Factors affecting the apparent clearance of tacrolimus in Korean adult liver transplant recipients.
OBJECTIVE
To identify the factors affecting tacrolimus apparent total body clearance (Cl/F [F = bioavailability]) in adult liver transplant recipients.


METHODS
Population pharmacokinetic analysis using data from a retrospective chart review.


METHODS
University-affiliated hospital in Seoul, South Korea.


METHODS
Fifty-one adult liver transplant recipients who had received tacrolimus after transplantation.


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.


CONCLUSIONS
These findings could be useful to the health care provider for adjustment of tacrolimus dosage in adult liver transplant recipients with various clinical factors.
Lee
Ju Yeun
JY
Department of Pharmacy, Seoul National University Hospital, Jongno-gu, Seoul, South Korea.
Hahn
Hyeon Joo
HJ
Son
In Ja
IJ
Suh
Kyung Suk
KS
Yi
Nam Joon
NJ
Oh
Jung Mi
JM
Shin
Wan Gyoon
WG
D000328:Adult; D000368:Aged; D044466:Asian People; D001663:Bilirubin / Q000097:blood; D001682:Biological Availability; D001835:Body Weight; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D019934:International Normalized Ratio; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D008499:Medical Records; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009929:Organ Size; D012044:Regression Analysis; D015203:Reproducibility of Results; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D007166:Immunosuppressive Agents; D001663:Bilirubin; D016559:Tacrolimus