Study objective: To identify the factors affecting tacrolimus apparent total body clearance (Cl/F [F = bioavailability]) in adult liver transplant recipients.
Design: Population pharmacokinetic analysis using data from a retrospective chart review.
Setting: University-affiliated hospital in Seoul, South Korea.
Patients: Fifty-one adult liver transplant recipients who had received tacrolimus after transplantation.
Measurements and main results: Data on 35 adult liver transplant recipients for model building and 16 patients for model validation were obtained retrospectively. Population average parameter estimates of Cl/F and apparent volume of distribution (V/F) were sought by using the nonlinear mixed-effect model (NONMEM) program. A number of clinical covariates were screened for their influence on these pharmacokinetic parameters. The final optimal population model related Cl/F to total bilirubin, early (< or = 3 days) and late (> 35 days) postoperative days, international normalized ratio (INR), and graft:recipient weight ratio (GRWR). The NONMEM estimates indicated that the Cl/F of tacrolimus was decreased in patients with a small graft, hyperbilirubinemia, and a high INR. In addition, the Cl/F of tacrolimus almost doubled 4 days after transplantation, but decreased with an increase in duration of therapy after day 35. Mean prediction error and mean absolute prediction error were 0.26 and 3.78 ng/ml, respectively, for the validation sample. A final analysis in all 51 patients, which consisted of 1775 blood samples for concentration measurements, identified the following regression model: Cl/F (L/hr) = (0.36 + 2.01/POD * L) * TBIL(-0.23 (TBIL = 1 if TBIL level < or = 1.2 mg/dl, otherwise TBIL = TBIL level)) *49((if POD < or = 3 days)) * 0.75((if INR > 1.4)) * 0.86((if GRWR < or = 1.25%)) * WT, where L was 1 if postoperative day (POD) was greater than 35 days, otherwise L was 0; V/F was 568 L, TBIL was total bilirubin, and WT was body weight. The interindividual variabilities (coefficients of variation) in Cl/F and V/F were 35.35% and 68.12%, respectively. The residual variability was 3.14 ng/ml.
Conclusion: These findings could be useful to the health care provider for adjustment of tacrolimus dosage in adult liver transplant recipients with various clinical factors.