C. Meaney,1 P. Sudchada,1 J. Consiglio,2 G. Wilding,2 R. Venuto,3 K. Tornatore1; 1School of Pharmacy and Pharmaceutical Sciences, Immunosuppressive Pharmacology Research Program, CBLS, University at Buffalo, Buffalo, NY, 2School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, 3School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY

BACKGROUND: Mycophenolic acid (MPA) area under the concentration-time curve (AUC) is recommended for therapeutic drug monitoring of renal transplant recipients (RTR) with no consideration of concurrent calcineurin inhibitor. The primary inactive metabolite, MPA glucuronide (MPAG), undergoes enterohepatic circulation (EHC) contributing up to 60% to MPA exposure and is rarely quantitated. We evaluated the relationship of cyclosporine (CYA) or tacrolimus (TAC) with MPA regimens on exposure of MPA and MPAG and presence of EHC in stable RTR.
METHODS: The MPA and MPAG 12-hour studies at steady-state were completed in 147 RTR on CYA + MPA (n=80) or TAC + MPA (n=67). Non-compartmental analysis quantitated AUC 0 to 12 hours (AUC0-12) for MPA and MPAG. EHC was characterized using standardized criteria as present or absent after absorption peak and MPA AUC 6-12 hours (AUC6-12). The groups were evaluated using general linear modeling.
RESULTS: RTR were 51±11 years old with eGFR 52±17ml/min/1.73m2. RTR on TAC + MPA regimen had increased MPA AUC0-12, AUC6-12 with lower MPAG AUC0-12 and MPAG AUC/MPA AUC ratio (Table). EHC occurred in 78% on TAC vs. 45% on CYA (p<0.0001).
CONCLUSION: In stable RTR, calcineurin inhibitor co-treatment appears to impact EHC of the primary metabolite, MPAG and alters exposure of the active immunosuppressant MPA.
MPA and MPAG Exposure
PK ParameterCYA+MPA (n=80)TAC+MPA (n=67)P-value
MPA dose (mg)693 ± 215570 ± 1790.0003
MPA AUC0-1241 ± 1869 ± 31<0.0001
MPAG AUC0-121509 ± 716905 ± 464<0.0001
MPAG AUC/MPA AUC41 ± 2014 ± 6.1<0.0001
MPA AUC6-1213 ± 7.226 ± 19<0.0001