Population pharmacokinetic models for cefuroxime and metronidazole used in combination as prophylactic agents in colorectal surgery: Model-based evaluation of standard dosing regimens

ABSTRACTBecause of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.

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Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00251-07 ◽

2007 ◽

Vol 51 (12) ◽

pp. 4351-4355 ◽

Cited By ~ 9

Author(s):

Paul G. Ambrose ◽

Alan Forrest ◽

William A. Craig ◽

Chistopher M. Rubino ◽

Sujata M. Bhavnani ◽

...

Keyword(s):

Bacillus Anthracis ◽

Survival Data ◽

Sensitivity Analyses ◽

Maximum Effect ◽

Infection Model ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

Concentration Time ◽

Dosing Regimens ◽

Adults And Children

ABSTRACT We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC of the drug for the organism (AUC0-24/MIC ratio) was the PK-PD measure most predictive of survival (R 2 = 0.96). The 50% effective dose (ED50) and the ED90 and ED99 corresponded to AUC0-24/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED99). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

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DO WE HAVE A CONSENSUS TO APPLY MODEL-BASED AMINOGLYCOSIDE THERAPY: A REVIEW OF POPULATION PHARMACOKINETIC MODELS

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.55 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.51-e1

Author(s):

Guo-Xiang Hao ◽

Sophie Teng ◽

Evelyne Jacqz-Aigrain ◽

Wei Zhao

Keyword(s):

Meta Analysis ◽

Pharmacokinetic Modeling ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

Related Factors ◽

Model Based ◽

Aminoglycoside Therapy ◽

Bibliographic Search ◽

Adults And Children

Background and ObjectiveAminoglycosides remain the standard antibiotic therapy for Gram-negative infections in both adults and children. The pharmacokinetic modeling approach has been widely used to evaluate aminoglycosides therapy. The aim of the present study is to review the published population pharmacokinetic models of commonly used aminoglycosides (gentamycin, amikacin and tobramycin), in order to determine if there was a consensus to apply model-based personalized aminoglycoside therapy in routine clinical practice.MethodsThe bibliographic search was performed electronically using PubMed on 30th January 2015, following the search strategy: “((population Pharmacokinetics) OR (Pharmacokinetic modeling)) AND (gentamycin OR gentamicin OR amikacin OR tobramycin)”.ResultsA total of 49 articles were identified. Persistent variabilities exist in terms of structure model; typical pharmacokinetic parameters and identified covariates.ConclusionA pharmacokinetic meta-analysis is required to evaluate the study-related factors influencing the pharmacokinetics of aminoglycosides. A clinical evaluation of pharmacokinetic model of aminoglycosides is required to demonstrate its clinical utility.

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O13 Improved early vancomycin exposure in neonates using a population pharmacokinetic model-based vancomycin dosing regimen

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.13 ◽

2019 ◽

Vol 104 (6) ◽

pp. e6.1-e6

Author(s):

A Smits ◽

E De Saeger ◽

A Vandendriessche ◽

V Cossey ◽

K Allegaert

Keyword(s):

Clinical Characteristics ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

List Type ◽

Loading Dose ◽

Dosing Regimen ◽

Model Based ◽

Postmenstrual Age ◽

Dosing Regimens ◽

Trough Levels

BackgroundWe previously documented that 2 published vancomycin dosing regimens resulted in subtherapeutic exposure in 66.3 and 76.2% of neonates.1 A new dosing regimen derived from a population pharmacokinetic (PK) analysis and using a loading dose, was implemented in our unit.2 We aimed to investigate if the new regimen results in improved vancomycin exposure (target trough 10–15 mg/L).MethodsClinical data and early (24 h after start) vancomycin therapeutic drug monitoring (TDM) in neonates receiving vancomycin for medical reasons, were retrospectively collected and pooled with 2 historical cohorts [cohort 1 (2011, n=193 observations), dosing based on postmenstrual age (PMA) and creatininemia and cohort 2 (2012, n=101 observations), dosing based on PMA and postnatal age (PNA)]. The new regimen [cohort 3 (2018, n=71 observations)] consists of a loading dose, followed by dosing based on birthweight, PNA and ibuprofen co-treatment [2]. Clinical characteristics and early TDM were compared across the cohorts using the Kruskal-Wallis Test. Results were significant if p< 0.05.ResultsClinical characteristics (cohort 1, 2 and 3 respectively) did not differ significantly across the cohorts. Median (IQ range) GA was 32.8 (28.4–37.6), 32.1 (28.5–37.5), 28 (26–38) weeks with p=0.097; PNA 13 (6–26), 12 (7–23), 14 (10–25) days with p=0.15 and creatininemia 0.43 (0.33–0.55), 0.49 (0.33–0.65), 0.45 (0.32–0.57) mg/dL with p=0.15. Median vancomycin trough level was 7.8 (5.1–11.3), 5.8 (4.1–8.7), 13.3 (9.9–17.3) mg/L with p< 0.0001. With the new regimen, 25.4% of trough levels was < 10 mg/L, 40.8% >15 mg/L, and 33.8% was on target, versus 23.3 and 19.8% on target in cohort 1 and 2 respectively.ConclusionA population PK model-based vancomycin dosing regimen using a loading dose, resulted in improved neonatal vancomycin exposure. Although only 25% of trough levels was subtherapeutic, dosing optimalisation for cases with supratherapeutic exposure is also needed, as well as further prospective validation.ReferencesVandendriessche, et al. Curr Ther Res Clin Exp 2014.Janssen, et al. AAC 2015.Disclosure(s)Nothing to disclose

