Exploring the comprehensive factors influencing tacrolimus pharmacokinetics in early renal transplant recipients: A population pharmacokinetic analysis.
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Abstract
Purpose: To establish a population pharmacokinetic (PopPK) model of tacrolimus in the early stages after renal transplantation and evaluate the model's predictive performance with external data.
Methods: Intravenous and oral tacrolimus were administered to 302 renal transplant recipients in the early posttransplantation stages. Related data were obtained from the electronic medical records. Single nucleotide polymorphisms in genes associated with tacrolimus pharmacokinetics were tested. The data were analyzed by NONMEM. The external data from 153 patients were subsequently used to evaluate model extrapolation.
Results: A one-compartment model was used to determine tacrolimus pharmacokinetics. The estimated clearance (CL), volume of distribution (V) and bioavailability (F) of tacrolimus were 4.91 L/h, 77 L and 26.5%, respectively. CL and V decreased with increasing hematocrit. CL and F decreased with increasing operation time. Diltiazem and Wuzhi capsule resulted in 28.4% and 43.9% decreases in the CL, respectively. Omeprazole or esomeprazole resulted in a 9% increase in F. The value of F for patients expressing CYP3A5 was 36.6% lower than that for the patients who did not express CYP3A5. The evaluation of external data revealed that the proportion of individual prediction error within 20% of the observed tacrolimus concentration was greater than 77.3%.
Conclusions: A PopPK model for tacrolimus was established for early renal transplantation. CYP3A5 was a significant covariate for F. Fat-free mass was the best predictor of the influence of body size on CL and V. The model could be extrapolated to stable renal transplant recipients.
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The European Journal of Clinical Pharmacology publishes original papers on all aspects of clinical pharmacology and drug therapy in humans. Manuscripts are welcomed on the following topics: therapeutic trials, pharmacokinetics/pharmacodynamics, pharmacogenetics, drug metabolism, adverse drug reactions, drug interactions, all aspects of drug development, development relating to teaching in clinical pharmacology, pharmacoepidemiology, and matters relating to the rational prescribing and safe use of drugs. Methodological contributions relevant to these topics are also welcomed.
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