Changing the method of monitoring ciclosporin (Neoral) blood levels could help to reduce acute rejection in transplant patients, research reported this week suggests.
A new study, reported at the International Society for Organ Transplantation congress in Rome, found that measurement of peak ciclosporin blood levels instead of the traditional trough levels was associated with improved outcome.
The three-month study was conducted at 29 sites in the UK, Italy, Canada and Brazil, with 307 liver transplant patients. It compared clinical outcomes after monitoring at two hours postdose (C2) with trough level monitoring (C0).
Presenting the results, Mr Steve Pollard (consultant surgeon, St James's University hospital, Leeds), said that the study had been carried out to test the theory that peak levels might be a better indicator of ciclosporin immunosuppression than trough levels. Ciclosporin was initiated at 15mg/kg/day for 48 hours and then adjusted according to predefined C2 or C0 ranges (C2 850-1400ng/ml, C0 250-400ng/ml). All patients received steroids and the majority received azathioprine.
Mr Pollard reported that both groups had excellent graft survival but that among patients with biopsy proven acute rejection (22 per cent in C2 and 30 per cent in C0), there was a significant 36 per cent reduction in moderate/severe acute rejection in the C2 group (47 per cent compared with 73 per cent), indicative of good long-term prognosis. Safety profiles were similar in the two groups. "These results indicate that dosing based on drug absorption is a superior monitoring strategy to conventional trough sampling with no detrimental impact on safety," he said. Mr Pollard told The Journal on August 29 that the congress had also heard data on the successful use of C2 monitoring for renal transplant patients.
Monitoring C2 allowed better individualisation of dosage, to take account of inter-patient variability in absorption, he said. "This is a new way of using the drug that could have a huge impact on clinical outcome if the trial results are borne out in practice," he said. There would be logistic problems in arranging for clinics to measure peak rather than trough levels (which were measured just before a dose) but it was not impossible.
Dr Deplef Niese (global head of transplantation, immunology and clinical development, Novartis) told The Journal that C2 was a surrogate for peak levels (the actual peak could vary by 30 minutes or so). Trough levels were convenient to measure but it was now clear that the peak level was a better predictor of clinical efficacy. Trough levels did not predict the peak levels, particularly in the critical early days after transplantation. "We have now learnt a better way to measure how much drug is absorbed," he said.
Dr Niese said that Novartis was supporting research groups that were investigating C2 monitoring. "We believe this is optimal monitoring for the future," he said.