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External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab

Pharmaceutics ◽

10.3390/pharmaceutics13081191 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1191

Author(s):

Celine Konecki ◽

Catherine Feliu ◽

Yoann Cazaubon ◽

Delphine Giusti ◽

Marcelle Tonye-Libyh ◽

...

Keyword(s):

Goodness Of Fit ◽

Inflammatory Diseases ◽

Plasma Concentrations ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

External Evaluation ◽

Immunomodulatory Treatment ◽

Weighted Residuals ◽

Prediction Distribution ◽

Target Plasma

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.

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External evaluation of published population pharmacokinetic models of polymyxin B

European Journal of Clinical Pharmacology ◽

10.1007/s00228-021-03193-y ◽

2021 ◽

Author(s):

Ya-qian Li ◽

Kai-feng Chen ◽

Jun-jie Ding ◽

Hong-yi Tan ◽

Nan Yang ◽

...

Keyword(s):

Polymyxin B ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

External Evaluation

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External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients

British Journal of Clinical Pharmacology ◽

10.1111/bcp.13431 ◽

2017 ◽

Vol 84 (1) ◽

pp. 153-171 ◽

Cited By ~ 13

Author(s):

Jun-Jun Mao ◽

Zheng Jiao ◽

Hwi-Yeol Yun ◽

Chen-Yan Zhao ◽

Han-Chao Chen ◽

...

Keyword(s):

Renal Transplant ◽

Population Pharmacokinetic ◽

Renal Transplant Recipients ◽

Pharmacokinetic Models ◽

Transplant Recipients ◽

External Evaluation

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External validation of the predictive performance of population pharmacokinetic models for phenobarbital in pediatric patients

10.1101/2020.09.10.20192005 ◽

2020 ◽

Author(s):

Sunae Ryu ◽

Woo Jin Jung ◽

Zheng Jiao ◽

Jung Woo Chae ◽

Hwi-yeol Yun

Keyword(s):

External Validation ◽

Predictive Performance ◽

Validation Dataset ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

Bayesian Forecasting ◽

Predictive Capability ◽

Young Infants ◽

Simulation Based

Aim: Several studies have reported population pharmacokinetic models for phenobarbital (PB), but the predictive performance of these models has not been well documented. This study aims to do external validation of the predictive performance in published pharmacokinetic models. Methods: Therapeutic drug monitoring data collected in neonates and young infants treated with PB for seizure control, was used for external validation. A literature review was conducted through PubMed to identify population pharmacokinetic models. Prediction- and simulation-based diagnostics, and Bayesian forecasting were performed for external validation. The incorporation of size or maturity functions into the published models was also tested for prediction improvement. Results: A total of 79 serum concentrations from 28 subjects were included in the external validation dataset. Seven population pharmacokinetic studies of PB were selected for evaluation. The model by Voller et al. [27] showed the best performance concerning prediction-based evaluation. In simulation-based analyses, the normalized prediction distribution error of two models (those of Shellhaas et al. [24] and Marsot et al. [25]) obeyed a normal distribution. Bayesian forecasting with more than one observation improved predictive capability. Incorporation of both allometric size scaling and maturation function generally enhanced the predictive performance, but with marked improvement for the adult pharmacokinetic model. Conclusion: The predictive performance of published pharmacokinetic models of PB was diverse, and validation may be necessary to extrapolate to different clinical settings. Our findings suggest that Bayesian forecasting improves the predictive capability of individual concentrations for pediatrics.

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