litters with short ribs and a decrease in the mean number of ossified caudal vertebrae occurred in the rat embryo-foetal toxicity development study at an exposure approximately 20 times the human exposure at 240 mg. These findings were noted at no maternal toxicity and were considered to be related to galcanezumab but non-adverse.
At Gestational Day 29, in rabbit embryo-foetal development toxicity study skull anomaly was found in one male foetus from mother treated with galcanezumab at an exposure approximately 33 times the human exposure at 240 mg.
In a juvenile toxicology study in which rats were administered galcanezumab twice weekly from Postnatal Day 21 through 90, systemic effects were limited to reversible, minimal, nonadverse decreases in total bone mineral content and bone mineral density at exposures approximately 50 times the human exposure at 240 mg.
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