Population pharmacokinetics of vancomycin in Chinese pediatric patients
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OBJECTIVE This study was conducted to develop a population pharmacokinetic (PopPK) model for vancomycin and to detect the significant covariates that influence the PopPKs to facilitate individualized therapy for Chinese pediatric patients. METHODS Patients ≤ 10 years old who received vancomycin for ≥ 72 hours between 2007 and 2010 were analyzed using a nonlinear mixed-effects modeling approach (-NONMEM). A one-compartment model with first-order elimination was chosen to depict the data. Stepwise covariate modeling (SCM) was employed to detect significant covariates and obtain a final model. Internal validation methods, including bootstrapping and visual predictive checks (VPC), were applied to evaluate the robustness and predictive power of the final model. RESULTS The analysis included 54 pediatric inpatients with 128 serum concentration samples. The mean age (range) was 124.30 (1.29 - 541.4) weeks, the mean weight was 10.36 (1.4 - 33.5) kg, and the mean baseline serum creatinine (Scr) level was 0.39 (0.15 - 1.32) mg/dL. Pneumonia was the most common indication for vancomycin therapy (33.33%), followed by bacteremia (25.93%), and meningitis (22.22%). A PopPK model of vancomycin in Chinese pediatric patients was developed. Postnatal age (PNA) significantly affected the vancomycin clearance (CL) of pediatric patients, and the influence was described using the sigmoid maximum effect (Emax) model. The effect of body weight (WT) on CL and volume of distribution (V) was investigated using an allometric scaling equation. The final model parameters were CL(L/h) = 11.75×[PNA0.4672/(PNA0.4672+33.30.4672)]×(WT/70)0.75×e0.362 and V(L) = 54.49×WT/70×e0.6711. The model evaluation results suggested robustness and good predictability of the final model. CONCLUSION A PopPK model of vancomycin for Chinese pediatric patients was developed in this study. The significant covariates distinguished in the final model can provide helpful information to facilitate individualized therapy for Chinese pediatric patients.
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[1]  N. V. Jiménez-Torres,et al.  Population pharmacokinetic parameters of vancomycin in critically ill patients , 2006, Journal of clinical pharmacy and therapeutics.

[2]  M. J. García,et al.  Population Pharmacokinetic Analysis of Vancomycin in Patients with Hematological Malignancies , 2005, Antimicrobial Agents and Chemotherapy.

[3]  J. N. van den Anker,et al.  Vancomycin: pharmacokinetics and administration regimens in neonates. , 2004, Clinical pharmacokinetics.

[4]  B. Legras,et al.  Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz, and modification of diet in renal disease formulas. , 2003, Kidney international.

[5]  L. Sheiner,et al.  Evaluating Pharmacokinetic/Pharmacodynamic Models Using the Posterior Predictive Check , 2001, Journal of Pharmacokinetics and Pharmacodynamics.

[6]  E. Capparelli,et al.  Neoral pharmacokinetics in Latino and Caucasian pediatric renal transplant recipients , 2001, Pediatric Nephrology.

[7]  R. Wrishko,et al.  Vancomycin Pharmacokinetics and Bayesian Estimation in Pediatric Patients , 2000, Therapeutic drug monitoring.

[8]  D. Lebel,et al.  A Population Pharmacokinetic Model for Vancomycin in Pediatric Patients and Its Predictive Value in a Naive Population , 2000, Antimicrobial Agents and Chemotherapy.

[9]  R. Schoemaker,et al.  Tobramycin population pharmacokinetics in neonates * , 1997 .

[10]  R. Slaughter,et al.  Vancomycin Pharmacokinetics in a Patient Population: Effect of Age, Gender, and Body Weight , 1994, Therapeutic drug monitoring.

[11]  R. Brundage,et al.  Population pharmacokinetics of vancomycin in neonates , 1994, Clinical pharmacology and therapeutics.

[12]  M. Boro,et al.  Vancomycin pharmacokinetics in middle-aged and elderly men. , 1994, American journal of hospital pharmacy.

[13]  John E. Murphy,et al.  Vancomycin Pharmacokinetics in Neonates and Infants: A Retrospective Evaluation , 1993, The Annals of pharmacotherapy.

[14]  U. Alon,et al.  Creatinine for estimation of glomerular filtration rate , 1992, Pediatric Nephrology.

[15]  B. Ackerman,et al.  Analysis of vancomycin time-kill studies with Staphylococcus species by using a curve stripping program to describe the relationship between concentration and pharmacodynamic response , 1992, Antimicrobial Agents and Chemotherapy.

[16]  M. Rybak,et al.  Nephrotoxicity of vancomycin, alone and with an aminoglycoside. , 1990, The Journal of antimicrobial chemotherapy.

[17]  J. Rotschafer,et al.  Vancomycin pharmacokinetics in patients with various degrees of renal function , 1988, Antimicrobial Agents and Chemotherapy.

[18]  R. Slaughter,et al.  Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy. , 1987, The American journal of medicine.

[19]  L. Brion,et al.  The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. , 1987, Pediatric clinics of North America.

[20]  G. Koren,et al.  Vancomycin pharmacokinetics and dose recommendations for preterm infants , 1987, Antimicrobial Agents and Chemotherapy.

[21]  G. Matzke,et al.  Clinical Pharmacokinetics of Vancomycin , 1986, Clinical pharmacokinetics.

[22]  R. Polin,et al.  Vancomycin pharmacokinetics in infants: relationships to indices of maturation. , 1986, Pediatric infectious disease.

[23]  R. Reichley,et al.  Vancomycin pharmacokinetics in small, seriously ill infants. , 1986, American journal of diseases of children.

[24]  G. Schumacher,et al.  Bayesian approaches in pharmacokinetic decision making. , 1984, Clinical Pharmacist.

[25]  T. Sorrell,et al.  Vancomycin therapy for methicillin-resistant Staphylococcus aureus. , 1982, Annals of internal medicine.

[26]  崎山美知代.  有効性に関するトピックの動向 ICH E11‐Addendum(R1):Clinical Investigation of Medicinal Products in the Pediatric Population Lisbon2016EWG会議の報告 , 2017 .

[27]  Imke H. Bartelink,et al.  Guidelines on Paediatric Dosing on the Basis of Developmental Physiology and Pharmacokinetic Considerations , 2006, Clinical pharmacokinetics.

[28]  M. Nahata,et al.  Dosage guidelines for the use of vancomycin based on its pharmacokinetics in infants , 2004, European Journal of Clinical Pharmacology.

[29]  T. Iga,et al.  Population pharmacokinetics of vancomycin in Japanese adult patients. , 1998, Therapeutic drug monitoring.

[30]  G. Mccracken,et al.  Clinical pharmacology and efficacy of vancomycin in pediatric patients. , 1980, The Journal of pediatrics.

[31]  Cockcroft Dw,et al.  Prediction of Creatinine Clearance from Serum Creatinine , 1976 .