TAKHZYRO (Page 3 of 8)
12.3 Pharmacokinetics
Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximately dose-proportional in the therapeutic dose range in patients with HAE (Table 2). The pharmacokinetic properties and exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, are provided in Table 2. Following subcutaneous administration of TAKHZYRO, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is ~ 2 weeks. The anticipated time to reach steady state concentration was approximately 70 days. At steady-state, the mean accumulation ratio is approximately 1.44, 1.42, and 2.43 for dosing regimen of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, respectively.
| Pharmacokinetic Parameters | Lanadelumab-flyo | ||
|---|---|---|---|
| 150 mg q4wks(N=28) | 300 mg q4wks(N=29) | 300 mg q2wks(N=27) | |
| CL/F: apparent clearance; Vc/F: apparent volume of distribution; AUCtau,ss : area under the curve over the dosing interval at steady-state; Cmax,ss : maximum concentration at steady-state; Cmin,ss : minimum concentration at steady state; Tmax : time to maximum concentration; t1/2 terminal elimination half-life. | |||
| CL/F(L/day) | 0.667 (0.162) | 0.742 (0.239) | 0.809 (0.370) |
| Vc/F(L) | 14.1 (2.93) | 14.9 (4.45) | 16.6 (4.79) |
| AUCtau,ss (µg*day/mL) | 233 (56.6) | 441(137) | 408 (138) |
| Cmax,ss (µg/mL) | 12.0 (3.01) | 23.3 (7.94) | 34.4 (11.2) |
| Cmin,ss (µg/mL) | 4.81 (1.40) | 8.77 (2.80) | 25.4 (9.18) |
| tmax (day) | 5.17 (1.09) | 5.17 (1.12) | 4.11 (0.377) |
| t1/2 (day) | 14.9 (2.00) | 14.2 (1.89) | 15.0 (2.48) |
Specific Populations
Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab-flyo after correcting for body weight. Body weight was identified as an important covariate describing the variability of clearance and volume of distribution, resulting in higher exposure (AUC and Cmax ) in lighter patients. However, this difference is not considered to be clinically relevant and no dose adjustments are recommended for any of these demographics.
Pediatric Population
Based on population pharmacokinetics (PK) analyses, the geometric mean lanadelumab-flyo average concentration at steady state (Cave ) was approximately 25% higher following subcutaneous administration of TAKHZYRO 300 mg q2wks in pediatric patients 12 to less than 18 years of age than the mean Cave in adult patients under the same dosing regimen, due to lower body weight in pediatric patients. Lanadelumab-flyo exposures in pediatric patients 2 to less than 12 years of age receiving TAKHZYRO 150 mg q2wks or q4wks are comparable to those in adult patients receiving TAKHZYRO 300 mg q2wks. The geometric mean lanadelumab-flyo Cave was approximately 7% higher following subcutaneous administration of TAKHZYRO 150 mg q2wks in pediatric patients 6 to less than 12 years of age compared to the mean Cave in adult patients receiving 300 mg q2wks. The mean lanadelumab-flyo Cave was approximately 14% lower following subcutaneous administration of TAKHZYRO 150 mg q4wks in pediatric patients 2 to less than 6 years of age compared to the mean Cave in adult patients receiving 300 mg q2wks.
Renal Impairment
No dedicated studies have been conducted to evaluate the PK of lanadelumab-flyo in renal impairment patients. Based on population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 mL/min/1.73m2 , [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-flyo.
Concomitant medications
The use of analgesic, antibacterial, antihistamine, anti-inflammatory and anti-rheumatic medications had no effect on clearance and volume of distribution of lanadelumab-flyo.
For breakthrough HAE attacks, use of rescue medications such as plasma-derived and recombinant C1-INH, icatibant or ecallantide had no effects on clearance and volume of distribution of lanadelumab-flyo.
12.6 Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of lanadelumab-flyo or of other lanadelumab products.
In Trial 1 with adult and pediatric patients 12 years of age and older, 10 (12%) lanadelumab-flyo-treated and 2 (5%) placebo-treated patients had at least 1 anti-drug antibody (ADA)-positive sample during the 26-week treatment period; antibody titers were low (range: 20 to 1280). The ADA response observed was transient in 2/10 lanadelumab-flyo and 1/2 placebo-treated patients. Pre-existing low titer antibodies were observed in 3 lanadelumab-flyo-treated patients and 1 placebo-treated patient with ADAs. Two patients receiving 150 mg q4wks had low titer antibodies classified as neutralizing.
In an open-label, multicenter study in pediatric patients 2 to less than 12 years of age, 3/20 (15%) lanadelumab-treated patients who completed the study developed ADAs during the 52-week treatment period; all of whom were in the 6 to less than 12 years age group. The ADA response observed was transient in all 3 patients. None of these patients had pre-existing antibodies. One patient had neutralizing antibodies.
The development of ADA including neutralizing antibodies against lanadelumab-flyo did not appear to adversely affect pharmacokinetics (PK), pharmacodynamics (PD), safety or clinical response.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to evaluate the carcinogenic potential of lanadelumab-flyo. Published literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule. However, the malignancy risk in humans from an antibody that inhibits plasma kallikrein activity, such as lanadelumab-flyo, which lowers bradykinin levels, is currently unknown.
Male and female fertility were unaffected based upon no observed adverse histopathological findings in the reproductive organs from sexually mature cynomolgus monkeys that received lanadelumab-flyo for 13 weeks at subcutaneous doses up to 50 mg/kg/week (resulting in approximately 22 times the exposure at the MRHD on an AUC basis).
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