Pharmacokinetic Modelling and Simulation Support the Age and Body-Weight-Adjusted Dosing of Dabigatran Etexilate in Pediatric Patients with Venous Thromboembolism

Background:

Dabigatran etexilate (DE), a direct oral thrombin inhibitor effective for the treatment of venous thromboembolism (VTE) in adults, is currently being evaluated for the treatment of VTE in children using several formulations across the age spectrum from birth to < 18 years.

Aims:

This study evaluated the pharmacokinetics (PK) of dabigatran in pediatric patients with VTE following administration of DE as oral solution, coated granules, or capsules. The appropriateness of a dabigatran pediatric dosing algorithm was assessed using simulations based on a population PK model.

Methods:

Pediatric data from three phase IIa and two phase IIb/III pediatric studies (N = 392) as well as data from 32 healthy males (< 40 years old), were used for the analysis (consent obtained, ethics committee approved). A population PK model was fitted to the data, using nonlinear mixed-effects modelling. The potential influence of covariates, such as age, body weight, and renal function, was evaluated using a stepwise covariate model-building procedure. The final population PK model was used for evaluating the performance of the original dabigatran pediatric clinical study dosing algorithms, as well as the final updated dosing algorithms, by comparing the simulated pediatric trough exposure with adult reference exposure.

Results:

The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and first-order absorption. All the disposition parameters increased with increasing body weight in accordance with allometric scaling. The apparent clearance increased with increasing age and decreased with decreasing renal function. The lowest observed baseline value of the estimated glomerular filtration rate in children was 48.3 mL/min/1.73m². The original pediatric dosing algorithms for DE, as well as the final updated dosing algorithms, both based upon age and body weight, were confirmed by simulations. The impact of dose titration was minimal regardless of dosing formulations.

Conclusions:

A population PK model of dabigatran for pediatric patients with VTE was developed. Simulation demonstrated that the final dosing algorithms for DE were appropriate for all formulations. No dose titration is needed when DE is administered to pediatric patients as oral solution, coated granules, or capsules (Figure).