Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis.
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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.
SUBMITTER: Chen L
PROVIDER: S-EPMC8423491 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The development of predictive engines based on pharmacokinetic-physiological mathematical models for personalised dosage recommendations is an immature field. Nevertheless, these models are extensively applied during the design of new drugs. This study presents new advances in this subject, through a stable population of patients who underwent kidney transplantation and were prescribed tacrolimus. We developed 2 new population pharmacokinetic models based on a compartmental approach, with one following the physiologically based pharmacokinetic approach and both including circadian modulation of absorption and clearance variables. One of the major findings was an improved predictive capability for both models thanks to the consideration of circadian rhythms, both in estimating the population and in Bayesian individual customisation. This outcome confirms a plausible mechanism suggested by other authors to explain circadian patterns of tacrolimus concentrations. We also discovered significant intrapatient variability in tacrolimus levels a week after the conversion from a fast-release (Prograf) to a sustained-release formulation (Advagraf) using adaptive optimisation techniques, despite high adherence and controlled conditions. We calculated the intrapatient variability through parametric intrapatient variations, which provides a method for quantifying the mechanisms involved. We present a first application for the analysis of bioavailability changes in formulation conversion. The 2 pharmacokinetic models have demonstrated their capability as predictive engines for personalised dosage recommendations, although the physiologically based pharmacokinetic model showed better predictive behaviour.
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Project description:Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid ?6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value < .05), which was faster in extensive (mean: 45.0 L/hr) and intermediate (29.5 L/hr) metabolizers than poor metabolizers (19.8 L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.
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