PKgraph: An R package for graphically diagnosing population pharmacokinetic models

2011 ◽  
Vol 104 (3) ◽  
pp. 461-471 ◽  
Author(s):  
Xiaoyong Sun ◽  
Kai Wu ◽  
Dianne Cook
Keyword(s):  
R Package ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models

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

Pharmaceutics ◽  
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.

External evaluation of published population pharmacokinetic models of polymyxin B

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

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

2017 ◽  
Vol 84 (1) ◽  
pp. 153-171 ◽  
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

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

2007 ◽  
Vol 51 (12) ◽  
pp. 4351-4355 ◽  
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.

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

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.

Tacrolimus population pharmacokinetic models according to CYP3A5/CYP3A4/POR genotypes in Chinese Han renal transplant patients

2018 ◽  
Vol 19 (13) ◽  
pp. 1013-1025 ◽  
Author(s):  
Wan Zhu ◽  
Ling Xue ◽  
Hongwei Peng ◽  
Zhouping Duan ◽  
Xuelian Zheng ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Chinese Han ◽  
Transplant Patients ◽  
Renal Transplant Patients

Development and comparison of population pharmacokinetic models of vancomycin in neurosurgical patients based on two different renal function markers

2019 ◽  
Vol 45 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Li Jing ◽  
Tao‐tao Liu ◽  
Qing Guo ◽  
Ming Chen ◽  
Jie‐jiu Lu ◽  
...  
Keyword(s):  
Renal Function ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Neurosurgical Patients

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

2015 ◽  
Vol 45 (5) ◽  
pp. 504-511 ◽  
Author(s):  
Eduardo Asín-Prieto ◽  
Amaia Soraluce ◽  
Iñaki F. Trocóniz ◽  
Eugenia Campo Cimarras ◽  
Jaione Sáenz de Ugarte Sobrón ◽  
...  
Keyword(s):  
Colorectal Surgery ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Model Based ◽  
Dosing Regimens

Modeling Population Pharmacokinetics of Lidocaine

2001 ◽  
Vol 94 (4) ◽  
pp. 566-573 ◽  
Author(s):  
Jette A. Kuipers ◽  
Fred Boer ◽  
Annemiek de Roode ◽  
Erik Olofsen ◽  
James G. Bovill ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Pharmacokinetic Models ◽  
Population Pharmacokinetic Modeling ◽  
Population Pharmacokinetic Study ◽  
Electrical Bioimpedance ◽  
Demographic Covariates ◽  
The Individual

Background Inclusion of cardiac output and other physiologic parameters, in addition to or instead of, demographic variables might improve the population pharmacokinetic modeling of lidocaine. Methods Thirty-one patients were included in a population pharmacokinetic study of lidocaine. After bolus injection of lidocaine (1 mg/kg), 22 or 10 blood samples per patient were taken from a radial artery. During the experiment, cardiac output was measured using a thoracic electrical bioimpedance method. The following four population pharmacokinetic models were constructed and their performances investigated: a model with no covariates, a model with cardiac output as covariate, a model with demographic covariates, and a model with both cardiac output and demographic characteristics as covariates. Model discrimination was performed with the likelihood ratio test. Results Inclusion of cardiac output resulted in a significant improvement of the pharmacokinetic model, but inclusion of demographic covariates was even better. However, the best model was obtained by inclusion of both demographic covariates and cardiac output in the pharmacokinetic model. Conclusions When population pharmacokinetic models are used for individualization of dosing schedules, physiologic covariates, e.g., cardiac output, can improve their ability to predict the individual kinetics.

scholarly journals Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

2015 ◽  
Vol 60 (2) ◽  
pp. 1013-1021 ◽  
Author(s):  
Esther J. H. Janssen ◽  
Pyry A. J. Välitalo ◽  
Karel Allegaert ◽  
Roosmarijn F. W. de Cock ◽  
Sinno H. P. Simons ◽  
...  
Keyword(s):  
Pediatric Population ◽  
External Validation ◽  
Population Pharmacokinetic ◽  
Target Area ◽  
Pharmacokinetic Models ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Model Based ◽  
Dosing Algorithm ◽  
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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