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Learning New Ways of Monitoring Neoral

The improved absorption and pharmacokinetic reproducihility ot Neoral is now leading to are-evaluation ot monitoring strategies for patients on treatment, with the aim ot further reducing the incidence of acute rejection. Traditionally trough levels have been the most convenient measurement hut evidence is emerging about the benetits of measuring peak concentration levels or of using abbreviated estimates ot the area under the time-blood cyclosporin A concentration curve (AUC). Given that monitoring patients using Creax or AUC measurements appears to be a better way torward tor achieving etfective immunosuppression with lower rejection rates than the traditional methods ot monitoring by trough level, there is now intense interest in establishing an accurate and practical approach to assessing Cmax and AUC levels. Studies in liver transplant patients have revealed reduced rejection rates ot 20 to 25 per cent in those patients who achieve high levels of Neoral in the  blood as measured by Cmax (peak concentration level) or AUC.

Neoral-treated patients with a Creax of at least 1 2CQngIhr/ml after five days, or a four hour AUC greater than 5050 units, have been identified as those at lowest risk of rejection (p=<0.03( (Figure 1) and there is no evidence of increased nephrotoxicity in these patients. Latest research in liver transplant patients suggests that 'limited 1200 sampling' of blood levels taken two hours after the morning dose I versus Cmax (C2) correlates closely with Cmax Ilantation and the AUC and has therefore been an accurate method of achieving optimal immunosuppressive dosage. A Canadian study of 31 stable liver transplant patients presented by Dr Marcello Cantarovich from Canada assessed the correlation between trough blood Neoral levels and levels taken one, two, three and four hours respectively after morning dosing. The study contirmed that among the individual data points C2 levels correlated more closely with AUC than either trough levels or those taken at one, three or tour hours after dosing.

The current focus of attention on optimising Neoral monitoring was addressed by an international consensus group meeting held in Vancouver in November 1997. Nine members from Canada, the USA and Furope met to discuss the new approaches to therapeutic drug monitoring such as limited sampling strategies. Summarising the conclusions of the consensus meeting, Prof Paul Keown from Canada said that the more consistent and reliable pharmacokinetics provided by the Neoral formulation of cyclosporin A have provided new impetus to explore and test more effective therapeutic drug monitoring methods for  optimising immunosuppression in the transplant recipient.

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Although there is no co'~sensus as yet to the ideal sparse sampling equation, options such as the two and  six hour or the zero and two hour combinations are being explored in well designed prospective studies. There may be opportunities to utilise single point sampling, such as C2, as an alternative monitoring method to the sparse sampling approach in liver transplant recipients. There is clearly a rationale for correlating peak' blood concentrations of cyclosporin A with optimising immunosuppression, but this method will require more rigorous testing before its value can be more fully assessed.

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" The improved absorption and pharmacokinetic reproducibility of Neoral is leading to a re-evaluation of monitoring strategies "

Finally, there are still many questions regarding the use of a single monitoring method in transplantation. A stratification of algorithms, based on the organ type, the patient population, eg paediatric or black, and time post-transplant, represent independent factors that require further investigation for application of sparse-sampling methods.