scholarly journals Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1238
Author(s):  
Sixuan Zhao ◽  
Na He ◽  
Yahui Zhang ◽  
Chuhui Wang ◽  
Suodi Zhai ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Renal Clearance ◽  
Pharmacokinetic Model ◽  
Area Under The Curve ◽  
Volume Of Distribution ◽  
Chinese Patients ◽  
Population Pharmacokinetic ◽  
Augmented Renal Clearance ◽  
Population Pharmacokinetic Modeling ◽  
Target Therapeutic Range

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400–650 mg·h/L, trough concentration: 10–20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.

scholarly journals Influence of Mechanical Ventilation on the Pharmacokinetics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Susanna Edith Medellín-Garibay ◽  
Silvia Romano-Moreno ◽  
Pilar Tejedor-Prado ◽  
Noelia Rubio-Álvaro ◽  
Aida Rueda-Naharro ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Creatinine Clearance ◽  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic

ABSTRACT Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation (n = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], −0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter).

The exploration of population pharmacokinetic model for meropenem in augmented renal clearance and investigation of optimum setting of dose

2018 ◽  
Vol 24 (10) ◽  
pp. 834-840 ◽  
Author(s):  
Tatsuro Tamatsukuri ◽  
Masayuki Ohbayashi ◽  
Noriko Kohyama ◽  
Yasuna Kobayashi ◽  
Toshinori Yamamoto ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Augmented Renal Clearance

scholarly journals β-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Alexandra Jacobs ◽  
Fabio Silvio Taccone ◽  
Jason A. Roberts ◽  
Frédérique Jacobs ◽  
Frederic Cotton ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Renal Clearance ◽  
Total Body Clearance ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Augmented Renal Clearance ◽  
Drug Concentrations ◽  
Trough Concentrations ◽  
Total Body ◽  
Body Clearance

ABSTRACTAugmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of ≥120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due toPseudomonas aeruginosa. There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r= −0.21,P= 0.01), trough concentrations of piperacillin (r= −0.28,P= 0.0071), concentrations at 50% of the dosage interval (r= −0.41,P< 0.0001), and total body clearance of piperacillin (r= 0.39,P= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain β-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

scholarly journals Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Du ◽  
Yue Zhou ◽  
Bo-Hao Tang ◽  
Yue-E Wu ◽  
Xin-Mei Yang ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Pharmacokinetic Study ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Augmented Renal Clearance ◽  
Population Pharmacokinetic Study ◽  
Dosing Regimens

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine.Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program.Results: The data (n = 36) from 20 infants (age range, 0.35–1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09–0.29) L/h/kg and 0.34 (0.24–0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively.Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.

scholarly journals Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052095228
Author(s):  
Jinlin Guo ◽  
Yayu Huo ◽  
Fang Li ◽  
Yuanping Li ◽  
Zhaojun Guo ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Chinese Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Mixed Effect ◽  
First Order ◽  
The Impact

Objective This prospective study aimed to establish the valproic acid (VPA) population pharmacokinetic model in Chinese patients and realise personalised medication on the basis of population pharmacokinetics. Methods The patients’ clinical information and VPA plasma concentrations were collected from The General Hospital of Taiyuan Iron & Steel (Group) Corporation (TISCO). Nonlinear mixed-effect modelling was used to build the population pharmacokinetic model. To characterise the pharmacokinetic data, a one-compartment pharmacokinetic model with first-order absorption and elimination was used. The first-order conditional estimation with η-ε interaction was applied throughout the model-developing procedure. The absorption rate constant (Ka) was fixed at 2.38 hour−1, and the impact of covariates on clearance and apparent volume of distribution were also explored. Medical records of 60 inpatients were reviewed prospectively and the objective function value (OFV) of the base model and final model were 851.813 and 817.622, respectively. Results Gender was identified as the covariate that had a significant impact on the volume of distribution, and albumin and CYP2C19 genotypes influenced clearance. Conclusion Bootstrap and VPC indicated that a reliable model had been developed that was based on the simulation results, and a simple-to-use dosage regimen table was created to guide clinicians for VPA drug dosing.

Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients

2018 ◽  
Vol 179 (5) ◽  
pp. 287-297 ◽  
Author(s):  
U Arshad ◽  
M Taubert ◽  
M Kurlbaum ◽  
S Frechen ◽  
S Herterich ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Pharmacokinetic Model ◽  
Structural Model ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Population Pharmacokinetic Modeling

ObjectiveMitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1–6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring (TDM).MethodsAppropriate dosing information, plasma concentrations (1137 data points) and covariates were available from TDM of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed-effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules.ResultsA one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. BMI was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high-dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity.ConclusionThe proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

scholarly journals Augmented renal clearance: a retrospective, cohort study of urinary creatinine clearance in critically ill patients in the United Kingdom

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110155
Author(s):  
Brian W Johnston ◽  
David Perry ◽  
Martyn Habgood ◽  
Miland Joshi ◽  
Anton Krige
Keyword(s):  
Risk Factors ◽  
United Kingdom ◽  
Creatinine Clearance ◽  
Renal Clearance ◽  
Repeated Measures ◽  
Apache Ii ◽  
Apache Ii Score ◽  
Augmented Renal Clearance ◽  
Urinary Creatinine ◽  
The United Kingdom

Objective Augmented renal clearance (ARC) is associated with sub-therapeutic antibiotic, anti-epileptic, and anticoagulant serum concentrations leading to adverse patient outcomes. We aimed to describe the prevalence and associated risk factors for ARC development in a large, single-centre cohort in the United Kingdom. Methods We conducted a retrospective observational study of critically unwell patients admitted to intensive care between 2014 and 2016. Urinary creatinine clearance was used to determine the ARC prevalence during the first 7 days of admission. Repeated measures logistic regression was used to determine risk factors for ARC development. Results The ARC prevalence was 47.0% (95% confidence interval [95%CI]: 44.3%–49.7%). Age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and sepsis diagnosis were significantly associated with ARC. ARC was more prevalent in younger vs. older (odds ratio [OR] 0.95 [95%CI: 0.94–0.96]), male vs. female (OR 0.32 [95%CI: 0.26–0.40]) patients with lower vs. higher APACHE II scores (OR 0.94 [95%CI: 0.92–0.96]). Conclusions This patient group probably remains unknown to many clinicians because measuring urinary creatinine clearance is not usually indicated in this group. Clinicians should be aware of the ARC risk in this group and consider measurement of urinary creatinine clearance.

scholarly journals Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

2001 ◽  
Vol 45 (2) ◽  
pp. 596-600 ◽  
Author(s):  
Andreas H. Groll ◽  
Bryan M. Gullick ◽  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Myrna Candelario ◽  
...  
Keyword(s):  
High Performance ◽  
Pharmacokinetic Model ◽  
Area Under The Curve ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Chromatography Method ◽  
Opportunistic Fungi ◽  
The Mean ◽  
Liquid Chromatography Method

ABSTRACT The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C max) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increasedVdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.

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