Clinical Pharmacokinetics of Tacrolimus after the First Oral Administration in Renal Transplant Recipients on Triple Immunosuppressive Therapy

Abstract

Monitoring of tacrolimus blood concentration is of utmost importance in the management of renal transplant recipients because of Narrow Therapeutic Index and highly variable pharmacokinetics. The aim of this study was to detect inter-patient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times of the area under the curve (AUC) seeking to find the best sampling time to predict the exposure of tacrolimus in renal transplant recipients with triple therapy. This oral dose tacrolimus pharmacokinetics study was conducted in 18 Serbian renal transplant recipients on triple immunosuppressive therapy, including basiliximab. The first oral dose of tacrolimus (0.05 mg ⁄ kg) was given on day 5 post-transplant; blood concentration was measured by microparticle enzyme immunoassay method. Associations between each sampling time-point of concentrations and AUC 12 were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses. The variance in the strength of association between predicted AUC (AUC p ) and AUC 12 was reflected by linear regression coefficients. AUC 12 showed remarkable inter-individual variations after the first oral dose of tacrolimus. The area of the maximum AUC was four times higher than that of the minimum AUC. C 4 seems to be an indicator of total body exposure to tacrolimus. Alternatively, the concentrations at 1.5, 4 and 8 hr as an abbreviated AUC were as good a predictor as a full pharmacokinetic study. Our results show a significant difference between men and women. A three-point sampling method seemed to be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.Rejection prophylaxis using calcineurin inhibitors (cyclosporine or tacrolimus) remains the best practice pending publication of long-term results using newer agents [1][2][3]. The choice of cyclosporine or tacrolimus depends on immunological risk, recipient characteristics, concomitant immunosuppression and socio-economic factors. Tacrolimus (FK 506) is superior to cyclosporine in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects [3,4]. Monitoring of tacrolimus blood concentrations is of utmost importance in the management of renal transplant recipients because of the narrow therapeutic range and highly variable pharmacokinetics of the drug [1][2][3][4]. If the concentration is lower than the range, the transplanted kidney will be rejected because of insufficient immunosuppression by tacrolimus. If the concentration is higher than the range, adverse effects will be observed because of the excess concentration of tacrolimus. High systemic exposure to tacrolimus might induce many side effects including nephrotoxicity, neurotoxicity and post-transplant diabetes mellitus [3,4]. Therapeutic monitoring of tacrolimus plays a crucial role not only in ...

Limited sampling strategies for tacrolimus exposure (AUC0-24) prediction after Prograf®and Advagraf®administration in children and adolescents with liver or kidney transplants

“…Therefore, the primary objective of this study was to develop LSSs predicting tacrolimus AUC 0-24 ; as far as we know, no LSS has been developed for the pediatric population that can predict 24-h tacrolimus exposure after Prograf â or Advagraf â administration. This is particularly Some older studies predicting tacrolimus AUC 0-12 have shown a very high r 2 obtained with only C0 [16,17], but prediction of AUC 0-12 by means of LSS after Prograf â administration is better than that obtained with C0 [18][19][20][21][22]. The use of LSSs to calculate AUC 0-24 after Prograf â administration is appealing because it indicates the total daily tacrolimus exposure instead of only the tacrolimus exposure after the morning dose.…”

“…Some older studies predicting tacrolimus AUC 0‐12 have shown a very high r 2 obtained with only C0 , but prediction of AUC 0‐12 by means of LSS after Prograf ® administration is better than that obtained with C0 . The use of LSSs to calculate AUC 0‐24 after Prograf ® administration is appealing because it indicates the total daily tacrolimus exposure instead of only the tacrolimus exposure after the morning dose.…”

Potential role of tacrolimus in erythrocytes’ antioxidative capacity in long-term period after renal transplantation

“…Tacrolimus pharmacokinetic variability may lead to under-immunosuppression and rejection episodes or overimmunosuppression, which can be potentially severe due to adverse effects that can occur. The previous studies showed that genetics was one of the main determinants, along with demographic factors and drug-drug interactions that contributed patients' variability in tacrolimus pharmacokinetics, but whether this variability might have influenced oxidative stress is unknown (MacPhee, 2012;Velickovic-Radovanovic et al, 2010, 2012. Individuals carrying at least one CYP3A5 ⁄ 1 allele, A at the position 6986, (expressers) expressed functionally active CYP3A5 protein, as well as required higher dose of tacrolimus to maintain optimal blood concentration than homozygous for the CYP3A5 ⁄ 3 allele (non-expressers) (MacPhee, 2012;Staatz et al, 2010a).…”

The relationship between tacrolimus concentration-dose ratio and genetic polymorphism in patients subjected to renal transplantation

“…Tacrolimus trough concentrations, most often used for TDM, are widely accepted as a guide for TCI and individualizing tacrolimus dose requirements in patients subjected to kidney transplantation 14,15 . On the other hand, although full dose interval area under the concentration-time curve is generally considered as the best marker for tacrolimus exposure, due to its complexity it has not been widely used as a routine method in clinical settings 16,17 . Quite recently, however, tacrolimus C/D ratio has been suggested as a potentially useful TDM strategy 7 .…”