Investigation of the Impact of CYP3A5 Polymorphism on Drug–Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling

Abstract

Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.

Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients

“…The PBPK modeling established by He et al. provided insights for the DDI between tacrolimus and WZC in patients with different CYP3A5 genotypes (He et al., 2021). In the future, we will further explore our model using different strategies.…”

“…Compared with PBPK modeling, our current popPK model had limitations in the extent of the physiology information and the drug that can be easily retained in the model (Nguyen et al, 2021). The PBPK modeling established by He et al provided insights for the DDI between tacrolimus and WZC in patients with different CYP3A5 genotypes (He et al, 2021). In the future, we will further explore our model using different strategies.…”

Application of physiologically based pharmacokinetic modelling for the prediction of drug–drug interactions involving anlotinib as a perpetrator of cytochrome P450 enzymes

“…It is of great need to gather precise DDIs information to guide the clinical decision. Simcyp® PBPK has been widely applied in DDIs among natural medicines, 28 predicting hepatotoxic doses 29 and labelling marketed drugs approved by the FDA, such as ibrutinib, cobimetinib and lenvatinib 30 . Back in 2013, the use of PBPK for DDIs prediction purposes was quite novel; it is now considered an ‘encouraged’ approach.…”

Investigation of the Impact of CYP3A5 and CYP2C19 Polymorphisms on Drug-Drug Interactions between Tacrolimus and Voriconazole Based on Physiologically-Based Pharmacokinetic Modeling

“…Such dose adjustment process often takes a long time and has a great impact on the therapeutic effect and life quality of patients after transplantation [38] . A number of studies used PBPK model to investigate the effect of enzyme genotype on drug PK when drugs were used alone or in combination [1,25,39,40] . In addition, patients who received a CYP3A5 genotype-based tacrolimus dose needed significantly less time and fewer dose adaptations to reach target, which would be helpful in some potential ways for the patients [34,[41][42][43] .…”

“…Combination therapy is common in clinical practice, which can result in pharmacokinetic drug-drug interactions (DDIs). It is usually caused by the interference of a perpetrator drug on the metabolizing enzymes or drug transporters of a victim drug [1] . Genetic polymorphisms that alter these enzymes or transporters thereby can affect the magnitude of DDIs.…”