Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Development of Physiologically Based Pharmacokinetic Model and Assessment of the Impact of Renal Underdevelopment in Preterm Infants on the Pharmacokinetics of Aminophylline

Objective:To develop a physiologically based pharmacokinetic (PBPK) model for individualization of the dosing regimen considering the physiological requirements of these preterm neonates. Methods: The study comprised preterm newborns with fewer than 34 weeks of gestation and six apneic episodes in 24 h. A PBPK model was created using PK-SIM (version 9, update 1, GitHub, San Francisco, CA, USA). A PBPK model is built using a typical loading dosage of 5 mg/kg and a maintenance dose of 1.5 mg/kg. Based on the verified base model, a PBPK model representing renal underdevelopment based on nRIFLE/pRIFLE categorization was developed. Results: The PK parameters of Aminophylline were computed using the PBPK model. As per the model prediction, T1/2 and area under the curve reduced as postnatal age increased, and in the event of renal underdevelopment, even while Cmax for patients under R (RISK), I (injury) was within the therapeutic range; it was greater compared to preterm without any renal complications. Mean Cmax (mol/L) was 59.53 and for R, I, and F (FAILURE) categories the values were 83.04, 99.69, and 126.98, respectively. Conclusion: The model was created using appropriate drug, study subject, and dosage protocol inputs. The established PBPK model could help in individualizing aminophylline dose in preterm babies.

Prediction of the bioequivalence of different crystal forms of rifampicin based on physiologically based pharmacokinetic model / 中国药科大学学报

@#The physiologically based pharmacokinetic (PBPK) modeling strategy was adopted to predict the pharmacokinetic behavior of crystal forms I and II of rifampicin in humans, which was used to determine whether the two were bioequivalent.After conducting studies in vitro of the two crystal forms, a rat PBPK model was established based on the pharmacokinetic data of intravenous administration in rats.The model was optimized by the pharmacokinetic data of oral administration in rats.Species were extrapolated to healthy humans, and the extrapolation model was used to predict such pharmacokinetic behaviors as the drug-time curve, absorption site, and absorption amount of the two crystal forms of rifampicin in healthy humans.The prediction results of the healthy human model showed that the cmax of form I and form II rifampicin were 8.42 and 10.35 μg/mL, tmax were 0.40 and 0.32 h,and AUC0-t were both 62.90 μg·h/mL.According to the prediction results of absorption, neither crystal form I nor crystal form II rifampicin was absorbed in the stomach, yet both were completely absorbed in the intestinal tract, with both the absorption site and the absorption amount were basically the same.The pharmacokinetic parameters of both crystal forms I and II of rifampicin were very close, which could indicate bioequivalence.

Current development of physiologically based pharmacokinetic model and its application in drug clinical study / 中国临床药理学与治疗学

The physiologically based pharmacokinetic (PBPK) model, as a physiological mechanism-based model, can simulate the absorption, distribution, metabolism and excretion of drugs in the body. In recent years, it has been widely used in drug-drug interaction study, special population extrapolation, clinical trial dose selection, individualized medication and impact of different factors on the pharmacokinetic course. This review briefly describes the history and current development of PBPK model, introduces the work flow of PBPK model, and reviews its application in drug clinical study in recent years. We hope this review could provide a reference for researchers who are interested in this field.

A Comparative Study of PBPK Model and Allometric Growth Model of Azithromycin in Extrapolation of Adult Pharmacokinetic Data to Pediatric Population / 中国药学杂志

OBJECTIVE: To establish an adult-pediatric transformation model of azithromycin to provide guiding recommendations for clinical using of pediatrics, reduce the risk of medicationfor children, and achieve clinical personalized medication for children. METHODS: The relevant literature was reviewed. The physiological parameters of the azithromycin oral administration test in adults combined with the drug-specific parameters of azithromycin were used to establish an allometric growth model, PBPK model. According to the clinical data of oral azithromycin extracted from individual children, the correctness of the parameter scaling formulas of these two models was verified. These two models were further used to simulate the pharmacokinetic parameters of children and calculate the relative deviation and relative standard error of these parameters. RESULTS: Through simulation, it is found that the pharmacokinetic parameters cmax, tmax, AUC0-∞ obtained by the two models are close to the measured values, which are all within the scope of the literature. It can be considered that the parameter conversion formulas of the two models are correct. Further, the relative deviation and relative standard error of the parameters are calculated, and the relative deviation and relative standard error of the adult-pediatric PBPK prediction model are smaller than those of the allometric growth model. CONCLUSION: The azithromycin PBPK model predicts that children's pharmacokinetic parameters are better than the allometric growth model. The scaling formula for the specific parameters of the oral-dose adult-child model used in this article, which was successfully verified by azithromycin, can be extrapolated to other drugs to facilitate the conversion of other oral-adulterated adult-pediatric models.

Establishment of Physiological Pharmacokinetic Model of Cefdinir in Healthy Volunteers and Its Application / 中国药房

OBJECTIVE:To establish physiological pharmacokinetic (PBPK) model of cefdinir in healthy volunteers,and to predict pharmacokinetic process of cefdinir in volunteers after oral administration. METHODS:Using“toubao dini”“cefdinir”“logP”“pKa”as keywords,related literatures about physico-chemical constants of cefdinir were retrieved from CNKI,ScienceDi-rect,PubMed and other databases;according to related guidelines and preliminary clinical trial plan of FDA,GastroPlusTM 8.6 soft-ware was used to establish PBPK model of oral administration of cefdinir;the effectiveness of the model was evaluated by multiple error. The model was used to simulate the absorption of cefdinir in the gastrointestinal tracts. The bioequivalence of test preparation and reference preparation were evaluated through single and population(n=500)simulation tests using cmax and AUC0-∞ of cefdinir reference preparation (capsule and granular formulation) as factors when release rate t85%=15 min (i.e. accumulatively released 85% within 15 min). RESULTS:The blood concentration-time curves of cefdinir predicted by PBPK model fitted well with mea-sured value(R2≥0.95);the pharmacokinetic parameters(cmax,tmax,AUC0-∞)were close to measured results,and the multiple er-rors were less than 2. After oral administration,cefdinir was mainly absorbed by the intestinal tract (45.6%),especially by seg-ment 1 of jejunum(14.8%);the absorption amount was significantly lower than the release amount of absorption site,and reached the maximal value(about 40%)within 4 h. The results of single simulation test showed that there was no statistical significance in cmax and AUC0-∞ between cefdinir test and reference preparations (P>0.05). The results of population simulation test showed that the relative bioavailability of cefdinir test particle and test capsule respectively were 99.01%-102.99% and 97.60%-105.90%;90%CI of cmax and AUC0-∞ values were within 80%-125% of reference preparation. CONCLUSIONS:The PBPK model is accurate and reliable in this study,can provide reference for pharmacokinetic study and bioequivalence evaluation of cefdinir preparations. Test preparation and reference preparation are equivalent.