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

Dose rationale for amoxicillin in neonatal sepsis when referral is not possible

Background: Despite the widespread use of amoxicillin in young children, efforts to establish the feasibility of simplified dosing regimens in resource-limited settings have relied upon empirical evidence of efficacy. Given the antibacterial profile of beta-lactams, understanding of the determinants of pharmacokinetic variability may provide a more robust guidance for the selection of a suitable regimen. Here we propose a simplified dosing regimen based on pharmacokinetic-pharmacodynamic principles, taking into account the impact of growth, renal maturation and disease processes on the systemic exposure to amoxicillin. Materials and Methods: A meta-analytical modeling approach was applied to allow the adaptation of an existing pharmacokinetic model for amoxicillin in critically ill adults. Model parameterization was based on allometric concepts, including a maturation function. Clinical trial simulations were then performed to characterize exposure, as defined by secondary pharmacokinetic parameters (AUC, Cmax, Cmin) and T>MIC. The maximization of the T>MIC was used as criterion for the purpose of this analysis and results compared to current WHO guidelines. Results: A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of amoxicillin in the target population. In addition to the changes in clearance and volume distribution associated with demographic covariates, our results show that sepsis alters drug distribution, leading to lower amoxicillin levels and longer half-life as compared to non-systemic disease conditions. In contrast to the current WHO guidelines, our analysis reveals that amoxicillin can be used as a fixed dose regimen including two weight bands: 125 mg b.i.d. for patients with body weight < 4.0 kg and 250 mg b.i.d. for patients with body weight ≥ 4.0 kg. Conclusions: In addition to the effect of developmental growth and renal maturation, sepsis also alters drug disposition. The use of a model-based approach enabled the integration of these factors when defining the dose rationale for amoxicillin. A simplified weight-banded dosing regimen should be considered for neonates and young infants with sepsis when referral is not possible

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

Cost-Effectiveness of Adding Bed Net Distribution for Malaria Prevention to Antenatal Services in Kinshasa, Democratic Republic of the Congo

We evaluated the cost-effectiveness of distributing insecticide-treated bed nets (ITNs) for malaria prevention at antenatal clinics in Kinshasa, Democratic Republic of the Congo. A decision tree model was used to estimate costs, outcomes, and incremental cost-effectiveness for 17,893 pregnant women attending 28 antenatal clinics who received long-lasting ITNs free of charge. Costs including purchase, transportation, storage, and distribution of ITNs were derived from program records. The ITN efficacy and other parameters were derived from peer-reviewed literature. Outcomes modeled included low birth weight (LBW) deliveries, infant deaths averted, life-years saved (LYs), and disability-adjusted life-years (DALYs) averted. Deterministic and probabilistic sensitivity analyses were conducted. For the 17,893 women in our program, ITN distribution would be expected to avert 587 LBW deliveries and 414 infant deaths. The incremental cost-effectiveness was US $17.22 per DALY averted (95$8.54-$30.90), US$15.70 per LY saved (95% CI = US $7.65-$27.68), and US $411.13 per infant death averted (95$353.95-$1,085.89). If resources were constrained, the greatest benefit would be among women in their first through fourth pregnancies. Thus, ITN distribution is a cost-effective addition to antenatal services

Model-Informed Drug Development:Steps Toward Harmonized Guidance

Global alignment of expectations is required to achieve consistency in the planning, conduct, reporting, and regulatory review of modelinformed drug development (MIDD) applications. An International Council for Harmonization (ICH) MIDD general principles guideline has been positioned to provide a common standard of practice including a framework for risk-based assessment of MIDD-derived evidence within the context of global regulatory decision-making. This perspective provides the background, our viewpoints, and the next steps in the development of this guideline

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

Bed net ownership, use and perceptions among women seeking antenatal care in Kinshasa, Democratic Republic of the Congo (DRC): Opportunities for improved maternal and child health

Abstract: Background: To describe malaria knowledge, attitudes toward malaria and bed net use, levels of ownership and use of bed nets, and factors associated with ownership and use among pregnant women attending their first antenatal care (ANC) visit in Kinshasa, DRC. Methods: Women attending their first ANC visit at one maternity in Kinshasa were recruited to take part in a study where they were given free insecticide treated bed nets (ITNs) and then followed up at delivery and 6 months post delivery to assess ITN use. This study describes the baseline levels of bed net ownership and use, attitudes towards net use and factors associated with net use Results: Among 351 women interviewed at baseline, 115 (33%) already owned a bed net and 86 (25%) reported to have slept under the net the previous night. Cost was reported as the reason for not owning a net by 48% of the 236 women who did not own one. In multivariable analyses, women who had secondary school or higher education were 3.4 times more likely to own a net (95% CI 1.6–7.3) and 2.8 times more likely to have used a net (95% CI 1.3–6.0) compared to women with less education Conclusion: Distribution of ITNs in antenatal clinics in this setting is needed and feasible. The potential for ITN use by this target population is high

Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: building model credibility

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk-based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick-start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts