title: Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation.
abstract: Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C(0) concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Åsberg
authors.forename: Karsten
authors.initials: K
authors.lastname: Midtvedt
authors.forename: Mike
authors.initials: M
authors.lastname: van Guilder
authors.forename: Elisabet
authors.initials: E
authors.lastname: Størset
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.forename: Stein
authors.initials: S
authors.lastname: Bergan
authors.forename: Roger
authors.initials: R
authors.lastname: Jelliffe
authors.forename: Anders
authors.initials: A
authors.lastname: Hartmann
authors.forename: Michael N
authors.initials: MN
authors.lastname: Neely
mesh_terms: D000328:Adult; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008954:Models, Biological; D018709:Statistics, Nonparametric; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP3A5; dosing; nonparametric; population pharmacokinetics; tacrolimus