Population pharmacokinetics(PK)/Pharmacodynamics(PD) modeling and simulation of vancomycin in pediatric infectious patients
Sungwoo Goo(1), Nayoung Han (1), Hyun-moon Back(1), Jihyun Jeon(1), Junyoung Kim(1), Kwang-il Kwon*(1), JaeWoo Kim(2)*, Hwi-yeol Yun(1)*
(1) Chungnam National University, Republic of Korea, (2) Clinical trial center, Chungnam National University Hospital
Objectives:
The aim of this study is to develop population PK/PD model of vancomycin in pediatric infectious patients for dose optimization of vancomycin.
Pediatric patient’s ADME is different to general adult patient’s. therefore, pediatric modeling should be considered about allometric scaling and maturation function.
Drug Plasma Concentration/MIC is used as antibiotics’ PD marker frequently. But time to get MIC value takes about a week commonly. Therefore, MIC is difficult to use clinically in early stage of infection. However, plasma levels of CRP may rise rapidly and markedly, as much as 1000-fold or more, after an acute inflammatory stimulus.[1] therefore, CRP is able to be used to PD markers at early stage of infection.
Methods: 81 pediatric patients’ PK and clinical laboratory data as PD data were obtained from Electronic Medical Record (EMR) at Chungnam National University Hospital. 81[HY1] demographics of patient were tested by PK covariates (postnatal age(PNA), postconceptional age(PCA), genital age(GA), weight, etc). C-Reactive protein(CRP) was selected as PD because this parameter is representative to infectious factor. Plasma concentrations were fitted with one-compartment and indirect response model(IDR) was selected to connecting between PK and PD model. Kin was defined CRP synthesis rate. Kout was defined CRP degradation rate.
Results: PK base model was described by 1-compartment model. And PK final model was explained by Allometric scaling and maturation function. Allometric scaling was applied to Vd and CL. And maturation function was applied to CL. Maturation function’s parameters that were TM50 and Hill were not estimated but gotten from reference.[2]
For Inhibitory Emax model, IC50 value was 10.7 mg/L that was in through therapeutic range(10-20 mg/L).
PD model was described by IDR model. Kin and Kout were estimated 0.0207/hr and 0.0129/hr. Kin’s and Kout’s individual variation were 123 CV% and 26 CV%.
Conclusions: Pediatric PK model had lower individual error when allometric scaling and maturation function were considered. Allometric scaling was applicable for all pediatric groups. The maturation function was applicable to infants.
PD model had higher individual error than PK model. PD model was not considered about covariate since PK model was considered about it and valid covariate is not defined during EDA. And PD model was not considered about time. So predicted CRP value had higher error after stopping dose than during dosing.
References:
[1] Black, Steven, Irving Kushner, and David Samols. "C-reactive protein." Journal of Biological Chemistry 279.47: 48487-48490 (2004)
[2]Nick Holford, Young-A Heo, Brian Anderson. A Pharmacokinetic Standard for Babies and Adults. Journal of Pharmaceutical Sciences. 102(9):2941-2952 (2013)
