Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing

Abstract

Aims: Tralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin-13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents.

Methods: Adolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57-day follow-up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents.

Results: Twenty adolescents (12-17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) ml day(-1)]. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight-based (4 mg kg(-1)) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab.

Conclusion: Single-dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.

Keywords: Adolescent; Asthma; Tralokinumab; dosing; interleukin-13; population pharmacokinetic modelling.

© 2015 The British Pharmacological Society.

Figures

Figure 1

Clinical study design. ADA, antidrug antibodies; PK, pharmacokinetics; s.c., subcutaneous

Figure 2

Schematic of the final pharmacokinetic model. CL, systemic clearance; D0, zero‐order absorption duration; Fr, dose fraction absorbed through first‐order process; i.v., intravenous; Ka, first‐order absorption rate; Q, intercompartmental clearance; s.c., subcutaneous; Tlag, first‐order absorption lag time; Vc, central volume; Vp, peripheral volume

Figure 3

Tralokinumab pharmacokinetic profile (single 300 mg s.c. dose) in adolescents with asthma (cohort 1: 12–14 years; cohort 2: 15–17 years), and healthy adults (NCT00638989 16). s.c., subcutaneous; SD, standard deviation. Tralokinumab 300 mg s.c. single dose: Adults (n=10), Adolescents cohort 1 (n=10), Adolescents cohort 2 (n=10)

Figure 4

Mean change from baseline in prebronchodilator FEV1 over time in adolescents. FEV1, forced expiratory volume in 1 s; s.c., subcutaneous; SEM, standard error of the mean

Figure 5

(A) Individual model‐predicted concentration–time profiles and observed pharmacokinetic data in the adolescent subpopulation at the 300 mg tralokinumab dose. Observed data, Individual predictions, Population predictions. (B) Visual predictive check obtained through n = 1000 simulations from the final pharmacokinetic model for adult (left panel; combined studies NCT00638989 4 and NCT01093040) and adolescent (right panel; current study) populations. Dark blue plain dots represent individual observed concentrations; solid lines represent the median observed (red) and predicted (black) concentration–time course, with the 95% confidence interval (CI) around the predicted median represented by the pink area; dotted lines represent the 5th and 95th percentiles of individual concentration–time course measures with their respective 95% CI model (blue areas)

Figure 6

Pharmacokinetic simulations with 90% prediction intervals for: (A) weight‐based vs. fixed dosing in all‐comers (adults and adolescents): tralokinumab 4 mg kg-1 Q2W s.c., tralokinumab 300 mg Q2W s.c.; (B) adolescents vs adults: tralokinumab 600 mg Q2W s.c. in adults (40−115 kg), tralokinumab 300 mg Q2W s.c. in adults (40−115 kg), tralokinumab 300 mg Q2W s.c. in adolescents (40−100 kg). Q2W, every 2 weeks; s.c., subcutaneous