Andrews, L. M. published the artcileA population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients, Related Products of pyridine-derivatives, the main research area is tacrolimus renoprotectant CYP3A4 albumin kidney transplantation adult; cytochrome P450 enzymes; genetics and pharmacogenetics; immunosuppression Immunology; pharmacokinetics; population analysis; renal transplantation.
To describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clin. tool for selecting the best starting dose for each patient. Data on tacrolimus exposure were collected for the first 3 mo following renal transplantation. A population pharmacokinetic anal. was conducted using nonlinear mixed-effects modeling. Demog., clin. and genetic parameters were evaluated as covariates. A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1, clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P 450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: Dosemg=222nghml-1*22.5lh-1*1.0ifCYP3A5*3/*3or1.62ifCYP3A5*1/*3orCYP3A5*1/*1*1.0ifCYP3A4*1or unknownor0.814ifCYP3A4*22*Age56-0.50*BSA1.930.72/1000 Both models were successfully internally and externally validated. A clin. trial was simulated to demonstrate the added value of the starting dose model. For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.
British Journal of Clinical Pharmacology published new progress about Adult, mammalian. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Related Products of pyridine-derivatives.