Clinical application of population pharmacokinetic methods developed for immunosuppressive drugs

After a brief overview of the relevant exposure indices for cyclosporine (CsA) and mycophenolate mofetil (MMF), as well as of the different steps necessary to develop maximum a posteriori Bayesian estimators (MAP-BE), this paper presents applications of MAP-BE for CsA or MMF to clinical cases and clinical trials. Ina renal transplant patient under CsA, grade I chronic allograft nephropathy was found at the sixth month posttransplantation, with CsA CO slightly above the target range and C2 markedly below; the AUCO0-12 h Bayesian estimate was quite high, at 5.6 mg h/L, as compared with a mean value of 4.3+0.9 mg.h/L in stable renal transplants at this period; the inconsistent C2 level found could be explained by delayed absorption of CsA in this patient, in which case C2 no longer represents the major part of the AUC. The patient was switched to sirolimus, which resulted in a slow and significant improvement of graft function with no acute rejection. In a 50-year-old female renal transplant recipient administered MMF and CsA and with a very favorable outcome otherwise, progressive anemia appeared 8 months posttransplantation. Clinical investigations were negative,but Bayesian estimation showed a rather high MPA AUCO0-12 h (69.8 mg h/L). After MMF dose reduction, hemoglobin level progressively returned to normal, without erythropoietin injection or blood transfusion. Finally, the feasibility of accurate dose adjustment using these MAP-BE is shown through preliminary results from 2 ongoing multicenter clinical trials, 1 evaluating an AUC-controlled cyclosporine-sparing strategy in stable renal transplants, the second evaluating the benefit of MMF therapeutic drug monitoring based on MPA AUCO0-12 h in de novo renal transplant recipients.