*4.1.1.2. Area under the blood concentration-time curve (AUC)*

to be maintained within therapeutic range in order to achieve the optimal benefit of drug

The introduction of CsA in the early 1980s was immediately associated with an enhanced one year renal allograft survival; however, the argument for the therapeutic monitoring to optimize

Over the past two decades, there have been changes to recommended CsA dosing, changes in concomitant medications, and one major change to the oral drug formulation. Lately, there has also been the introduction of generic formulations of CsA [75]. In 1988, in a prospective study showed that although C0 (trough concentration) levels of CsA correlated poorly with dose, Cmax was significantly correlated with dose, Area Under the Curve (AUC) and elimi‐ nation half-life (t1/2). Those who suffered acute rejection had a significantly lower Cmax by 15– 31% [76]. The problem with this method for adjusting the dosage of CsA is that it relies on only one aspect of CsA pharmacokinetics, the predose or trough concentration. With the original formulation of CsA, Sandimmune®, this was the best practice, but during the conversion of patients from that formulation to the improved formulation, Neoral® the 2 h post-dose concentration has been advocated as a single concentration monitoring alternative to C0 [77]. The microemulsion formulation of CsA, Neoral®, makes CsA pharmacokinetics more predictable and reduces the effects of bile and food on absorption [78]. Nevertheless the predose concentration is still widely used in clinical practice. Currently, most transplant centers measure a single steady-state CsA concentration as either a C0 predose trough or 2 hours postdose, while some conduct multiple measurements to determine CsA AUC estimates [79]. The target predose concentrations varied not only with transplanted organ and time after transplant but also with the analytical method used. The therapeutic range of CsA used by clinicians varies greatly according to the type of assay used to measure CsA and whether blood

Thus, it has reported by high pressure liquid chromatography, monoclonal fluorescence polarization immunoassay (monoclonal TDx assay, Abbott Diagnostics®), or monoclonal radioimmunoassay (various manufacturers), the level of therapeutic concentrations in blood are 10-400 ng/mL. By high pressure liquid chromatography, monoclonal fluorescence polari‐ zation immunoassay (monoclonal TDx assay, Abbott Diagnostics®), or monoclonal radioim‐ munoassay (various manufacturers), the level of therapeutic concentrations in serum are 50-150 ng/mL. By polyclonal fluorescence polarization immunoassay (monoclonal TDx assay, Abbott Diagnostics®), or polyclonal radioimmunoassay (various manufacturers) the level of

efficacy and safety, has been discussed in the last 25 years and it is still debated [74].

therapy, rendering TDM necessary for these drugs.

324 Current Issues and Future Direction in Kidney Transplantation

**4.1. Cyclosporine (CsA)**

*4.1.1. Therapeutic monitoring*

*4.1.1.1. Trough concentration (C0) monitoring*

**4. Monitoring of individual immunosuppressive agents**

or serum concentrations are determined by the clinical laboratory.

The first steps towards the development of a more precise monitoring strategy for CsA resulted from the landmark studies by Lindholm and Kahan and Kahan et al., which identified a link between the pharmacokinetics of CsA and clinical outcomes in the individual transplant recipient [80,81]. The area under the concentration-time curve for CsA over a 12-hour drug administration interval (AUC0-12h) was a more precise predictor of graft loss and incidence of acute rejection than other parameters, including the C0. Since then, subsequent studies on the pharmacokinetics of CsA in renal transplant patients have identified that intrapatient varia‐ bility in AUC values over time was directly correlated with the risk of chronic rejection [77,82].

Proper calculation of AUC requires administration of a dose, followed by blood collection according to an intensive sampling strategy. Concentration values obtained are used to calculate AUC, usually by the trapezoidal method [78]. Some advantages of AUC monitoring are that it is the most precise indicator of drug exposure, can characterize abnormal absorption patterns, appears to be a predictor of clinical outcomes, generates a concentration-time profile, allows calculation of oral pharmacokinetic parameters, and reduces the problems associated with laboratory errors and single concentrations [74,83,84].

Despite its appealing potential advantages, the major disadvantage of AUC monitoring is its inherent need for multiple blood samples. The increased number of samples required, makes AUC monitoring impractical for routine clinical use, more expensive in the short term because of increased sample collection, analysis and interpretation of results, and inconvenient for patients, especially those in an outpatient setting [77,85]. AUC has been advocated as a better parameter to monitor than trough concentrations, because trough concentrations give no indication of exposure to CsA. For example, 2 patients could have the same trough concen‐ tration, but one could have a much lower AUC and, therefore, exposure to CsA. Unfortunately, AUC monitoring is not clinically feasible because of the added time, expense and inconven‐ ience required to collect a sufficient number of samples to properly calculate AUC. Although the full AUC for CsA has been demonstrated as being a sensitive monitoring tool, there may be an alternative approach to the determination of the degree and variability of CsA exposure in the individual patient [77,83].
