Establishment Of A Population Pharmacokinetic Model Of Voriconazole In Children And Optimization Of Drug Delivery Scheme

Objectives:(1)The aim of this study was to explore the influencing factors of the effective and safe serum concentration of voriconazole in children;(2)To establish a(Population pharmacokinetics,PPK)model of voriconazole in children.(3)Based on the established voriconazole PPK model,the optimal dosing regimen with a steady-state trough concentration of 0.5～5 mg·L-1 in different conditions was developed.Methods:(1)Child patients(2～17 years old)with intravenous voriconazole≥72h and at least once steady-state serum trough concentration determination were included by prospectively study method.The demographic data,blood routine index,liver function related indexes,C-reactive protein(CRP),main diagnosis,voriconazole administration scheme,combined medication and blood concentration monitoring information were recorded to establish a database.(2)Voriconazole steady-state serum trough concentrations were divided into<0.5 mg·L-1 group and ≥0.5 mg·L-1 group when investigating the factors affecting the effective serum concentration.When the factors affecting the safe serum concentrations were investigated,it was divided into<5 mg·L-1 group and>5 mg·L-1 group.SPSS20.0 statistical software was used to analyze the data with single-factor and multi-factor logistic regression models to find out the influencing factors of effective serum concentration and safe serum concentration of voriconazole in child patients.(3)The PPK model of voriconazole in children was established by using the method of non-linear mixed model(NONMEM).The final model was internally evaluated by Goodness of Fit Plots(GOFs),Non-parameter Bootstrap,and Normalized prediction distribution error(NPDE),to examine the stability and predictive performance.(4)Monte Carlo simulation method was used to simulate the optimal dosing regimen of target steady-state trough concentration of 0.5～5 mg·L-1 based on the established voriconazole PPK model and calculate the probability of target acquisition(PTA).Results:(1)Forty-night voriconazole initial steady-state serum trough concentrations from 49 patients were included.Children’s voriconazole initial steady-state serum trough concentrations compliance rate was 55.10%.Factors affecting the effective serum concentration of the children are phenytoin(within one week before administration)(OR,0.057;95%CI:0.013-0.246;P=0.000)and pantoprazole(OR,0.169;95%CI:0.030-0.945;P=0.043).(2)A voriconazole PPK model was established by incorporating 114 steady-state serum trough concentrations data and relevant pathophysiology and combined medication information from 75 child patients.The pharmacokinetic parameters were estimated by using First Order Conditional Estimation Interaction(FOCEI).The final model was a one-compartment model which was formulated as:CL(L/h)=2.9 × 1.79(MMF-1)×e0.152;V1(L)=6.17 x e0.401(when PLT<25 × 109/L),V2(L)=7.67(when PLT≥25×109/L).GOFs showed that the predicted values of the final model had a good correlation with the measured values.The scatter plots of the condition weight residues(CWRES)versus time and CWRES versus population predicted values(PRED)revealed that most of the residuals were uniformly distributed symmetrically on the X-axis within ±2.Bootstrap showed that the robustness rate of the model was 99.3%,95%CI contained the target value and did not contain 0.The median of the estimated pharmacokinetic parameters was close to the final model.The NPDE results showed that the t test P=0.579,Fisher test P=0.145,Shapiro-Wilks test P=0.339,overall correction test P=0.435,all P values were>0.05.It illustrated that the final model was normal distribution.All the internal evaluations revealed a good stability and predictive performance of the final model.(3)The model was used to simulate and recommend the optimal dosage regimen under different conditions.The average PTA of the target steady-state trough serum concentration in the range of 0.5～5 mg～L-1 was 64.4%.The compliance rate was higher than before.Conclusions:(1)The compliance rate of child patients’ voriconazole initial steady-state serum trough concentration was 55.10%.Phenytoin sodium(within one week before medication)and pantoprazole were the influencing factors of children’s voriconazole effective serum concentration.Therefore,it was necessary to formulate voriconazole medication plan according to patients’specific case conditions and combined medication conditions.(2)The pharmacokinetics of children using voriconazole were quite different,and the variability of steady-state serum trough concentration was significant,which might be related to factors such as the patient’s physical condition and drug interaction.Mycophenolate mofetil was the main influencing factor for voriconazole clearance;Platelet IV reduction(PLT<25 x 109/L)affected the apparent volume of voriconazole.The internal validation of the voriconazole PPK model established in this study showed good stability and predictive performance,but more data was needed for external validation to confirm the personalized medicine of clinical voriconazole.(3)According to the model,the average PTA of voriconazole obtained by different dosage regimens was 64.4%,which was higher than the previous compliance rate(55.10%).This model had certain clinical application value.