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Pharmacokinetic Therapeutic Drug Monitoring of Advagraf in More Than 500 Adult Renal Transplant Patients, Using an Expert System Online

Marquet, Pierre, MD, PhD*,†,‡,§; Bedu, Anne*,†,‡,§; Monchaud, Caroline, PharmD, PhD†,‡,§; Saint-Marcoux, Franck, PharmD, PhD*,†,‡,§; Rérolle, Jean-Philippe, MD§,¶; Etienne, Isabelle, MD; Kamar, Nassim, MD, PhD**,††,‡‡; Moulin, Bruno, MD, PhD§§; Cassuto, Elisabeth, MD¶¶; Essig, Marie, MD, PhD*,†,§,¶; Woillard, Jean-Baptiste, PharmD, PhD*,†,‡,§

doi: 10.1097/FTD.0000000000000503
Original Article

Background: Immunosuppressant Bayesian dose adjustment (ISBA) is an online expert system, routinely used by approximately 140 transplantation centers in the world for the dose adjustment of immunosuppressive drugs in transplant patients. This system determines the area under the curve (AUC) of the drug by pharmacokinetic modeling and Bayesian estimation. The purpose of this study was to analyze tacrolimus exposure after administration of its modified-release formulation (Advagraf) in kidney allograft recipients, to optimize its therapeutic drug monitoring.

Methods: This is a retrospective study of exposure indices measured locally [trough tacrolimus concentration (C0), C0/dose] or estimated through ISBA (AUC, AUC/dose, AUC/C0), of their evolution over posttransplantation time, and of the correlations between them.

Results: A total of 922 requests posted by 28 different centers for routine Advagraf adjustment in 530 different patients treated with Advagraf were studied. The exposure to, and dose requirement of, tacrolimus significantly increased across the first posttransplant months before reaching steady state. The AUC:C0 ratio (on which C0 monitoring is implicitly based) was stable across the different posttransplant periods, although with high interindividual variability. C0–AUC correlation was stronger in the late than in the early posttransplant period (r 2 = 0.75 versus 0.63; P = 0.0075). Using the regression equations obtained, AUC ranges corresponding to different applicable C0 target ranges were calculated to guide dose adjustment. When one of the doses recommended was administered, the following AUC was significantly more often in the predicted target ranges (P < 0.0001).

Conclusions: This study improves our knowledge of Advagraf pharmacokinetic variability and relations between exposure indices and the scientific background of the expert service provided through the ISBA Web site.

*University of Limoges, UMR 1248;

INSERM, U1248;

CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance;


CHU Limoges, Service de Néphrologie, Dialyse et Transplantation, Limoges, France;

Department of Nephrology, University Hospital, Rouen, France;

**Department of Nephrology and Organ Transplantation, CHU Rangueil;

††Université Toulouse III Paul Sabatier;

‡‡INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France;

§§Department of Nephrology and Organ Transplantation, Hôpital Civil, Strasbourg; and

¶¶Transplant Unit, University Hospital, Nice, France.

Correspondence: Pierre Marquet, MD, PhD, INSERM U1248, CBRS, Faculté de Médecine, Université de Limoges, 2 rue du Dr. Marcland, 87025 Limoges cedex, France (e-mail:

Supported by Limoges University Hospital, Limoges, France.

P. Marquet has received research grants and honoraria from Chiesi and Sandoz. The remaining authors declare no conflicts of interest.

Received December 06, 2017

Accepted February 27, 2018

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.