Population Pharmacokinetics of Tralokinumab in Adult Subjects With Moderate to Severe Atopic Dermatitis

Abstract

Tralokinumab is the first biologic therapy for moderate-to-severe atopic dermatitis (AD) that specifically neutralizes interleukin-13 activity, a key driver of AD signs and symptoms. Tralokinumab is a human immunoglobulin G4 monoclonal antibody administered subcutaneously every 2 weeks (with possibility of maintenance dosing every 4 weeks). This population pharmacokinetic (PK) analysis aimed to identify sources of PK variability and relevant predictors of tralokinumab exposure in adults with moderate to severe AD. Nonlinear mixed-effect modeling, including covariate analysis, was used on a data set including 2561 subjects (AD, asthma, healthy) from 10 clinical trials. A 2-compartment model with first-order absorption and elimination adequately described the tralokinumab PK. Body weight was identified as a relevant predictor of tralokinumab exposure; other covariates including age, sex, race, ethnicity, disease type, AD severity, and renal and hepatic impairment were not. For body weight, the difference in exposure between the upper- and lower-weight quartiles in patients with AD was <2-fold, supporting the appropriateness of flat dosing (300 mg). Given the reduced exposure associated with higher body weight, coupled with the reduced exposure provided by dosing every 4 weeks, it is uncertain whether higher-weight patients will achieve sufficient exposure to maintain efficacy if dosed every 4 weeks instead of the standard every 2 weeks.

Trial registration: ClinicalTrials.gov NCT03526861.

Keywords: IL-13; atopic dermatitis; population pharmacokinetics; tralokinumab.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2022 LEO Pharma A/S. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Structural representation of the 2‐compartment population pharmacokinetic model of tralokinumab, including first‐order absorption and linear elimination. CL, clearance; F, bioavailability; IV, intravenous; ka, absorption rate constant; Q, intercompartmental clearance; SC, subcutaneous; V2, central volume of distribution; V3, peripheral volume of distribution.

Figure 2

Final model: goodness‐of‐fit plots. Top left: Correlation between the dependent variable (tralokinumab serum concentration) and the population predictions. Top right: Correlation between the dependent variable (tralokinumab serum concentration) and the individual predictions. Bottom left: Correlation between the conditional weighted residuals and the population predictions. Bottom right: Correlation between the conditional weighted residuals and time. The black circles represent the individual observations/predictions/conditional weighted residuals and the red line is the trend line (locally estimated scatterplot smoothing). The black line in the upper panels is the line of unity.

Figure 3

Final model: visual predictive check for weeks 0‐16 in ECZTRA trials (subjects with atopic dermatitis). Visual predictive check (VPC) of the serum concentration‐time profile of tralokinumab in subjects with atopic dermatitis following subcutaneous administration of tralokinumab 300 mg (including loading dose), depicting the observed concentration of tralokinumab (circles), the median of the observed concentration of tralokinumab (solid line), the 95%CI of the simulated median (orange shaded area), the 95%CI of the simulated lower 5th and the upper 95th percentiles (blue shaded areas), and the observed 5th and 95th percentile (dashed line). For visual purposes, serum concentrations

Figure 4

Final model: area under the serum concentration‐time curve (AUC) from week 14 to 16 vs weight quartiles in ECZTRA trials. Boxplot depicting the correlation between individually predicted AUC from week 14 to 16 for all subjects in ECZTRA trials, grouped by weight quartiles (approximative quartiles with n = 361 in Q1, n = 356 in Q2, n = 363 in Q3, n = 350 in Q4). The top, middle, and bottom of each box are the third quartile, median, and the first quartile of data in each category. The whiskers are drawn to the nearest value not beyond 1.5 times the interquartile range (IQR). The circles represent individual values outside 1.5 times the IQR. Only data from subjects who received ≥6 doses of tralokinumab during the first 119 days and who had a PK sample in the time interval 105 to119 days are included in the plot.

Figure 5

Final model simulations. Serum concentration‐time profile for tralokinumab, simulated using the final population pharmacokinetic model and based on the following dosing scenario: an initial loading dose of 600 mg at week 0, 300 mg every 2 weeks from week 0 to week 14, and a maintenance dose of 300 mg every 4 weeks from week 16 to week 40 (steady state) for a subject with a body weight of either 50, 75, or 120 kg. For each dose 1000 subjects were simulated and the plots show the 5th, 50th, and 95th percentiles in the population.

Figure 6

Percentage of EASI‐75 responders by body weight subgroups in ECZTRA 1 and ECZTRA 2 trials. Percentage of responders, defined as at least 75% reduction in Eczema Area and Severity Index (EASI‐75) from baseline to week 16, by body weight subgroups in the clinical trials ECZTRA 1 and ECZTRA 2. All subjects treated with tralokinumab in the initial part of each trial received a dose of 300 mg every 2 weeks. Subjects who received rescue medication were considered nonresponders, and subjects with missing data at week 16 were imputed as nonresponders. Body weight was split into groups by the 25th and 75th percentiles, and the highest body weight group was further split into 101 to 120 kg and >120 kg.