Lanadelumab is a fully human, monoclonal antibody (IgG1/κ-light chain). Lanadelumab inhibits active plasma kallikrein proteolytic activity. Increased plasma kallikrein activity leads to angioedema attacks in patients with HAE through the proteolysis of high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin. Lanadelumab provides sustained control of plasma kallikrein activity and thereby limits bradykinin generation in patients with HAE.
Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after SC administration of lanadelumab 150 mg every 4 weeks, 300 mg every 4 weeks or 300 mg every 2 weeks in subjects with HAE.
The PK-PD relationship between lanadelumab and cHMWK is described by an indirect exposure-response pharmacological model. The cHMWK formation rate was maximally reduced by 53.7% with an IC50 of 5705 ng/ml.
The single and multiple dose pharmacokinetics of lanadelumab have been studied in patients with HAE. Pharmacokinetics of lanadelumab showed linear dose-exposure response with doses up to 400 mg and reproducible exposure following subcutaneous administration up to 12 months. The absolute bioavailability of lanadelumab after subcutaneous administration has not been determined. In the HELP study, patients treated with 300 mg q2 wks presented mean (SD) area under the curve over the dosing interval at steady-state (AUCtau,ss), maximum concentration at steady-state (Cmax,ss) and minimum concentration at steady-state (Cmin,ss) of 408 μg*day/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.
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.
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.
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.
No dedicated studies have been conducted to evaluate 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.
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.
In repeat-dose studies evaluating 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 evaluation has been conducted. Carcinogenicity has not been evaluated 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 evaluated 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 C max and AUC, respectively.
In the ePPND study in pregnant c ynomolgus 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, grow th, and/or postnatal development of offspring. Exposures in the ePPND study were approximately 32-fold greater than that noted at 300 mg q2 wks based on AUC.
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