Background: Mycophenolate mofetil (MMF) is used as an immunosuppressant for the treatment and prevention of graft-versus host disease (GVHD) in bone marrow transplantation (Nash et al 2005) and acute graft rejection in solid organ transplantation (Srinivas et al 2003). Mycophenolic acid (MPA) is the active metabolite of MMF. MPA displays variability in treatment response which supports the need for individualised dose regimens to optimize clinical outcomes. The present study aims to characterise the population pharmacokinetics of MPA and evaluate current dose regimens using accepted therapeutic drug monitoring targets in children and young people undergoing bone marrow, kidney and liver transplantation.
Methods: MPA concentrations (859) were measured in plasma samples collected from 38 patients (age: 5 months-20 years) who had received multiple doses of either intravenous infusion MMF or oral dose (10-15 mg/kg). A nonlinear mixed effect modelling approach implemented in the NONMEM (Ver 5.1.1) software was employed to characterise MPA population pharmacokinetics using first order conditional estimation with interaction (FOCEI) and identify influential covariates. Simulations (n=1000) were conducted to assess the ability of current dose regimens to maintain MPA AUC0-12 h between 30 and 60 mg.h/L which has been associated with reduced GVHD or an acceptable acute rejection rate.
Results: A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration-time data. Population mean estimates of clearance (CL), volume of distribution in the central (V1) and peripheral (V2) compartments, inter-compartmental clearance (Q), absorption rate (ka) and bioavailability (F) were 6.42 L/h, 7.24 L, 16.8 L, 3.74 L/h, 0.39 /h and 0.48, respectively. Inclusion of body weight and type of concomitant immunosuppressant (cyclosporine or tacrolimus) in the final pharmacokinetic model reduced the inter-individual variability in CL from 54% to 32%. Simulations revealed that the current dosing regimen may not be optimal for the prevention of GVHD or acute rejection in all patients. Over 9% or 27% of the patients weighing 25-50 kg achieved the target AUC after oral or intravenous infusion of MMF, respectively. Children with a body weight of 10 kg appeared to be relatively under-dosed and may be at a greater risk of acute rejection. Whereas with a higher body weight (50 kg) receiving intravenous infusion MMF administered concomitantly with tacrolimus may receive an inappropriately high dose and at greater risk of developing adverse reactions.
Conclusion: This validated population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation.
- Nash RA et al. Biol Blood Marrow Transplant. 2005; 11: 495-505.
- Srinivas TR et al. Expert Opin Pharmacother. 2003; 4: 2325-45.