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Clinical application of population pharmacokinetic methods developed for immunosuppressive drugs

P. Marquet

Ann Transplant 2008; 13(1): 22-22 :: ID: 880176

Abstract

If the survival of patients within the first year post-grafting has been significantly improved over decades as a result of improvements in surgical techniques, immunosuppressive drugs and use of these drugs, little has been gained on graft survival in the long term. Also, 100% of renal transplant patients present chronic allograft nephropathy of grade I or more (Banff criteria) at 3 years post-transplantation. Interdose AUC is probably the best alternative to C0 for monitoring immunosuppressive drugs. However, classic estimation of an interdose AUC usually requires the collection and analysis of 8 to 12 blood samples. Several, and sometimes many, multiple linear regression equations based on 2-3 blood levels have been proposed for the AUC estimation of cyclosporine (CsA), mycophenolate mofetil (MMF) or tacrolimus (TAC), but they suffer from their relative intolerance to sampling time inaccuracy and are not generally accepted. Another approach is that of maximum a posteriori Bayesian estimation (MAP-BE) of individual pharmacokinetic parameters, based on an accurate pharmacokinetic model in the population of interest, on the distribution of these parameters in the population to which the patient belongs and on individual information, generally a few concentrations and possibly biometric and biological characteristics. Such MAP-BE have been developed for CsA, TAC, MMF and sirolimus (SRL) in different patient populations, as defined by graft type, age, associated drug and post-transplantation periods. Population pharmacokinetic (popPK) analysis is another approach, capable of identifying the individual biometric, biological, or pathologic covariates responsible for a part of the drug interindividual pharmacokinetic variability. It is also a way of generalizing Bayesian estimators to larger populations, encompassing different patient groups with different statuses or covariate values. The more the populations' characteristics are known, the more efficient Bayesian estimation can be. The feasibility of accurate dose adjustment of MMF and CsA using MAP-BE was demonstrated in two multicenter clinical trials, one evaluating an AUC-controlled cyclosporine-sparing strategy in stable renal transplants, the other evaluating the benefit of MMF therapeutic drug monitoring based on MPA AUC[sub]0-12h[/sub] in de novo renal transplant recipients. Several other trials based on AUC0[sub]-12h[/sub] Bayesian estimation of different immunosuppressants are on-going in kidney, liver and lung transplant recipients. These MAP-BEs have been made available to the transplantation community for the last 3 years through a website called ISBA (ImmunoSuppressant Bayesian dose Adjustment, at https://pharmaco.chu-limoges.fr/abis.htm). General statistics about the >8,000 requests received and results reported will be presented.

Keywords: immunosuppressive drugs, Cyclosporine, pharmacokinetic parameters

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358