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

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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Influences of renal function descriptors on population pharmacokinetic modeling of vancomycin in Chinese adult patients

Acta Pharmacologica Sinica ◽

10.1038/aps.2017.57 ◽

2017 ◽

Vol 39 (2) ◽

pp. 286-293 ◽

Cited By ~ 11

Author(s):

Xi-wei Ji ◽

Shuang-min Ji ◽

Xiao-rong He ◽

Xiao Zhu ◽

Rong Chen ◽

...

Keyword(s):

Renal Function ◽

Pharmacokinetic Modeling ◽

Adult Patients ◽

Population Pharmacokinetic ◽

Population Pharmacokinetic Modeling ◽

Chinese Adult

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Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01957-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01957-18 ◽

Cited By ~ 3

Author(s):

Anne B. Leuppi-Taegtmeyer ◽

Laurent Decosterd ◽

Michael Osthoff ◽

Nicolas J. Mueller ◽

Thierry Buclin ◽

...

Keyword(s):

Renal Function ◽

Body Weight ◽

Renal Replacement Therapy ◽

Continuous Renal Replacement Therapy ◽

Normal Renal Function ◽

Maintenance Dose ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Optimal Dosing ◽

Colistimethate Sodium

ABSTRACT Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

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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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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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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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