USE OF MTOR INHIBITORS AND MPA I

H. Tedesco-silva¹, C. Sommerer², W. Arns³, F. Contieri⁴, D.M. Kuypers⁵, S. Vaidya⁶, K. Budde^7
1, Hospital do Rim e Hipertensao, Sao Paulo/BRAZIL, ²Department Of Nephrology, University of Heidelberg,, Heidelberg/GERMANY, ³Department Of Nephrology, Medical Clinic Ko¨ln-Merheim, Cologne/GERMANY, ⁴, Universidade Federal do Parana, Curitiba/BRAZIL, ⁵, University Hospitals of Leuven, Leuven/BELGIUM, ⁶Pk/pd, Translational Sciences, Novartis Institutes for Biomedical Research, East Hanover/NJ/UNITED STATES OF AMERICA, ⁷Medizinische Klinik, Universitätsklinik Charité, Berlin/GERMANY

Body: Introduction: Early adequate MPA exposure (AUC0-12 >30 µg.h/mL) is an important determinant for effective rejection prophylaxis in de novo renal transplant recipients (RTs). This study compared pharmacokinetics (PK) of MPA following intensified and standard EC-MPS dosing regimens in a sub-group of RTs in two 6-month, parallel-run studies, (ERLDE12 and ERL2419). Methods: RTs were randomized (1:1) to Intensified EC-MPS group (2880 mg/d for 2 wks; subsequently 2160 mg/d for 4 wks; 1440 mg/d thereafter) or Standard EC-MPS group (1440 mg/d) with CsA, steroids +/- anti-IL2R induction. MPA PK profiles were obtained on Day (D) 3, D10, D21, D42, D56 and D87. Steady state PK parameters (AUC0-12, Cmax, Cmin, Tmax and CL/F) were estimated by non-compartmental analysis. PK of MPA metabolites and free MPA were also assessed. Results: Demographics, baseline characteristics, steroid dosing, blood levels of CsA and compliance to EC-MPS dosing were comparable. MPA AUC0-12 >30 µg.h/mL at D3 was observed in 80% Intensified and 43% Standard patients. Selected PK parameters (mean SD) for pooled data are listed in the Table. The Intensified group exhibited approximately 33-47% greater AUC0-12 than Standard group in the first 6 wks post-Tx, with similar exposure thereafter. Mean AUC was statistically higher in the Intensified group at D3 (p<0.001), D10 (p=0.001), D21 and D42 (p<0.05 each). Tmax (median range 2.0-3.2h) was similar in both groups. Conclusions: The initially intensified EC-MPS dosing regimen of EC-MPS together with CsA was consistently associated with adequate MPA exposure from Day 3 post-Tx with 80% of patients already achieving AUC0-12 >30 µg.h/mL at this first timepoint. These results support the hypothesis that early adequate MPA exposure in RTs can be achieved with a higher starting dose which may translate into improved efficacy.

Disclosure: All authors have declared no conflicts of interest.