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

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.

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.

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

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.

Effects of Cardiopulmonary Bypass on Sufentanil Pharmacokinetics in Patients Undergoing Coronary Artery Bypass Surgery

2004 ◽  
Vol 101 (4) ◽  
pp. 862-871 ◽  
Author(s):  
Robert J. Hudson ◽  
Ian R. Thomson ◽  
Rajive Jassal
Keyword(s):  
Cardiopulmonary Bypass ◽  
Coronary Artery ◽  
Coronary Artery Bypass ◽  
Artery Bypass ◽  
Compartment Model ◽  
Pharmacokinetic Modeling ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Log Likelihood ◽  
Three Compartment Model

Background Complete pharmacokinetic modeling, including assessment of the effect of cardiopulmonary bypass (CPB) on sufentanil disposition, has not been reported. The aims of this investigation were to define a model that accurately predicted sufentanil concentrations during and after cardiac surgery and to determine if CPB had a clinically significant impact on sufentanil pharmacokinetics. Methods Population pharmacokinetic modeling was applied to data from 21 patients undergoing coronary artery bypass grafting. The predictive ability of models was assessed by calculating bias, accuracy, and measured:predicted concentration ratios versus time. A simple three-compartment model, without covariates, was initially compared with models having weight or gender as covariates and was subsequently used as the foundation for multiple CPB-adjusted models (allowing step-changes of parameters at the start or end of CPB). The primary criterion for choosing more complex models was a significant improvement in log-likelihood; secondary criteria were significant improvement in bias or accuracy. Results Neither covariate (weight or gender) models improved bias or accuracy compared with the simple three-compartment model. A final CPB-adjusted model with V2 and Cl3 changing at the start of CPB and V1, Cl2, and Cl3 changing at the end of CPB had significantly greater log-likelihood values when compared with the simple three-compartment model and with less elaborate CPB-adjusted models. However, bias and accuracy for this final model were not significantly different from the simple three-compartment model. Conclusions When sufentanil is infused at a constant rate, with initiation of CPB, a pharmacokinetic model adjusted for CPB predicts that the sufentanil concentration will decrease approximately 17% and that it will begin to return to the prebypass concentration 12 min after initiation of CPB. At the end of CPB, this model also predicts a brief spike of the sufentanil concentration. These predictions reflect changes in the measured sufentanil concentrations. However, compared with a simple, three-compartment model, incorporating step-changes of pharmacokinetic parameters at the start or end of cardiopulmonary bypass (or both) did not significantly improve overall perioperative prediction of measured sufentanil concentrations. This suggests that CPB has clinically insignificant effects on sufentanil kinetics in adults.

scholarly journals Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1244
Author(s):  
Silvia Marquez-Megias ◽  
Amelia Ramon-Lopez ◽  
Patricio Más-Serrano ◽  
Marcos Diaz-Gonzalez ◽  
Maria Remedios Candela-Boix ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Predictive Performance ◽  
Stochastic Simulations ◽  
University Hospital ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Inflammatory Bowel ◽  
The Individual

Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.

scholarly journals PK-DB: PharmacoKinetics DataBase for Individualized and Stratified Computational Modeling

2019 ◽  
Author(s):  
Jan Grzegorzewski ◽  
Janosch Brandhorst ◽  
Dimitra Eleftheriadou ◽  
Kathleen Green ◽  
Matthias König
Keyword(s):  
Computational Modeling ◽  
Computational Models ◽  
Smoking Status ◽  
Meta Analysis ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Special Focus ◽  
Biological Ontologies ◽  
Time Courses

ABSTRACTA multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials including pre-clinical research. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) measured pharmacokinetic time-courses; (iv) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve). Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/DB), or population pharmacokinetic (pop PK) modeling.

Multiple Dose Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers

2000 ◽  
Vol 92 (3) ◽  
pp. 665-673 ◽  
Author(s):  
Talmage D. Egan ◽  
Amarnath Sharma ◽  
Michael A. Ashburn ◽  
Jur Kievit ◽  
Nathan L. Pace ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Maximum Concentration ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Multiple Dosing ◽  
Fentanyl Citrate ◽  
Minimum Concentration ◽  
Intravenous Fentanyl ◽  
Oral Transmucosal Fentanyl Citrate

Background Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. Methods Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. Results The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. Conclusions The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.

scholarly journals Population Pharmacokinetic Modeling of Acetaminophen Protein Adducts in Adults and Children

2019 ◽  
Author(s):  
Sibo Jiang ◽  
Kumpal Madrasi ◽  
Tanay Samant ◽  
Chakradhar Lagishetty ◽  
Valvanera Vozmediano ◽  
...  
Keyword(s):  
Pharmacokinetic Modeling ◽  
Protein Adducts ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling ◽  
Adults And Children

Suramin: development of a population pharmacokinetic model and its use with intermittent short infusions to control plasma drug concentration in patients with prostate cancer.

1994 ◽  
Vol 12 (1) ◽  
pp. 166-175 ◽  
Author(s):  
D I Jodrell ◽  
L M Reyno ◽  
R Sridhara ◽  
M A Eisenberger ◽  
K H Tkaczuk ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Linear Model ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Hormone Refractory Prostate Cancer ◽  
Pharmacokinetic Models ◽  
Hormone Refractory

PURPOSE This study aimed to (1) develop a population pharmacokinetic model for suramin; (2) use Bayesian methods to assess suramin pharmacokinetics in individual patients; (3) use individual patients' pharmacokinetic parameter estimates to individualize suramin dose and schedule and maintain plasma suramin concentrations within predetermined target ranges; and (4) assess the feasibility of outpatient administration of suramin by intermittent, short infusions. METHODS Plasma suramin concentrations were measured by high-performance liquid chromatography (HPLC), and compartmental pharmacokinetic models were fit using a Bayesian algorithm. Population pharmacokinetic models were developed using an iterative two-stage approach. Estimates of each patient's central-compartment volume were used to calculate suramin dosage. Simulation of that patient's suramin clearance was used to predict the time of his next dose. Using this approach, plasma suramin concentration was maintained at between 200 and 300, 175 and 275, 150 and 250, or 100 and 200 microgram/mL in four sequential patient cohorts. The ability of two- and three-compartment, open, linear models to fit the pharmacokinetic data was compared. Population pharmacokinetic parameters were estimated, using both two- and three-compartment structural models in 69 hormone-refractory prostate cancer patients. RESULTS Target plasma suramin concentrations in individual patients were rapidly achieved. Concentrations were maintained within desired ranges for > or = 85% of treatment duration in all cohorts. A three-compartment, open, linear model described suramin pharmacokinetics better than did a two-compartment, open, linear model. Population pharmacokinetic estimates generated for two- and three-compartment pharmacokinetic models demonstrated modest interpatient pharmacokinetic variability and the long terminal half-life of suramin. CONCLUSION Suramin can be administered by intermittent short infusion. Adaptive-control-with-feedback dosing facilitated precise control of plasma suramin concentrations and allowed a number of different concentration ranges to be studied. This approach is expensive and labor-intensive. Although we have demonstrated the ability to control drug exposure, simpler dosing schedules require critical evaluation. Population pharmacokinetic parameters generated in men with hormone-refractory prostate cancer will facilitate rational design of such schedules.

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