Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

Abstract

Purpose In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients. Patients and Methods We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated. Results The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, CYP3A5*3 genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h −1 , and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect. Conclusion Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.

Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients

“…The CL/F of CYP3A5 non‐expressers (patients who have at least one function allele, CYP3A5*1 allele) was 2.38 h/L less than the expressers (homozygous for the variant allele, CYP3A5*3 allele). It was reported in one recently published study (Chen et al., 2021) that Wuzhi dose, CYP3A5*3 genetic polymorphisms were significant covariates for CL/F of tacrolimus; consistently, we observed the same results in this study. However, they also found Cr clearance rate and HCT as significant covariates in the final popPK model to characterize the PK of tacrolimus in Chinese kidney transplant recipients, which was inconsistent with our study that we did not investigate the correlations between CL/F of tacrolimus and Cr clearance rate, CL/F of tacrolimus and HCT.…”

Effects of WuZhi preparations on tacrolimus in pediatric and adult patients carrying the CYP3A5*1 allele of heart transplant during the early period after transplantation

“…7,17,32 In the current study, we found a significant increase in TAC C 0 /D after co-administration with WZP. 33 Our findings are also consistent with previous study, 15 and we discovered that the fold changes in TAC C 0 /D prompted by WZP had a sizeable inter-individual variation of up to four or five fold.…”

“…36 A study from Chinese adult liver transplant recipients found that the effect of increasing age on The available literature confirms that the WZ capsule extract inhibits CYP3A in a concentration-and time-dependent inhibitory manner. 33 The effect of WZP on TAC C 0 is largely determined by WZP dosage. 19 Consistent with our previous study, 15 we found that the fold changes of C 0 /D increased with the dose of SchA in adult patients, but not in pediatric patients.…”

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food

“…Side effects, such as hyperkalaemia or fever, were reported after SchE and tacrolimus co-administration and were accounted for as a result of an increased tacrolimus blood concentration [ 78 , 86 ]. Several population pharmacokinetic models have been developed to support the individualization of tacrolimus dosing for different groups: renal transplant recipients [ 81 , 83 , 85 , 87 , 88 ], liver transplant recipients [ 89 , 90 ], cardiac transplant recipients [ 91 , 92 ], patients with refractory nephrotic syndrome [ 93 , 94 ], membranous nephropathy [ 95 , 96 ], lupus nephritis [ 97 , 98 ] or myasthenia gravis [ 99 ]. SchE may significantly increase tacrolimus bioavailability and reduce its therapeutic costs by 40–60%, nevertheless, authors highly recommend blood tacrolimus concentration monitoring while co-administering with SchE [ 78 , 79 , 82 , 85 ].…”