Pharmacokinetic modelling of the plasma protein binding of mycophenolic acid in renal transplant recipients

Background and Objectives: Renal function and the plasma albumin concentration have been shown to correlate with clearance of total mycophenolic acid (MPA). The hypothesis for the underlying mechanism is that low plasma albumin concentrations and accumulation of the glucuronide metabolite of MPA (MPAG) decrease the binding of MPA to albumin. The subsequent increase in the unbound fraction (fu) of MPA (MPAu) produces an increase in total MPA (MPAt) clearance. This study aimed to develop an empirical population pharmacokinetic model to describe the relationships between renal function and albumin concentration and MPAG, MPAuand MPAt, in order to provide insight into the mechanism by which renal function and plasma albumin affect the disposition of MPA. Methods: 774 MPAt, 479 MPAuand 772 total MPAG (MPAGt) plasma concentrations were available from 88 renal transplant recipients on days 11 and 140 after transplantation. Data were analysed using non-linear mixed-effects modelling. Results: Time profiles of MPAuand MPAGtconcentrations were adequately described by two 2-compartment pharmacokinetic models with a link between the central compartments, representing the glucuronidation of MPAuto form MPAG. MPAtconcentrations were modelled using: [MPAt] = [MPAu] + [MPAu]• θpb, with [MPAu] • θpbrepresenting the bound MPA concentration, where [MPAt], [MPAu] and θpbrepresent MPAtconcentration, MPAuconcentration and a factor that correlates to the total number of protein binding places, respectively. According to this equation, fu= [MPAu]/[MPAt] = 1/(1 + θpb) • θpb, and therefore [MPAt], was significantly and independently correlated with creatinine clearance (CLCR), the plasma albumin concentration and the MPAGtconcentration (all p < 0.001). A reduction in CLCRfrom 60 to 25 mL/min correlated with an increase in fufrom 2.7% to 3.5%, accumulation of MPAGtconcentrations from 50 to 150 mg/L correlated with an increase in fufrom 2.8% to 3.7%, and a decrease in plasma albumin concentration from 40 to 30 g/L correlated with an increase in fufrom 2.6% to 3.5%. No significant correlations were detected between MPAuclearance and the plasma albumin concentration or CLCR. Conclusion: The model shows that low CLCR, low plasma albumin concentrations and high MPAG concentrations decrease MPAtexposure by affecting MPA binding to albumin.

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