Open AccessInclusion of CYP 3 A 5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation
Author(s) -
Åsberg Anders,
Midtvedt Karsten,
van Guilder Mike,
Størset Elisabet,
Bremer Sara,
Bergan Stein,
Jelliffe Roger,
Hartmann Anders,
Neely Michael N.
Publication year - 2013
Publication title -
transplant international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.998
H-Index - 82
eISSN - 1432-2277
pISSN - 0934-0874
DOI - 10.1111/tri.12194
Subject(s) - medicine , tacrolimus , dosing , transplantation , population , calcineurin , genotyping , pharmacology , genetics , biology , genotype , gene , environmental health
Summary 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 CYP 3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP 3A5 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 CYP 3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP 3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP 3A5 genotype provided an initial advantage, but only until 3‐4 tacrolimus concentrations were known. After this, a model without CYP 3 A 5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.