Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients.
OBJECTIVE
The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.


METHODS
The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.


RESULTS
A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 +/- 0.2 l h(-1). Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 +/- 0.5 days, with a maximal value of 5.6 l h(-1). Moreover clearance increased by approximately 1.6 fold (range 0.5-1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 +/- 13 l kg(-1)) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.


CONCLUSIONS
The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.
Antignac
Marie
M
Pharmacy Department, Pitié Salpêtrière Hospital, AP HP-47 Bd de l'hôpital, 75013 Paris, France. marie.antignac@psl.ap-hop-paris.fr
Barrou
Benoit
B
Farinotti
Robert
R
Lechat
Philippe
P
Urien
Saïk
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D015331:Cohort Studies; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D016559:Tacrolimus