Evaluation of Predictability for Vancomycin Dosage Regimens by the Bayesian Method with Japanese Population Pharmacokinetic Parameters

Background In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk–Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk–Zaske and Bayesian methods in Japanese cancer patients is not completely understood. Objective To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk–Zaske method and the Bayesian method in Japanese cancer patients. Methods Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. Results Prediction of the trough and peak vancomycin concentrations by the Sawchuk–Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. Conclusion The Sawchuk–Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.

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Application of a Bayesian method to monitor and adjust vancomycin dosage regimens.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.34.6.1165 ◽

1990 ◽

Vol 34 (6) ◽

pp. 1165-1171 ◽

Cited By ~ 60

Author(s):

A K Hurst ◽

M A Yoshinaga ◽

G H Mitani ◽

K A Foo ◽

R W Jelliffe ◽

...

Keyword(s):

Bayesian Method ◽

Dosage Regimens ◽

Vancomycin Dosage

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Prediction of Serum Vancomycin Concentrations using One-, Two- and Three-compartment Models with Implemented Population Pharmacokinetic Parameters and with the Bayesian Method

Journal of Pharmacy and Pharmacology ◽

10.1111/j.2042-7158.1998.tb03999.x ◽

1998 ◽

Vol 50 (8) ◽

pp. 851-856 ◽

Cited By ~ 10

Author(s):

GUANG WU ◽

MARIO FURLANUT

Keyword(s):

Bayesian Method ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Compartment Models ◽

Serum Vancomycin

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Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis

Antibiotics ◽

10.3390/antibiotics10111392 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1392

Author(s):

Chuhui Wang ◽

Chao Zhang ◽

Xiaoxiao Li ◽

Sixuan Zhao ◽

Na He ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Dosage Regimen ◽

Surgical Intensive Care Unit ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Recommended Dosage ◽

Surgical Intensive Care ◽

Dosage Regimens ◽

Vancomycin Dosage

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

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EUROPEAN PAEDIATRIC ONCOLOGY OFF-PATENT MEDICINES CONSORTIUM (EPOC): A PHARMACOKINETIC STUDY OF DOXORUBICIN IN CHILDREN WITH CANCER

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.14 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.6-e1

Author(s):

Miriam Krischke ◽

Alan V Boddy ◽

Georg Hempel ◽

Swantje Völler ◽

Nicolas André ◽

...

Keyword(s):

Pharmacokinetic Study ◽

Cardiac Troponin ◽

Troponin T ◽

Paediatric Oncology ◽

Patient Acceptance ◽

Pharmacokinetic Parameters ◽

Blood Levels ◽

Population Pharmacokinetic ◽

Older Children ◽

Treatment Regimens

BackgroundDoxorubicin is a key component of a number of treatment regimens used in paediatric oncology. The pharmacology data on which current dosing regimens are based are very limited.MethodsWe conducted a multicentre, multinational pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after 2 administrations, with 5 samples collected in children 3 yrs. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. NT-proBNP and cardiac troponin T were measured to evaluate their role as early indicators of cardiotoxicity.Results101 children could be recruited including 27 patients less than 3 years and among those 5 infants younger than 1 year. Overall, the patient acceptance of the trial was very good.Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a lower clearance (21.1±5.8 l/h/m2) than older children (26.6±6.7 l/h/m2) (p=0.0004), after correcting for body weight. Pharmacogenetic variants, including those in transporters and drug metabolizing enzymes, had little influence on pharmacokinetic parameters.Natriuretic peptides plasma levels increased significantly shortly after doxorubicin administration, whereas cardiac troponin levels increased only with the administered cumulative anthracycline dose. Only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.ConclusionThe paediatric need concerning missing PK-data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were found to be justified based on our PK analyses.

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POPULATION PHARMACOKINETICS AND DOSING OPTIMIZATION OF TEICOPLANIN IN CHILDREN WITH MALIGNANT HAEMATOLOGICAL DISEASE

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.46 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.41-e1

Author(s):

Wei Zhao ◽

Daolun Zhang ◽

Thomas Storme ◽

André Baruchel ◽

Xavier Declèves ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Haematological Malignancy ◽

External Validation ◽

Predictive Performance ◽

Paediatric Population ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

High Risk Population ◽

Dosing Regimen

BackgroundChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.ResultsEighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10 mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10 mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg·h/L, 18 mg/kg was required for infants, 14 mg/kg for children and 12 mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

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1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1501 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S670-S671

Author(s):

Ronald G Hall ◽

Jotam Pasipanodya ◽

William C Putnam ◽

John Griswold ◽

Sharmila Dissanaike ◽

...

Keyword(s):

Human Plasma ◽

Kidney Injury ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Population Parameter ◽

Full Thickness ◽

Severe Burns

Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)

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Pharmacodynamics of High-Dose Methotrexate in Pediatric Patients

Annals of Pharmacotherapy ◽

10.1345/aph.1a446 ◽

2002 ◽

Vol 36 (9) ◽

pp. 1344-1350 ◽

Cited By ~ 20

Author(s):

Irene Aquerreta ◽

Azucena Aldaz ◽

Joaquín Giráldez ◽

Luis Sierrasesúmaga

Keyword(s):

High Risk ◽

Daily Practice ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

High Dose ◽

Hematologic Toxicity ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Nonhematologic Toxicity ◽

The Relationship

OBJECTIVE: To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects. METHODS: This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression. RESULTS: Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h (p < 0.001). CONCLUSIONS: The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 μmol/L was confirmed as an indicator of high risk of toxicity.

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Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00661-09 ◽

2009 ◽

Vol 54 (2) ◽

pp. 778-782 ◽

Cited By ~ 33

Author(s):

Akihiro Tanaka ◽

Tetsuya Aiba ◽

Takashi Otsuka ◽

Katsuya Suemaru ◽

Tatsuya Nishimiya ◽

...

Keyword(s):

Renal Function ◽

Cystatin C ◽

Predictive Performance ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Serum Cystatin C ◽

Serum Cystatin ◽

New Model ◽

The Mean

ABSTRACT We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoek's formula correlated linearly with VAN clearance (VAN clearance [ml/min] = 0.825 × GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (−3.45 to −1.38) of the difference in each value of the mean absolute error (−2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

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Population Pharmacokinetics of Meropenem in Preterm Infants

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1449 ◽

2021 ◽

Vol 76 (5) ◽

pp. 497-505

Author(s):

Irina B. Bondareva ◽

Sergey K. Zyryanov ◽

Aleksandra M. Kazanova

Keyword(s):

Therapeutic Drug Monitoring ◽

Pharmacokinetic Parameter ◽

Gestational Age ◽

Drug Monitoring ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Pharmacokinetic Variability ◽

Older Children ◽

Term Neonates

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

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