Malek Okour (1), Misba Beerahee (1), Colm Farrell (2), Mary Ann Lukas (1), Mita M Thapar (2)
(1) GlaxoSmithKline Research & Development Limited*, (2) ICON plc
Introduction: Pulmonary arterial hypertension (PAH) is a rare, progressive, highly debilitating disease, characterised by vascular obstruction and the variable presence of vasoconstriction, leading to increased pulmonary vascular resistance and right-sided heart failure and if left untreated, ultimately leading to right ventricular failure and death. Ambrisentan is an oral medication classified as an endothelin receptor antagonist (ERA) which is approved for the treatment of PAH in adults. The pharmacokinetics (PK) of ambrisentan have previously been characterised in adult healthy subjects and patients with PAH using non-linear mixed effects modelling. The PK of ambrisentan has been recently characterised in 8 to
Objectives: The primary objectives of the analyses were:
- To evaluate the predictive performance of the previously developed adult ambrisentan population pharmacokinetic (PK) model using the data from 8 to
- To develop a population PK model for ambrisentan using data from 8 to
- To explore the exposure-response relationship between
- ambrisentan PK and change from baseline in 6 minute walk distance (6MWD) at 12 and 24 weeks;
- ambrisentan exposure and incidence of adverse events (AE) related to ambrisentan.
Methods: NONMEM® program version VII level 4.1 was used for all analyses using PDx-Pop (Version 5.2) as an interface. The final Pop PK model was evaluated by performing a confidence interval prediction-corrected visual predictive check (CI pc-VPC)1.
Data: The data used for development of population PK model was from a 24-week randomised, open label study aiming to evaluate safety, tolerability, and efficacy of high and low dose ambrisentan (adjusted for body weight) treatment groups in subjects aged 8 to
Results:
- A CI pc-VPC with the parameter estimates from the previously reported final population PK model in adult population demonstrated adequacy of the adult final population PK model in predicting the observed ambrisentan data in 8 to
- Ambrisentan PK in 8 to
- For a subject of 70 kg, the estimated mean (95% CI) values were CL/F=1.17 (1.04, 1.33) L/hr, Vc/F=12.3 (8.94, 16.8) L, Vp/F=81.3 (50.2, 132) L, Q/F=0.457 (0.302, 0.691) L/hr, Ka=2.46 (1.49, 4.07) hr-1, ALAG=0.525 (0.393, 0.700) hr. The effect of weight on both CL/F and V/F were fixed to the theoretical values for allometric scaling. For the range of weights in the Study AMB112529 analysis dataset (20-77 kg), CL/F ranged from 0.457-1.26 L/hr. V/F scaled linearly with weight, ranging from 3.51-13.5 L across the weight range.
- Ambrisentan systemic exposure was neither strongly correlated to change from baseline in 6MWD at 12/24 weeks nor to the incidence of ambrisentan-related AEs.
Conclusions:
- Ambrisentan plasma concentrations in the 8 to < 18-year-old paediatric population were well interspersed with the historical adult data where ambrisentan PK were well described by a two-compartment model with first-order absorption and elimination and an absorption lag-time.
- Ambrisentan systemic exposure (AUCss and Cmax,ss) observed in the 8 to
Ambrisentan exposure-response analyses in adults and paediatric subjects were similar as neither analysis identified any strong relationships between exposure to ambrisentan and effects in 6MWD or incidence of ambrisentan-related AEs.
*this study was sponsored by GlaxoSmithKline Pharmaceuticals.
References:
[1] Bergstrand M, Hooker AC, Wallin JE, et al (2011), Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. The AAPS Journal; 13(2):143-51
Reference: PAGE () Abstr 9337 [www.page-meeting.org/?abstract=9337]
Poster: Drug/Disease Modelling - Paediatrics