Time-related clinical determinants of long-term tacrolimus pharmacokinetics in combination therapy with mycophenolic acid and corticosteroids: a prospective study in one hundred de novo renal transplant recipients.
BACKGROUND
Tacrolimus is an efficient primary immunosuppressive drug in renal transplantation but its long-term use is associated with calcineurin-inhibitor-related toxicity. The specific characteristics of the inter-relationship between dose, concentration and clinical (side-)effects for tacrolimus have not yet been identified and extensive long-term pharmacokinetic studies are presently lacking.


OBJECTIVE
To establish the characteristics of the long-term pharmacokinetics of tacrolimus, to determine the time-dependent factors that influence the pharmacokinetics within the first critical post-transplant year and to identify a more appropriate way of monitoring drug exposure in clinical practice.


METHODS
A prospective pharmacokinetic study of tacrolimus was conducted in 100 de novo renal allograft recipients during the first year post-transplantation.


METHODS
Area under the concentration-time curve (AUC) blood samplings for tacrolimus were performed on days 7, 42, 90, 180 and 360 for all patients. Model-independent pharmacokinetic parameters for tacrolimus were calculated and dose-corrected when appropriate: AUC12, peak plasma concentration (Cmax), pre-dose trough concentration (C0), time to Cmax, average steady-state blood concentration, steady-state total body clearance, terminal half-life, volume of distribution and an estimate for tacrolimus bioavailability was derived from additional steady-state intravenous clearance data. The association between tacrolimus pharmacokinetic parameters and different clinical variables was evaluated on days 7, 42, 90, 180 and 360. The clinical variables were either donor-related (e.g. donor age), transplantation-related (e.g. delayed graft function), recipient-related (e.g. bodyweight), biochemical (e.g. serum albumin), therapeutic variables (e.g. corticosteroid dose) or disease variables (e.g. liver dysfunction).


RESULTS
Long-term tacrolimus dose-corrected exposure (AUC12, C0) is characterised by a late significant increase towards the end of the first year post-transplantation as the result of a significant increase in tacrolimus bioavailability (p < 0.05) and a slow decrease in tacrolimus steady-state clearance. Consequently, tacrolimus dose-requirements corrected for bodyweight decrease significantly in the first postoperative year (p < 0.05), in part because of the simultaneous tapering of the corticosteroid dose which significantly affects tacrolimus bioavailability (p < 0.05). Other clinical variables that significantly influenced tacrolimus administration, exposure and bioavailability in a time-related fashion were identified in this study (renal allograft function [p < 0.05], liver dysfunction [p < 0.05], diarrhoea [p < 0.05]), while the clinical relevance of other variables was considerably moderated by our findings (serum albumin, haematocrit). Time-unrelated variables proved to be of significant continuing clinical importance for tacrolimus dose-exposure pharmacokinetics throughout the first post-transplant year (recipient age [p < 0.05], gender [p < 0.01] and donor-receptor gender mismatch [p < 0.05]), while donor hypotension (p < 0.05) and cold ischaemia time (p < 0.05) also proved significant although at present the reasons for this are unknown. Finally, using multiple stepwise regression analysis we demonstrated that classical assessment of tacrolimus exposure by monitoring pre-dose trough blood concentration (or any other single concentration sampling timepoint) is not the most reliable method and that abbreviated AUC measurements may constitute a more accurate clinical tool for (therapeutic) monitoring of drug exposure.


CONCLUSIONS
Tacrolimus pharmacokinetics in the first year after renal transplantation are characterised by a specific time-dependent evolution. The identification of clinical variables that determine tacrolimus pharmacokinetics is an important aid in the development of reliable drug monitoring strategies using abbreviated AUC measurements.
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
Dirk R J
DR
Kuypers
Kathleen
K
Claes
Pieter
P
Evenepoel
Bart
B
Maes
Willy
W
Coosemans
Jacques
J
Pirenne
Yves
Y
Vanrenterghem
D000305:Adrenal Cortex Hormones / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000465:Algorithms; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors
D000305:Adrenal Cortex Hormones; D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus