Pharmacokinetics of Mycophenolic Acid Administered 3 Times Daily after Hematopoietic Stem Cell Transplantation with Reduced-Intensity Regimen

Mycophenolate mofetil (MMF) is an immunosuppressive drug used as a prophylactic agent to prevent acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation (HSCT). After reduced-intensity conditioning (RIC) regimen, administration of MMF orally 3 times a day (tid) seems to be more beneficial than twice a day (bid). However, information regarding the pharmacokinetic (PK) parameters of mycophenolic acid (MPA), the active metabolite of MMF, administered in this regimen are very limited. We performed a prospective study in 15 patients for whom 3 sets of sampling were performed: at the beginning of the treatment, after 1 week, and after 1 month. Two consecutive 8-hour sets of sampling were performed at day 0 (D0) and D7. Plasma concentrations of MPA were quantified and areas under the curve for 8hours (AUC_0-8), and maximal and through concentrations were calculated. The results show that AUC_0-8 increases between the beginning of treatment and the end of the first week, but remains stable thereafter. Moreover, a trend to lower AUC_0-8 was observed for the patients who experienced GVHD ≥2 compared to those patients who did not. The other PK parameters are not associated with pharmacodynamic events. A limited sampling strategy with Bayesian estimators is currently under investigation to confirm these data and the role of D7 AUC_0-8 as a potential target of therapeutic drug monitoring (TDM).

key Words: Mycophenolate mofetil, Pharmacokinetics, Reduced-intensity hematopoietic cell transplantation, GVHD