Pharmacokinetics- guided targeting of mycophenolate mofetil (MMF) in combination renal transplantation treatment confirms the need for dose reduction

Purpose To use a prospective population pharmacokinetic (PK) method, and Bayesian estimates of the AUC, to optimize mycophenolate mofetil (MMF) dosing in maintenance combination therapy after renal transplantation.

Methods The patient cohort of 27 adult (19/8 male/female) renal transplant recipients, studied, had MMF administered with methylprednisolone (Md) in combination with sirolimus (SRL – 6 patients), cyclosporine (CsA – 13 patients), tacrolimus (Tac – 4 patients), tacrolimus without Md (2 patients) or MMF with Md alone (2 patients). The study started several months posttransplantation when patients were stable with serum creatinine (mean [range]) 1.9 (1.0 – 4.0) mg/dL, and albumin 4.2 (2 – 5) mg/dL. A total of 111 blood samples were analyzed from predose troughs (C0), and 30 min (C₃₀) and 2 h (C₂) postdose, sampled from each patient, with 13 repeat occasions. A nonlinear mixed effects method (NONMEM) was used to build population pharmacokinetic (PK) priors for a two compartment oral absorption model with time lag, as patients entered the study, followed by Bayes estimation of individual patient PK parameters. Systemic clearance, CL, was used to titrate the dose for a putative target AUC (range) for MMF of 50 mg h/L (40 – 60 mg h/L). Demographic and biochemical variables were used for covariate modeling with the PK parameters.

Results The patients had, ages 41.5 (20 – 71) y and weights 68.8 (37 – 94) kg. Administered doses were 731.7 (250 – 1000) mg b.i.d., and AUC_0-12 of 63 (15.8 – 160.4) mg h /L. The bioavailability (F) – scaled NONMEM FOCE population PK parameters for MMF were (true value, interindividual coefficient of variation, CV%), for CL/F = 12.4 L/h (33%), central volume of distribution, V/F = 11.5 L (15%), intercompartmental clearance, Q = 20.2 L/h (45%), deep tissue volume of distribution, V3 = 208 L (CV% not estimated), absorption rate constant, ka = 2.27 h^-1 (CV% not estimated), and absorption time delay, Tlag = 0.35 h (CV% not estimated). The C0 and the C2 appear valid surrogates of the AUC, although the Bayes method is more reliable.

Conclusion Dosage was reduced overall in the patient group, after information from the population screen. TDM may be required for MMF in combination immunosuppression after renal transplantation.