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Comparative Study
. 2007 Dec;64(6):750-7.
doi: 10.1111/j.1365-2125.2007.02895.x. Epub 2007 Apr 10.

Population Pharmacokinetics and Bioavailability of Tacrolimus in Kidney Transplant Patients

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Free PMC article
Comparative Study

Population Pharmacokinetics and Bioavailability of Tacrolimus in Kidney Transplant Patients

Marie Antignac et al. Br J Clin Pharmacol. .
Free PMC article

Abstract

Aims: 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.

Figures

Figure 1
Figure 1
Tacrolimus observed trough whole blood concentrations vs. time (.). Median, solid line; 2.5th and 97.5th percentiles, dashed lines
Figure 2
Figure 2
Individual clearance values as a function of days postoperation. Lines are drawn according to the final population model
Figure 3
Figure 3
a) Model-predicted (PRED) vs. observed (DV) trough whole blood tacrolimus concentrations (ng ml−1). The solid line is the line of identity. The mean bias (± SD) was −0.64 (± 3.7) ng ml−1, not significantly different from 0. b) Individual model-predicted (iPRED) vs. observed (DV) trough whole blood tacrolimus concentrations (ng ml−1). The solid line is the line of identity. The mean bias (± SD) was −0.02 (± 1.52) ng ml−1, not significantly different from 0

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