2010 - TTS International Congress


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Clinical Immunosuppression Kidney early

22.28 - Clinical pharmacokinetics of tacrolimus in renal transplant patients and determination of best sampling time for correlation with drug exposure

Presenter: PILAR, SALVADOR, A CORUÑA, Spain
Authors: SALVADOR P., OUTEDA M., ALONSO A., LOPEZ A., FERNANDEZ C., SILVA P., MARTIN I.

CLINICAL PHARMACOKINETICS OF TACROLIMUS IN RENAL TRANSPLANT PATIENTS AND DETERMINATION OF BEST SAMPLING TIME FOR CORRELATION WITH DRUG EXPOSURE

CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY

M. Outeda1, P. Salvador2, A. Alonso3, A. Lopez3, C. Fernandez3, P. Silva1, I. Martin1
1Pharmacy Department, UNIVERSITY HOSPITAL OF A CORUÑA, A CORUÑA/SPAIN, 2Pharmacy Department, A Coruña University Hospital, A CORUÑA/SPAIN, 3Nephrology Department, UNIVERSITY HOSPITAL OF A CORUÑA, A CORUÑA/SPAIN

Body:
Background Tacrolimus has a narrow therapeutic index with a wide inter and intrapatient variation in pharmacokinetics. The gold standard of determining drug exposure is the estimation of the area-under-the-concentration-time-curve (AUC0-12). However, in routine clinical practice, trough concentration (Ctrough) is used to predict this exposure. The aim of this study is 1)to determine the pharmacokinetic variability of Prograf® in the early and in the stable period after transplantation and 2)to assess the correlation between individual concentrations at various times and the AUC0-12 to find the best sampling time to predict the exposure of Prograf® in a Spanish population of renal transplant recipients. Methods Prospective study of patients who underwent a cadaveric renal transplantation at University Hospital of A Coruña (Spain) between July 2009 and January 2010 and with tacrolimus trough levels in the range 5-15 ng/mL. All recipients were Spanish (Caucasian) and received a triple-immunosuppressive-drug regimen, which consisted of tacrolimus, mycophenolate mofetil or enteric-coated mycophenolate sodium, and steroids. The pharmacokinetics of tacrolimus was assessed 15 days and 3 months after the transplantation. All patients received the same tacrolimus dosage for at least 4 days before this study. Blood samples were taken just before and 1, 2, 3, 4, 6 and 8 h after morning oral administration. Tacrolimus concentrations were measured using chemiluminescent immunoassay on ARCHITECT® platform. AUC0-12 was calculated using the linear trapezoidal rule. Statistical analysis was performed using SPSS version 17.0. Associations between each sample time-point of concentrations and AUC0-12 were evaluated by correlation of determination (r2). The research protocol was approved by the local Ethics Committee and is part of a research project authorized by Carlos III Institute of Health (Ministry of Science and Innovation). Results Twenty renal transplant patients with a mean age of 54.2 ± 12.3 years and a mean body weight of 73.8 ± 16.2 kg were included in the study. The pharmacokinetic parameters are shown in table below.

Early period Stable period
Mean ± SD AUC0-12/C (r2) Mean ± SD AUC0-12/C (r2)
Dose/day/body weight (mg/kg) 0.09 ± 0.04 0.06 ± 0.05
Ctrough (ng/mL) 10.3 ± 3.3 0.438 12.3 ± 2.0 0.509
C1 (ng/mL) 19.0 ± 9.4 0.199 17.3 ± 5.8 0.833
C2 (ng/mL) 18.1 ± 6.7 0.344 20.3 ± 7.1 0.948
C3 (ng/mL) 15.5 ± 6.1 0.497 18.0 ± 5.1 0.913
C4 (ng/mL) 15.6 ± 6.7 0.471 16.1 ± 3.1 0.902
AUC0-4 (ng.h/mL) 59.7 ± 15.7 0.501 69.4 ± 19.9 0.972
AUC0-12 (ng.h/mL) 163.6 ± 49.2 180.2 ± 31.1

Conclusions In the early postoperative period, when the patients are still unstable, there was no correlation between tacrolimus exposure and the concentration at 0 and 4 h. In the stable period, the AUC0-12 showed a significant correlation between the concentrations C1, C2, C3 and C4, however, not with Ctrough. The trough tacrolimus level was not a good predictor of total drug exposure. The best correlation was obtained 2 h postdose. In the initial posttransplant period, to determine the degree of tacrolimus exposure, an AUC0-12 should be calculated, this not being justified in stable patients.

Disclosure: All authors have declared no conflicts of interest.


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