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      Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition

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          Abstract

          Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad‐spectrum antimicrobials. Parenteral ceftriaxone is currently a second‐line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty‐one patients with SAM (aged 2–45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three‐compartment model adequately described free ceftriaxone, with a Michaelis–Menten model for concentration and albumin‐dependent protein binding. A one‐compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first‐pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.

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          Most cited references 37

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          Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions.

           R Savic,  O. Karlsson (2009)
          Empirical Bayes ("post hoc") estimates (EBEs) of etas provide modelers with diagnostics: the EBEs themselves, individual prediction (IPRED), and residual errors (individual weighted residual (IWRES)). When data are uninformative at the individual level, the EBE distribution will shrink towards zero (eta-shrinkage, quantified as 1-SD(eta (EBE))/omega), IPREDs towards the corresponding observations, and IWRES towards zero (epsilon-shrinkage, quantified as 1-SD(IWRES)). These diagnostics are widely used in pharmacokinetic (PK) pharmacodynamic (PD) modeling; we investigate here their usefulness in the presence of shrinkage. Datasets were simulated from a range of PK PD models, EBEs estimated in non-linear mixed effects modeling based on the true or a misspecified model, and desired diagnostics evaluated both qualitatively and quantitatively. Identified consequences of eta-shrinkage on EBE-based model diagnostics include non-normal and/or asymmetric distribution of EBEs with their mean values ("ETABAR") significantly different from zero, even for a correctly specified model; EBE-EBE correlations and covariate relationships may be masked, falsely induced, or the shape of the true relationship distorted. Consequences of epsilon-shrinkage included low power of IPRED and IWRES to diagnose structural and residual error model misspecification, respectively. EBE-based diagnostics should be interpreted with caution whenever substantial eta- or epsilon-shrinkage exists (usually greater than 20% to 30%). Reporting the magnitude of eta- and epsilon-shrinkage will facilitate the informed use and interpretation of EBE-based diagnostics.
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            Reference intervals for serum creatinine concentrations: assessment of available data for global application.

            Reference intervals for serum creatinine remain relevant despite the current emphasis on the use of the estimated glomerular filtration rate for assessing renal function. Many studies on creatinine reference values have been published in the last 20 years. Using criteria derived from published IFCC documents, we sought to identify universally applicable reference intervals for creatinine via a systematic review of the literature. Studies were selected for inclusion in the systematic review only if the following criteria were met: (a) reference individuals were selected using an "a priori" selection scheme, (b) preanalytical conditions were adequately described; (c) traceability of the produced results to the isotope dilution-mass spectrometry (IDMS) reference method was demonstrated experimentally, and (d) the collected data received adequate statistical treatment. Of 37 reports dealing specifically with serum creatinine reference values, only 1 report with pediatric data and 5 reports with adult data met these criteria. The primary reason for exclusion of most papers was an inadequate demonstration of measurement traceability. Based on the data of the selected studies, we have collated recommended reference intervals for white adults and children. Laboratories using methods producing traceable results to IDMS can apply the selected reference intervals for serum creatinine in evaluating white individuals.
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              Modeling interindividual variation in physiological factors used in PBPK models of humans.

              Modeling interindividual variation in internal doses in humans using PBPK models requires data on the variation in physiological parameters across the population of interest. These data should also reflect the correlations between the values of the various parameters in a person. In this project, we develop a source of data for human physiological parameters where (1) the parameter values for an individual are correlated with one another, and (2) values of parameters capture interindividual variation in populations of a specific gender, race, and age range. The parameters investigated in this project include: (1) volumes of selected organs and tissues; (2) blood flows for the organs and tissues; and (3) the total cardiac output under resting conditions and average daily inhalation rate. These parameters are expressed as records of correlated values for the approximately 30,000 individuals evaluated in the NHANES III survey. A computer program, Physiological Parameters for PBPK Modeling (P3M), is developed that allows records to be retrieved randomly from the database with specification of constraints on age, sex, and ethnicity. P3M is publicly available. The database and accompanying software provide a convenient tool for parameterizating models of interindividual variation in human pharmacokinetics.
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                Author and article information

                Contributors
                j.standing@ucl.ac.uk
                Journal
                Clin Pharmacol Ther
                Clin. Pharmacol. Ther
                10.1002/(ISSN)1532-6535
                CPT
                Clinical Pharmacology and Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                0009-9236
                1532-6535
                19 April 2018
                December 2018
                19 April 2018
                : 104
                : 6 , HIV ( doiID: 10.1002/cpt.2018.104.issue-6 )
                : 1165-1174
                Affiliations
                [ 1 ] Great Ormond Street Institute of Child Health University College London London UK
                [ 2 ] Paediatric Infectious Diseases Research Group Institute for Infection and Immunity, St. George's, University of London London UK
                [ 3 ] Center for Research in Therapeutic Sciences Strathmore University Nairobi Kenya
                [ 4 ] KEMRI‐Centre for Clinical Research Nairobi Kenya
                [ 5 ] KEMRI‐Wellcome Trust Research Programme Kilifi Kenya
                [ 6 ] Mbagathi County Hospital Nairobi Kenya
                [ 7 ] Coast General Hospital Mombasa Kenya
                [ 8 ] Analytical Services International, St George's University of London London UK
                [ 9 ] Institute of Chemistry University of Tartu Tartu Estonia
                [ 10 ] The Childhood Acute Illness & Nutrition (CHAIN) Network Nairobi Kenya
                [ 11 ] Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine University of Oxford Oxford UK
                Author notes
                [* ]Correspondence: Joseph F. Standing ( j.standing@ 123456ucl.ac.uk )
                Article
                CPT1078
                10.1002/cpt.1078
                6282491
                29574688
                © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 2, Pages: 10, Words: 6474
                Product
                Funding
                Funded by: United Kingdom Medical Research Council/Department for International Development/Wellcome Trust Joint Global Health Trials Scheme
                Award ID: MR/M007367/1
                Funded by: United Kingdom Medical Research Council Fellowship
                Award ID: MR/M008665/1
                Funded by: National Institute for Health Research Biomedical Research Centre
                Funded by: Hospital for Children NHS Foundation Trust
                Funded by: Bill & Melinda Gates Foundation
                Award ID: OPP1131320
                Categories
                Articles
                Research
                Articles
                Custom metadata
                2.0
                cpt1078
                December 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:06.12.2018

                Pharmacology & Pharmaceutical medicine

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