Therapeutic drug monitoring of immunosuppressant drugs.

Individualizing a patient’s drug therapy to obtain the optimum balance between therapeutic efficacy and the occurrence of adverse events is the physician’s goal. However, achieving this goal is not always straight forward, being complicated by within and between patient variability in both pharmacokinetics and pharmacodynamics. In the early 1960s new analytical techniques became available allowing the measurement of the low drug concentrations seen in biological fluids during drug treatment. This offered the opportunity to reduce the pharmacokinetic component of variability by controlling drug therapy using concentrations in the body rather than by dose alone. This process became known as therapeutic drug monitoring (TDM) [1]. For a drug to be a suitable candidate for therapeutic drug monitoring it must satisfy the following criteria:- ✓ There should be a clear relationship between drug concentration and effect. ✓ The drug should have a narrow therapeutic index; that is, the difference in the concentrations exerting therapeutic benefit and those causing adverse events should be small. ✓ There should be considerable between-subject pharmacokinetic variability and, therefore, a poor relationship between dose and drug concentration/response. ✓ The pharmacological response of the drug should be difficult to assess or to distinguish from adverse events. The immunosuppressive drug cyclosporin satisfies all four of these criteria and, despite over 16 years of clinical use with therapeutic drug monitoring, there is still no firm consensus on the best way to use the drug. In addition, the number of available agents for use as immunosuppressants has more than doubled in recent years and the range of diseases in which these drugs are used has also widened [2]. The purpose of this review is to examine the current strategies in use for the therapeutic drug monitoring of immunosuppressant drugs [3] and to discuss some of the factors that impinge on the monitoring of these drugs. Azathioprine, steroids, anti-lymphocyte globulin, and OKT3 The combination of azathioprine and prednisolone was responsible for making clinical transplantation viable [4]. With the addition of anti-lymphocyte globulin [5] (ALG or ATG if human thymocytes instead of human lymphocytes are used to immunise the animal host) they formed the basis of immunosuppression in the early years of transplantation and these drugs are still in widespread use today. Monitoring the blood or plasma concentration of these drugs is not considered worthwhile as they all have relatively wide therapeutic indices. The three agents are generally given in fixed doses and are not subjected to therapeutic drug monitoring. However, a case can be made for the measurement of the activity of the enzyme thiopurine methyltransferase (TPMT) as an adjunct to azathioprine therapy [6]. Azathioprine is not directly immunosuppressive, since it must be metabolised first to 6-mercapto-purine, then by TPMT to 6-methyl-mercapto-purine and then on to the pharmacologically active 6-thioguanine nucleotides. The expression of the enzyme TPMT is inherited in an autosomal co-dominant fashion and consequently varies widely within the population [7] with 11% of the Caucasian population heterozygous and 0.3% homozygous with respect to TPMT deficiency [8]. Potentially fatal complications could be avoided if TPMT activity was monitored in erythrocytes [9]. The therapeutic drug monitoring of azathioprine in cancer chemotherapy is outside the scope of this article but has been reviewed recently in this journal by Lennard [10]. OKT3 (muromonab-CD3) is a mouse-monoclonal antibody directed against the CD3 complex on T cells [11]. When complexed with its antigen, the antibody prevents the initiation of signal transduction and blocks all T cell function [12]. In a pilot study using OKT3 serum concentrations as a guide to therapy in kidney transplant patients excellent results were reported for the prevention of early graft rejection [13]. Although there is a correlation between OKT3 concentration and T cell killing the relationship is complicated by the patients’ antibody response to murine-derived protein [14]. In another study using flow cytometry measurements to monitor OKT3 therapy the authors not only measured OKT3 concentration but also anti-OKT3 antibody concentration and the number of CD3+ cells (the therapeutic target of OKT3) [15]. Although the authors’ conclusions were positive about the use of flow cytometry for monitoring, their over all conclusions were that ‘this treatment cannot protect against acute cellular rejection due to the presence of a dimly positive CD3+ population’. In those centres using muromonab-CD3, TDM for OKT3 is not in widespread use.