Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients

Simplified Dosing Regimens for Gentamicin in Neonatal Sepsis

Background: The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods: A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results: In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands: 10 mg for patients with body weight <2.5 kg, 16 mg for patients with body weight between 2.5 and 4 kg, and 30 mg for those with body weight >4 kg. Conclusion: The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0–59 days

Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014)

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale

In silico tools predict effects of drugs on bone remodelling.

status: publishe