Is continuous infusion of beta-lactam antibiotics worthwhile?--efficacy and pharmacokinetic considerations

The most important pharmacodynamic parameter for beta-lactam antibiotics has been shown to be the time above the MIC, which is used as an argument to administer beta-lactam antibiotics by continuous infusion. Studies in vitro and in laboratory animals comparing efficacy of continuous an

Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

We developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of ceftazidime in Pseudomonas aeruginosa killing experiments with an in vitro pharmacokinetic model were used. The basic PK-PD model was a maximum-effect model which described the number of viable bacteria (N) as a function of the growth rate (lambda) and killing rate (epsilon) according to the equation dN/dt = [lambda - epsilon x [Cgamma(EC50gamma + Cgamma)]] N, where gamma is the Hill factor, C is the concentration of antibiotic, and EC50 is the concentration of antibiotic at which 50% of the maximum effect is obtained. Next, four different models with increasing complexity were analyzed by using the EDSIM program (MediWare, Groningen, The Netherlands). These models incorporated either an adaptation rate factor and a maximum number of bacteria (Nmax) factor or combinations of the two parameters. In addition, a two-population model was evaluated. Model discrimination was by Akaike's information criterion. The experimental data were best described by the model which included an Nmax term and a rate term for adaptation for a period up to 36 h. The absolute values for maximal growth rate and killing rate in this model were different from those in the original experiment, but net growth rates were comparable. It is concluded that the derived models can describe bacterial growth and killing in the presence of antibiotic concentrations mimicking human pharmacokinetics. Application of these models will eventually provide us with parameters which can be used for further dosage optimization

Deprescribing interventions and their impact on medication adherence in community-dwelling older adults with polypharmacy: a systematic review

Background: Polypharmacy, and the associated adverse drug events such as non-adherence to prescriptions, is a common problem for elderly people living with multiple comorbidities. Deprescribing, i.e. the gradual withdrawal from medications with supervision by a healthcare professional, is regarded as a means of reducing adverse effects of multiple medications including non-adherence. This systematic review examines the evidence of deprescribing as an effective strategy for improving medication adherence amongst older, community dwelling adults. Methods: A mixed methods review was undertaken. Eight bibliographic database and two clinical trials registers were searched between May and December 2017. Results were double screened in accordance with pre-defined inclusion/exclusion criteria related to polypharmacy, deprescribing and adherence in older, community dwelling populations. The Mixed Methods Appraisal Tool (MMAT) was used for quality appraisal and an a priori data collection instrument was used. For the quantitative studies, a narrative synthesis approach was taken. The qualitative data was analysed using framework analysis. Findings were integrated using a mixed methods technique. The review was performed in accordance with the PRISMA reporting statement. Results: A total of 22 original studies were included, of which 12 were RCTs. Deprescribing with adherence as an outcome measure was identified in randomised controlled trials (RCTs), observational and cohort studies from 13 countries between 1996 and 2017. There were 17 pharmacy-led interventions; others were led by General Practitioners (GP) and nurses. Four studies demonstrated an overall reduction in medications of which all studies corresponded with improved adherence. A total of thirteen studies reported improved adherence of which 5 were RCTs. Adherence was reported as a secondary outcome in all but one study. Conclusions: There is insufficient evidence to show that deprescribing improves medication adherence. Only 13 studies (of 22) reported adherence of which only 5 were randomised controlled trials. Older people are particularly susceptible to non-adherence due to multi-morbidity associated with polypharmacy. Bio-psycho-social factors including health literacy and multi-disciplinary team interventions influence adherence. The authors recommend further study into the efficacy and outcomes of medicines management interventions. A consensus on priority outcome measurements for prescribed medications is indicated

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Novel therapeutic modalities: the future is now

Pharmacolog

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps.

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.Pediatric Research advance online publication, 11 April 2018; doi:10.1038/pr.2018.38

Tutorial on model selection and validation of model input into precision dosing software for model-informed precision dosing

There has been rising interest in using model-informed precision dosing to provide personalized medicine to patients at the bedside. This methodology utilizes population pharmacokinetic models, measured drug concentrations from individual patients, pharmacodynamic biomarkers, and Bayesian estimation to estimate pharmacokinetic parameters and predict concentration-time profiles in individual patients. Using these individualized parameter estimates and simulated drug exposure, dosing recommendations can be generated to maximize target attainment to improve beneficial effect and minimize toxicity. However, the accuracy of the output from this evaluation is highly dependent on the population pharmacokinetic model selected. This tutorial provides a comprehensive approach to evaluating, selecting, and validating a model for input and implementation into a model-informed precision dosing program. A step-by-step outline to validate successful implementation into a precision dosing tool is described using the clinical software platforms Edsim++ and MwPharm++ as examples.</p

Leopard Panthera pardus density and survival in an ecosystem with depressed abundance of prey and dominant competitors

The leopard Panthera pardus is in range-wide decline, and many populations are highly threatened. Prey depletion is a major cause of global carnivore declines, but the response of leopard survival and density to this threat is unclear: by reducing the density of a dominant competitor (the lion Panthera leo) prey depletion could create both costs and benefits for subordinate competitors. We used capture-recapture models fitted to data from a 7-year camera-trap study in Kafue National Park, Zambia, to obtain baseline estimates of leopard population density and sex-specific apparent survival rates. Kafue is affected by prey depletion, and densities of large herbivores preferred by lions have declined more than the densities of smaller herbivores preferred by leopards. Lion density is consequently low. Estimates of leopard density were comparable to ecosystems with more intensive protection and favourable prey densities. However, our study site is located in an area with good ecological conditions and high levels of protection relative to other portions of the ecosystem, so extrapolating our estimates across the Park or into adjacent Game Management Areas would not be valid. Our results show that leopard density and survival within north-central Kafue remain good despite prey depletion, perhaps because (1) prey depletion has had weaker effects on preferred leopard prey compared to larger prey preferred by lions, and (2) the density of dominant competitors is consequently low. Our results show that the effects of prey depletion can be more complex than uniform decline of all large carnivore species, and warrant further investigation

Manuscript for Drug Metabolism and Disposition Title Developmental changes in hepatic OCT1 protein expression from neonates to children

Abstract Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinicallyimportant drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Presently, knowledge of OCT1 protein expression in children is very limited, especially among neonates and small infants. Here, we report on the characterization of OCT1 protein expression in neonatal, infant and pediatric liver samples performed by Immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal day 1 -2. This youngest group showed significantly lower OCT1 expression normalized by GAPDH (0.03 ±0.02 arbitrary unit (AU), mean ± SD, N=7) compared to samples aged 3 -4 weeks (0.08 ±0.03 AU, N=5, **P&lt; 0.01), 3 -6 months (0.23 ± 0.15 AU, N=7, **P&lt; 0.01), 11 months -1 year (0.42 ± 0.32 AU, N=6, **P&lt; 0.01), and 8 -12 years (1.00 ± 0.44 AU, N=7, **P&lt; 0.01). These data demonstrate an age-dependent increase in OCT1 expression from birth up to 8-12 years of age, and the findings of this study contribute to the understanding of OCT1 functional capacity and their effect of the disposition of OCT1 substrates in neonates and small infants