Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling), first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH

Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial

Background Selective androgen receptor modulators (SARMs) increase muscle mass via the androgen receptor. This phase 2A trial investigated the effects of a SARM, GSK2881078, in conjunction with exercise, on leg strength in patients with chronic obstructive pulmonary disease (COPD) and impaired physical function. Methods 47 postmenopausal women and 50 men with COPD (forced expiratory volume in 1 s 30%–65% predicted; short physical performance battery score: 3–11) were enrolled into a randomised double-blind, placebo control trial. Patients were randomised 1:1 to once daily placebo or oral GSK2881078 (females: 1.0 mg; males: 2.0 mg) for 13 weeks with a concurrent home-exercise programme, involving strength training and physical activity. Primary endpoints were change from baseline in leg strength at 90 days (one-repetition maximum; absolute (kg) and relative (% change)) and multiple safety outcomes. Secondary endpoints included lean body mass, physical function and patient-reported outcomes. Results GSK2881078 increased leg strength in men. The difference in adjusted mean change from baseline and adjusted mean percentage change from baseline between treatment and placebo were: for women, 8.0 kg (90% CI −2.5 to 18.4) and 5.2% (90% CI −4.7 to 15.0), respectively; for men, 11.8 kg (90% CI −0.5 to 24.0) and 7.0% (90% CI 0.5 to 13.6), respectively. Lean body mass increased, but no changes in patient-reported outcomes were observed. Reversible reductions in high-density lipoprotein-cholesterol and transient elevations in hepatic transaminases were the main treatment-related safety findings. Conclusions GSK2881078 was well tolerated and short-term treatment increased leg strength, when expressed as per cent predicted, in men with COPD more than physical training alone

Population model of longitudinal FEV1 data in asthmatics: meta-analysis and predictability of placebo response

Asthma is an obstructive lung disease where the mechanism of disease progression is not fully understood hence motivating the use of empirical models to describe the evolution of the patient’s health state. With reference to placebo response, measured in terms of FEV1 (Forced Expiratory Volume in 1 s), a range of empirical models taken from the literature were compared at a single trial level. In particular, eleven GSK trials lasting 12 weeks in mild-to-moderate asthma were used for the modelling of longitudinal placebo responses. Then, the chosen exponential model was used to carry out an individual participant data meta-analysis on eleven trials. A covariate analysis was also performed to find relevant covariates in asthma to be accounted for in the meta-analysis model. Age, gender, and height were found statistically significant (e.g. the taller the patients the higher the FEV1, the older the patients the lower the FEV1, and females have lower FEV1). By truncating each trial at week 4, the predictive properties of the meta-analysis model were also investigated, showing its ability to predict long-term FEV1 response from truncated trials. Summarizing, the study suggests that: (i) the exponential model effectively describes the placebo response; (ii) the meta-analysis approach may prove helpful to simulate new trials as well as to reduce trial duration in view of its predictive properties; (iii) the inclusion of available covariates within the meta-analysis model provides a reduction of the inter-individual variability

First-order longitudinal population model of FEV1 data: single-trial modeling and meta-analysis

Objectives: Asthma is a complex and multi-factorial disease and the underlying physiopathological mechanism is not completely known. Therefore, empirical models are usually adopted to describe the evolution of the patient's health state. The first objective of this work is to develop a parsimonious population model to describe the time course of placebo response. The clinical response is measured by the Forced Expiratory Volume in the first second (FEV1). The second objective is to perform a model-based meta-analysis, in order to assess differences among studies and to estimate the inter-trial variability. Methods: Placebo FEV1 longitudinal data from 11 clinical trials in subjects with mild-to-moderate asthma were available. All studies lasted 12 weeks. A parametric first-order response model was developed and identified on each dataset. Based on a single-trial analysis, the proposed model was compared to the linear, polynomial, Inverse Bateman and Weibull-and-Linear models. All the models were implemented in WinBUGS 1.4.3 [1] and compared through the Deviance Information Criterion (DIC). The best model was then adopted to perform a meta-analysis on the 11 datasets together. In the meta-analysis model, each individual parameter was defined as the sum of a term relative to the subject and one relative to the study. For both the single-trial analysis and the meta-analysis, log-normal distribution was assumed for all the parameters. Graphical outputs were obtained through R 2.13.1 [2]. Results: In the single-trial analysis, the first-order parametric model here proposed yielded the best performance in terms of DIC in most cases. Good individual fittings and Visual Predictive Checks were obtained for all the 11 trials. Hence, meta-analysis was performed. The proposed model yielded good performances also when applied in a meta-analysis context. Moreover, it was found that the inter-individual variability in each study is higher than the inter-trial one (baseline: 24% vs 6%; maximal response: 148% vs 28%; time constant: 906% vs 71%). Conclusion: A parsimonious parametric model able to describe FEV1 data from different studies in mild-to-moderate asthma was developed. The proposed model performs well both in the single-trial analysis and meta-analysis context. Moreover, the model can be extended by including clinically relevant covariates which may affect the patient's health state. A further work is to assess the model capabilities in predicting long-term outcomes from short-term trials in placebo group. References: [1] D.J. Lunn, A. Thomas, N. Best and D. Spiegelhalter, WinBUGS A Bayesian modelling framework: concepts, structure and extensibility, Statistics and Computing 10, 325-337, 2000 [2] R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria (2011). http://www.R-project.org

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

Objective Airway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells, and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough. Methods A two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a washout between treatments. Pharmacokinetic samples were collected for analysis of GSK2798745 at end of study. The primary end-point was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing. Results Interim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (mean 61 years; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% credible interval: −3%, +85%) numerical increase for GSK2798745 compared to placebo. Conclusion There was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug