PII-105 - EFFECT OF P-GLYCOPROTEIN INHIBITION ON TWO TACROLIMUS FORMULATIONS: A RANDOMIZED, 4-SEQUENCE, CROSS-OVER, DRUG-DRUG INTERACTION STUDY

F. LEMAITRE^1,2,3, C. Tron⁴, F. Lainé⁵, S. Lalanne⁶, B. Franck⁶, M. Ferrand-Sorre⁷, S. Connan-Perrot⁸, M. Verdier⁹, B. Laviolle¹⁰; ¹Rennes University Hospital, Rennes, France, Rennes, France, ²INSERM IRSET UMR_S 1085, Rennes, France, ³FHU SUPORT, Rennes, France, ⁴Rennes University Hospital, Rennes, France, ⁵CHU de Rennes, Rennes University Hospital, France, France, ⁶CHU de Rennes, Rennes University Hospital, Rennes, France, ⁷INSERM, Rennes University, Rennes, France, France, ⁸INSERM, Rennes University, Rennes, France, ⁹CHU de Rennes, Rennes University Hospital, France, ¹⁰Rennes University Hospital, Rennes University Hospital, Rennes, France.

Background: Tacrolimus, the pivotal drug for graft rejection prevention in solid organ transplantation, is a P-glycoprotein (P-gp) substrate. The drug exists under multiple formulations, notably two extended-release (ER) formulation allowing once daily intake. Because, P-gp is differently expressed along the digestive tract and the two ER tacrolimus have distinct absorption sites, the influence of P-gp inhibitors can be different between the different formulations.

Methods: The DIPLOID study is a randomized, 4-sequence, cross-over, drug-drug interaction (DDI) study aiming at comparing the blood and intracellular (peripheral blood mononuclear cells expressed in pg/1,000,000 PBMC) pharmacokinetic parameters of two ER tacrolimus (Advagraf or ER-TAC and Envarsus or LCP-TAC) when administered alone or with a P-gp inhibitor (Verapamil) in 20 healthy volunteers. Geometric mean ratio (GMR) and their 90% confidence interval (CI90%) were compared between the two formulations.

Results: GMR and CI90% of the area under the curve of tacrolimus blood concentrations over dose (AUC0-24h/D) of ER-TAC with and without verapamil was 1.67 [1.52-1.83], while it was 1.33 [1.21-1.45] with LCP-TAC. The GMR and CI90% of the peak concentration over dose (Cmax/D) was 1.51 [1.32-1.71] for ER-TAC and 1.28 [1.10-1.45] for LCP-TAC. Finally, GMR and CI90% of tacrolimus trough concentration over dose (Cmin/D) was 1.69 [1.34-2.03] for ER-TAC and 1.18 [0.93-1.43] for LCP-TAC. Regarding intracellular concentrations, GMR and CI90% of PBMC AUC0-24h/D was 1.68 [1.43-1.83] and 1.42 [1.36-1.48] for ER-TAC and LCP-TAC, respectively. GMR and CI90% for PBMC Cmax/D were 1.74 [1.55-1.93] and 1.50 [1.41-1.59] for ER-TAC and LCP-TAC, respectively.

Conclusion: This randomized DDI study shows a lower DDI magnitude for blood and intracellular tacrolimus with the P-gp inhibitor verapamil for LCP-TAC than ER-TAC. Due to its absorption profile, LCP-TAC may be less likely to be influenced by the inhibition of the P-gp efflux pomp and might be a better option when the drug is combined with a P-gp inhibitor. In such a context, the two drugs cannot be used interchangeably.