Populatiefarmacokinetische meta-analyse van mycofenolzuur bij niertransplantatiepatiënten: Onderzoek naar oorzaken van de variabiliteit in blootstelling aan mycofenolzuur ter optimalisering van de dosis mycofenolaat mofetil

Objective and design: Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid. However, conflicting results have been reported about the influence of patient characteristics that explain the variability in mycophenolic acid exposure. This population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients was performed to explore the determinants of total mycophenolic acid exposure. Methods: 13,346 mycophenolic acid concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 years after transplantation. Concentration-time data were analyzed with nonlinear mixed effect modelling. Results: Exposure to total mycophenolic acid, as determined by mycophenolic acid clearance, significantly increased with improving renal function and increasing plasma albumin level as well as with decreasing ciclosporine pre-dose levels (p <0.001). These variables could explain 18% of the between-and 38% of the within-patient variability in mycophenolic acid exposure. Differences in mycophenolic acid exposure between patients with or without delayed graft function are likely to be caused by the effect of renal function on mycophenolic acid exposure. Conclusion: The clinical implication is that a change in renal function or plasma albumin level provides an indication for therapeutic drug monitoring as mycophenolic acid exposure may be altered. Patients in whom ciclosporine and mycofenolate mofetil are combined may need higher mycofenolate mofetil doses especially during the early phase post-transplant than currently recommended for optimal mycophenolic acid exposure.