Cyclosporin therapeutic drug monitoring--an established service revisited.

Despite the routine application of therapeutic drug monitoring of cyclosporin (CsA) for two decades, there remain significant analytical issues. In addition, new developments have arisen in the delivery of this laboratory service as well as alternative clinical strategies for delivering optimal benefit to organ transplant recipients. Sample collection strategies are evolving away from the traditional pre-dose/trough (C0) sample in favour of estimates of the absorption phase in the first 4-6 hours after the oral dose of CsA. This is based on the recognition of the relatively poor relationship between C0 and CsA exposure indices, such as area under the blood CsA concentration versus time curve (AUC), especially in the first few hours after the dose. By collecting serial blood samples over this limited period (4 hr after the dose) and estimating the AUC(0-4), one can gain insight into how well CsA has been absorbed for each transplant recipient, and individualise CsA dosage. However, a recent survey of Australasian CsA laboratories revealed that such AUC(0-4) sampling strategies in the early post-dose period were poorly accepted in clinics across Australasia. The alternative that has proven to be more clinically acceptable is the use of a single sample 2-hours after the dose (C2). The C2 concentration has been demonstrated (particularly in kidney and liver transplant recipients) as correlating well with AUC(0-4), allowing it to be used as a surrogate index of CsA absorption and exposure. The laboratory survey also showed several areas of concern in the analytical sphere. The major one is that the majority of laboratories employ the two immunoassays that deliver the least specific result on C0 samples within the range of monoclonal methods, leading to high variability and clinically significant errors with patient samples. Laboratories have also adopted a range of dilution protocols for the significantly higher C2 concentrations, and this has proved a source of significant error. In addition, around 30% of laboratories were not involved in a proficiency-testing program. Thus there is clear opportunity to do much better analytically. Hence, there remain significant challenges ahead to deliver better quality CsA assay services and dosage individualisation to further improve outcomes for the organ transplant recipients that we care for.