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.

scholarly journals Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients

2019 ◽  
Vol 20 (7) ◽  
pp. 592-600 ◽  
Author(s):  
Zhiqi Wang ◽  
Nan Zhang ◽  
Chaoyang Chen ◽  
Shuqing Chen ◽  
Junyu Xu ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Genetic Factors ◽  
Plasma Concentrations ◽  
Chinese Patients ◽  
Estimation Methods ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
The Impact

Background: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. Objective: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. Method: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. Results: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h- 1)=1.69. Conclusion: : In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.

scholarly journals A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
C. C. Llanos-Paez ◽  
C. E. Staatz ◽  
R. Lawson ◽  
S. Hennig
Keyword(s):  
Pediatric Oncology ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
External Evaluation ◽  
Oncology Patients ◽  
Mixed Effect ◽  
Final Model

ABSTRACT To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, −3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.

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).

scholarly journals Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Si-Chan Li ◽  
Qi Ye ◽  
Hua Xu ◽  
Long Zhang ◽  
Yang Wang
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Nonparametric Bootstrap ◽  
Bootstrap Analysis ◽  
Final Model

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.

scholarly journals Optimization of Dosage Regimen of Meropenem in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation: A Prospective Cohort Study

2021 ◽  
Author(s):  
Soyoung Kang ◽  
Seungwon Yang ◽  
Jongsung Hahn ◽  
June Young Jang ◽  
Kyoung Lok Min ◽  
...  
Keyword(s):  
Cohort Study ◽  
Dosage Regimen ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Optimal Dosage Regimen ◽  
Venoarterial Extracorporeal Membrane Oxygenation ◽  
Va Ecmo

Abstract BackgroundPatients receiving venoarterial extracorporeal membrane oxygenation (VA ECMO) therapy often require antibiotics to prevent and treat infections. Our objective was to determine an optimal dosage regimen of meropenem in patients receiving VA ECMO by developing a population pharmacokinetic model.MethodsThis was a prospective cohort study. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF). The population pharmacokinetic model was developed using nonlinear mixed-effects modelling. A Monte Carlo simulation was used (n=10,000) to assess the probability of target attainment.ResultsThirteen adult patients on ECMO receiving meropenem were included. Meropenem pharmacokinetics was best fitted by a two-compartment model. Covariate analysis indicated that continuous renal replacement therapy (CRRT) was negatively correlated with clearance (CL). The final pharmacokinetic model was: CL (L/h) = 3.79 × 0.44CRRT; where use of CRRT = 1, no CRRT = 0, central volume of distribution (L) = 2.4, peripheral volume of distribution (L) = 8.56, and intercompartmental clearance (L/h) = 21.3. According to the simulation results, 1–2 g q8h intravenous administration over 20 min was sufficient in patients without CRRT for both susceptible (minimum inhibitory concentration (MIC) = 2 mg/L) and resistant (MIC = 8 mg/L) pathogens, regardless of ECMO use (40% fT>MIC target). However, if more aggressive treatment is needed (100% fT>MIC target), dose increment or extended infusion is recommended.ConclusionsWe established a population pharmacokinetic model for meropenem in patients receiving VA ECMO and suggested an optimal dosage regimen. These results should improve treatment success and survival in VA ECMO patients. Clinicaltrials.gov registration # NCT02581280

scholarly journals Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

2022 ◽  
Vol 12 ◽  
Author(s):  
SiChan Li ◽  
SanLan Wu ◽  
WeiJing Gong ◽  
Peng Cao ◽  
Xin Chen ◽  
...  
Keyword(s):  
Maintenance Dose ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Immunocompromised Patients ◽  
First Order ◽  
Dosing Regimens

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

scholarly journals Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiao-duo Guan ◽  
Xian-ge Tang ◽  
Ying-jun Zhang ◽  
Hong-ming Xie ◽  
Lin Luo ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Healthy Volunteers ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Oral Clearance ◽  
First Order ◽  
Apparent Oral Clearance ◽  
Significant Covariates

Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h−1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

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