Mechanism-based pharmacokinetic modelling of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients
Brenda CM de Winter(1), Ferdi Sombogaard(1), Reinier M van Hest(1), Teun van Gelder(1,2), Ron AA Mathot(1)
(1)Department of Hospital Pharmacy, (2)Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Introduction: Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent rejection in renal transplant recipients. MPA is mainly glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). Both drug are highly protein bounded, MPA for 97% and MPAG for 82%. Low plasma albumin levels, impaired renal function and coadministration of ciclosporin (CsA) are associated with increased clearance of total MPA (tMPA). Decreased tMPA exposure is correlated with a higher risk for acute rejection, whereas increased unbound MPA (fMPA) exposure may produce side effects.
Objectives: A mechanism-based population PK model was developed describing the relationship between dose and tMPA, fMPA, tMPAG and fMPAG and the influence of renal function, plasma albumin levels and cotreatment with CsA on this relationship.
Methods: tMPA, fMPA, tMPAG and fMPAG concentration-time profiles of renal transplant recipients cotreated with CsA (n=48) and tacrolimus (n=45) were analysed retrospectively using NONMEM.
Results: A 2- and 1- compartment model were used to describe the PK of fMPA and fMPAG, respectively. MPA and MPAG were allowed to competitively bind with albumine (bMPA and bMPAG). tMPA and tMPAG were modelled as fMPA+bMPA and fMPAG+bMPAG, respectively. In the model clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (p<0.001). In this situation the mechanistic model adequately described how increasing fMPAG concentrations decrease tMPA AUC due to displacement of MPA from the binding sites. With a MMF dose of 1000 mg and CsA cotreatment fMPA AUC decreased from 2.5 to 2.3 mmol*h/L and tMPA AUC from 69 to 56 mmol*h/L due to a decrease in CrCL from 50 to 10 mL/min. fMPA clearance remained unchanged. Albumine was correlated with the maximum number of binding sites available for MPA and MPAG (p<0.001). A decrease in plasma albumin levels from 0.5 to 0.4 mmol/L resulted in 27% reduction of tMPA AUC, whereas the reduction in fMPA AUC was less (8%). EHC, decreased due to CsA cotreatment (p<0.001), was modelled by transportation of fMPAG to the gall bladder.
Conclusion: A mechanistic PK model has been developed which describes the relationship between dose and both free and total MPA exposure. The model adequately describes the influence of renal function, plasma albumin and CsA co-medication. This model may be used to further explore the relationship between dose and both therapeutic efficacy and toxicity.
