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Abatacept is a recombinant soluble fusion protein that inhibits the CD80/CD86:CD28 costimulatory signal required for T cell activation and has demonstrated efficacy in the treatment of rheumatoid arthritis. The objectives of this analysis were to provide support for a body weight-tiered dosing regimen approximating 10 mg/kg by (1) quantifying the effect of body weight on exposure and (2) characterizing the relationship between exposure and serum interleukin (IL)-6 concentration. The abatacept exposure and exposure-response models were developed with 2148 abatacept serum concentrations (from 388 subjects) and 1894 IL-6 serum concentrations (from 799 subjects), respectively, followed by simulation with these models to address the above objectives. Abatacept exposure was characterized by a linear 2-compartmental model, in which clearance was linearly related to body weight. The IL-6 response was characterized by an indirect-response model, in which the IL-6 production rate increased with baseline C-reactive protein levels. Model-based simulations demonstrated that body weight-tiered dosing was desirable to ensure consistent steady-state abatacept trough concentrations across a range of body weights; doses approximating 10 mg/kg (500, 750, 1000 mg for subjects weighing < 60, 60-100, and > 100 kg, respectively) provided consistent exposure across the body weight groups. In addition, doses > 10 mg/kg did not result in further increases in IL-6 suppression. These modeling and simulation results indicate that the body weight-tiered abatacept therapeutic doses approximating 10 mg/kg will ensure consistent abatacept exposure and optimal IL-6 suppression. Keywords: Population pharmacokinetics; exposure response; abatacept; rheumatoid arthritis; IL-6, The concept of model-based drug development, first proposed by Sheiner,(1)has been identified by the US Food and Drug Administration and the European Medicines Agency as a key opportunity for improving [...]

Moxidectin is a frontrunner drug candidate in the treatment of strongyloidiasis. A dose of 8 mg is recommended to treat this indication, which shows a reasonably good efficacy and tolerability profile. Yet, owing to the unique life cycle of Strongyloides stercoralis (S. stercoralis) that entails internal autoinfection, a curative treatment would be desirable. Population‐based pharmacometric modeling that would help to identify an ideal dosing strategy are yet lacking. The aims of this study were to (i) explore the exposure‐efficacy response relationship of moxidectin in treating S. stercoralis and (ii) evaluate whether moxidectin treatment outcomes in terms of cure rates at baseline as compared to post‐treatment could be optimized. Our pharmacodynamic model suggests high predictive power (area under the concentration time curve‐receiver operating characteristic [AUC‐ROC] 0.817) in the probability of being cured by linking an exposure metric (i.e., AUC0‐24 or maximum concentration [Cmax]) to baseline infection intensity. Pharmacometric simulations indicate that with a minimum dose of 4 mg a maximum cure rate of ~ 95% is established in the low infection intensity group (larvae per gram [LPG] ≥0.4–1), whereas in the moderate‐to‐high intensity group (LPG >1) the cure rate plateaus at ~ 87%, following an 8 mg dose. To enhance efficacy further, studies using repeated dosing based on the duration of the autoinfection cycle, for example a two‐dose regimen 3 weeks apart should be considered. Simulations revealed similar Cmax in both treatment courses of a two‐dose regimen; hence safety should not be a concern. Collectively, our results provide evidence‐based guidance for enhanced dosing strategies and should be considered when designing future treatment strategies. [ABSTRACT FROM AUTHOR]

Objectives: Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment.Methods: A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24-41), a postnatal age (PNA) of 21 days (2-153) and a body weight (BW) of 1.16 kg (0.5-4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM).Results: A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 μmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively.Simulated regimens using a dose of 20-25 mg/kg every 6-12 h according to postnatal age led to the highest PTA (T>MIC over 100% of time).Conclusions: Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates. [ABSTRACT FROM AUTHOR]

Objective Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. Design Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates. Setting Neonatal intensive care unit at McMaster Children's Hospital. Patients Neonates with a gestational age =28+6 weeks treated with oral ibuprofen for closure of a PDA. Methods Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation. Main outcome measure Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0-72h >900 mg·hour/L). Results Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours' postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0-72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. Conclusion We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0-72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA. [ABSTRACT FROM AUTHOR]

The experience of Switzerland's Jura Arc region demonstrates how industrial districts can become technology districts through innovation and the organization of a region into a dynamic. A territory's construction can significantly affect its people's ability to make innovative decisions and create technologies which helps destroy the old industrial productive capacity and creates a new technology-oriented productive capacity., INTRODUCTION The purpose of this paper is to contribute to the economic analysis of local processes of structural change as can be observed within certain local systems of production and [...]