New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine

Abstract

The calcineurin inhibitors cyclosporine and tacrolimus form the cornerstones of most immunosuppression protocols. Because of their variable pharmacokinetics, and their narrow therapeutic indices, post-transplant immunosuppressive drug monitoring is an essential part of patient care to minimize the risks of toxicity or acute rejection. Furthermore, a reduction in the rate of acute rejection has been shown to result in a lower rate of graft loss due to chronic rejection. The introduction of the microemulsion formulation of cyclosporine with its more consistent bioavailability has renewed interest in the use of alternative sampling strategies to the trough cyclosporine concentration. Both pharmacokinetic and pharmacodynamic considerations support the concept that determination of cyclosporine during the absorption phase (0–4 h) might offer a better prediction of cyclosporine immunosuppressive efficacy. Initial investigations suggest that monitoring a 2-h postdose concentration C₂ may provide a more efficacious alternative to trough monitoring for optimizing therapy with Neoral. Tacrolimus has a 10- to 100-fold greater in vitro immunosuppressive activity compared with cyclosporine. Consistent with its greater potency, therapeutic whole blood trough concentrations for tacrolimus are around 20-fold lower than the corresponding cyclosporine concentrations. The correlation between toxicity and tacrolimus trough concentrations appears to be stronger than that for acute rejection. The results from a concentration-ranging trial in primary kidney-transplantation and liver-transplantation trials all found a significant relationship between toxicity and tacrolimus trough levels. Azathioprine is converted in vivo to 6-mercaptopurine, which is subsequently metabolized to the pharmacologically active 6-thioguanine nucleotides. The latter are also responsible for the cytotoxic side effects. Reliance on blood counts to monitor azathioprine therapy can be misleading, and they do not provide information on immunosuppresive efficacy. More pertinent information can be obtained through the measurement of thiopurine S-methyltransferase activity and the quantification of intracellular 6-thioguanine nucleotides concentrations in red blood cells. Prospective studies have demonstrated the clinical utility of determining 6-thioguanine nucleotides to individualise immunosuppressive therapy with azathioprine not only in the field of transplantation, but also in inflammatory bowel disease.

Introduction

In recent years, improved knowledge of the immunologic mechanisms underlying transplant rejection, as well as the discovery of novel biologic and pharmaceutical agents, which selectively block various steps of the immune response, has enabled the effective control of graft rejection by the use of combined immunosuppressive therapy. The importance of a better control of acute rejection in the early post-transplant phase is underlined by the results from several studies [1], [2], [3]. The long-term data from two multicenter trials [1], [2] revealed that the rate of graft loss at 3 yr was around four times higher in those patients having at least one biopsy-proven rejection episode within the first 6 months of transplantation compared to those with none. In an analysis of all renal transplantations performed in the United States between 1988 to 1996 [3], clinical acute rejection within the first year after transplantation was found to have a detrimental effect on long-term graft survival. This held true for transplants from living donors as well as for cadaveric transplants. The authors concluded from their analysis that the reduction in the rate of acute rejection from 1988 to 1996 has resulted in lower rates of graft failure due to chronic rejection. They also suggested that the long-term toxicity of cyclosporine does not blunt its short-term benefit.

Presently, the calcineurin inhibitors cyclosporine and tacrolimus form the cornerstones of most immunosuppression protocols. Because of their variable pharmacokinetics, as well as their narrow therapeutic indices, post-transplant immunosuppressive drug monitoring is an essential part of patient care to maintain blood levels within the respective therapeutic ranges and thereby reduce the risks of toxicity or rejection. The original cyclosporine formulation was characterized by its unpredictable bioavailability and its highly variable pharmacokinetics. To overcome these problems, an oral microemulsion formulation was developed, which has an enhanced and more consistent bioavailability and a greatly improved dose linearity [4]. The introduction of this new formulation with its more consistent pharmacokinetic absorption profile has renewed interest in alternative monitoring strategies to the traditional trough monitoring of this drug.

Azathioprine is one of the oldest immunosuppressive drugs and has been in use for over 25 yr in clinical transplantation. This drug is now finding increasing use in the treatment of chronic inflammatory diseases. Advances in our understanding of the pharmacogenetic basis and molecular mechanisms underlying the immunosuppressive and toxic effects of azathioprine have led to the development of new monitoring strategies to individualize treatment with this drug.

This review will focus on some of the more recent developments with regard to the monitoring of these three immunosuppressants. Careful monitoring of these drugs is an essential part of patient management, to reduce the risk of their inherent toxicity and to lower the incidence of acute rejection in the early post-transplant phase, which will also lead to an overall long-term clinical benefit in terms of lower graft loss due to chronic rejection.