Abstract
This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.
Highlights
Tacrolimus (TAC), the backbone of immunosuppressive drug therapy in organ transplantation, is mostly used in combination with mycophenolate mofetil (MMF) as a maintenance immunosuppressive regimen to prevent graft rejection and improve overall graft and patient survival in kidney transplant recipients[1,2]
These all suggest that a detailed knowledge of the potential pharmacokinetic interaction between TAC and MMF and its magnitude are of great importance in understanding of the variability of TAC pharmacokinetics, which is crucial in the clinical management of kidney transplant patients
The present study was the first study to evaluate the effect of drug-drug interaction (DDI) between TAC and MMF in stable kidney transplant recipients with the integrated population pharmacokinetic model and further suggest the dosing algorithm of TAC
Summary
Tacrolimus (TAC), the backbone of immunosuppressive drug therapy in organ transplantation, is mostly used in combination with mycophenolate mofetil (MMF) as a maintenance immunosuppressive regimen to prevent graft rejection and improve overall graft and patient survival in kidney transplant recipients[1,2]. As the genetic variations of the respective enzymes and transporters are known to affect the trough levels and the dosage requirements in transplant patients, it is important to know the effect of genetic polymorphism on the pharmacokinetic variability[20,21]. These all suggest that a detailed knowledge of the potential pharmacokinetic interaction between TAC and MMF and its magnitude are of great importance in understanding of the variability of TAC pharmacokinetics, which is crucial in the clinical management of kidney transplant patients. The information on the sources of variability is limited, especially on the effects of co-administered MMF on the pharmacokinetics of TAC
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