Population Pharmacokinetics of Mycophenolic Acid in Haploidentical Transplant Recipients Receiving Post-Transplant Cyclophosphamide Based GvHD Prophylaxis

Post-transplant Cyclophosphamide (PTCy) based Graft versus Host disease (GvHD) prophylaxis has improved the success of Haploidentical transplantation (HaploHCT) in recent years. Therapeutic drug monitoring (TDM) of Mycophenolic acid [MPA-active metabolite of Mycophenolate Mofetil (MMF)] has proved beneficial in solid organ transplantation; however, there are no TDM recommendations in the HCT setting yet. In the present study, we sought to create a population pharmacokinetic (POPPK) model of oral MMF in haploidentical HCT recipients receiving PTCy/MMF/CyclosporineA (CsA) based GvHD prophylaxis and to evaluate the feasibility of TDM by assessing the impact of MPA exposure on clinical outcomes.

Thirty-six patients with various underlying diagnoses who underwent HaploHCT between October 2021 and June 2022 were enrolled. All patients received GvHD prophylaxis comprising of Cyclophosphamide (I.V. 50 mg/kg/day x 2days (day+3 & +4) and i.v. Cyclosporine (2.5mg/kg; Q12H) with oral MMF (15 mg/kg; Q8H) from day +5 post HCT. Plasma was separated from the peripheral blood collected at predetermined time points at day+8 post HCT. Plasma MPA was analyzed using a validated HPLC-UV method, and the concentration was expressed as ug/ml. MPA PK was estimated using nonlinear mixed effects modeling via Monolix (version 2021R2). The covariates tested for MPA PK were: age, sex, body weight, BSA, and Creatinine clearance. The PK parameters AUC, CL, V, and k were estimated on day+8 for MPA. The influence of MPA PK on GvHD and graft rejection was assessed by the Mann-Whitney test (GraphPad Prism 8).

MPA levels were available for thirty-one patients. A one-compartment model with first-order absorption best described MPA PK. We observed a 5-fold inter-individual variation (IIV) in MPA exposure. None of the covariates explained IIV in MPA PK. Two patients died before engraftment, while graft rejection was noted in 3 patients (1 primary and 2 secondary). Fifteen patients experienced acute GvHD, and there were nine deaths (25%) at the last follow-up of 3.7 ± 2.4 months. Interestingly, POPPK analysis revealed that all the 31 patients had MPA underexposure [Median: 14.1 (4.5 – 24.0)ug*hr/ml lesser than the lower limit of the therapeutic range of 30ug*hr/ml]. No associations were observed with clinical outcomes, including acute GvHD (p=0.8) or graft rejection (p=0.6). The MPA underexposure in the present study could be attributed to potential drug-drug interaction (DDI) with concomitant CsA administration that inhibits MRP2-mediated enterohepatic circulation causing decreased systemic MPA exposure. Numerous transplant centers across the globe use cyclosporine and tacrolimus interchangeably (Ruggeri et al. TCT 2020). However, the available retrospective data comparing the two calcineurin inhibitors appears to be conflicting (Castagna et al. BMT 2016, de Lima VJT et al. Ann Hematol 2022).

On the PTCy platform for haploidentical transplantation, our results highlight that concomitant administration of CsA reduces systemic exposure of MPA. The impact of this effect on the clinical outcomes needs to be studied further and may potentially affect the choice of the calcineurin inhibitor for the PTCy platform.