ml (138), 34.4 µg/mL (11.2), and 25.4 µg/mL (9.18), respectively. The anticipated time to reach steady state concentration was approximately 70 days.
Absorption
Following SC administration, the time to maximum concentration is approximately 5 days. The site of SC injection (thigh, arm, or abdomen) and self-administration did not affect the absorption of lanadelumab.
Distribution
The mean (SD) volume of distribution of lanadelumab in patients with HAE is 14.5 litres (4.53). Lanadelumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.
Elimination
Lanadelumab has a mean (SD) total body clearance of 0.0297 L/h (0.0124) and a terminal elimination half-life of approximately 14 days.
Special populations
No dedicated studies have been conducted to eva luate the pharmacokinetics of lanadelumab in special patient populations including gender, age, pregnant women or the presence of renal or hepatic impairment.
In a population pharmacokinetic analysis, after correcting for body weight, no influence of gender or age (12 to 75 years) was apparent on the clearance or volume of distribution of lanadelumab.
Although body weight was identified as an important covariate describing the variability of clearance, a 300 mg q2wks dose regimen provided sufficient exposure for the indication (see section 5.1).
Renal and hepatic impairment
As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment or hepatic impairment is not expected to influence clearance of lanadelumab.
Accordingly, in a population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 ml/min/1.73 m2 [mild, N=98] and 30 to 59 ml/min/1.73m2 [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab.
5.3 Preclinical safety data
In repeat-dose studies eva luating once weekly SC injection in both rats (up to 28 days) and cynomolgus monkeys (up to 6 months) lanadelumab was well-tolerated at doses of up to and including 50 mg/kg (highest dose tested) with no organs of toxicity identified. Exposures in cynomolgus monkeys following 6 months of administration were approximately 23-fold greater than that noted at 300 mg q2 wks based on AUC.
Lanadelumab is not expected to interact directly with DNA or other chromosomal material, as it is made up entirely of naturally occurring amino acids and contains no inorganic or synthetic linkers or other nonprotein portions; therefore no genotoxicity eva luation has been conducted.
Carcinogenicity has not been eva luated in animals as based on the weight of evidence approach, lanadelumab is considered to have a low risk for carcinogenicity.
The effects of lanadelumab on fertility were eva luated in sexually mature cynomolgus monkeys. In a 13-week study, once weekly SC administration of lanadelumab had no effects on male or female fertility at doses of 10 or 50 mg/kg (highest dose tested). Exposures in sexually mature cynomolgus monkeys in the fertility study were approximately 20-and 22-fold greater than that noted at 300 mg q2 wks based on Cmax and AUC, respectively.
In the ePPND study in pregnant cynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg (highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition, embryo-foetal development, survival, growth, and/or postnatal development of offspring. Exposures in the ePPND study were approximately 32-fold greater than that noted |
