Randomised trialomania? The multicentre liver transplant trials of tacrolimus
Authors: T.E Starzl, J.J Fung, J.P McMichael, S Todo, A Donner, M Eliasziw, L Stitt, P Meier
Journal: The Lancet (1995)

In 1989-90 our group reported that tacrolimus (FK 506) could systematically control liver allograft rejection that had been intractable despite conventional cyclosporin-based immunosuppression.1,2 The “rescued” patients were maintained on tacrolimus, and manifested no unique or unexpected toxicity. Consequently, a pilot trial was begun in which tacrolimus was substituted for cyclosporin from the time of operation. By early 1990, nearly 200 liver, kidney, and other kinds of organ recipients who had been entered had superior actuarial survival, lower requirement for prednisone, and better quality of life than observed in our past experience.3,4 The upgrading of outlook after liver transplantation3 was as obvious as when cyclosporin succeeded azathioprine as the baseline immunosuppressant a decade before.5 By November, 1993, 1391 primary liver-transplant recipients had been treated in Pittsburgh with the new drug.6 Only 35 (2·5%) of the patients crossed over from tacrolimus to cyclosporin and 15 of these changed back when rejection supervened.

The keystone management principle
The new drug was user friendly. As with all previous baseline immunosuppressants,7-9 the management secret with tacrolimus was administration of doses up to the limit imposed by the drug's toxicity. Dose-manoeuvrable prednisone or other adjuvant agents were then added as needed to control or reverse rejection, or given prophylactically. Because the dose-limiting side-effects of cyclosporin10 and tacrolimus3,4,11,12 were the same (nephrotoxicity, neurotoxicity, and diabetogenicity), these organ-system-specific toxic manifestations could be used from the first day of treatment to determine dose ceilings; the occurrence of rejection helped to establish the floor. The folly of making invidious toxicity comparisons between cyclosporin and tacrolimus when the scales could be tilted one way or the other by ratcheting the doses up or down was self-evident.12 The only adverse effects observed exclusively with one but not the other drug were dose-related hirsutism, gingival hyperplasia, and facial brutalisation with cyclosporin.10

It was easy, as it had been a decade earlier with cyclosporin,13 to deduce the meaning of trough plasma and blood concentrations (the plasma/blood ratio was about 0·1) and to relate these to toxic manifestations, rejection, and the preceding tacrolimus dose. When we realised that the first Pittsburgh patients had been overdosed, this was corrected in subsequent cases within a few postoperative days or hours by responding to the clinical events with flexible dosing. Nevertheless, we had lowered both the starting intravenous and oral doses in Pittsburgh by January, 1990;12 subsequently these were reduced again.14

These were important revisions no matter what the transplanted organ but especially so with the liver because the metabolism of tacrolimus is more dependent than that of cyclosporin on good hepatic function. 12,15,16 In addition, absorption of tacrolimus is little disturbed compared with that of cyclosporin by the absence of bile or by intestinal disorders. 15 These and other details of the pharmacokinetics of tacrolimus, dose ranges, appropriate management strategies, and adverse events were well worked through by the time of meetings to organise multicentre trials in March, 1990. 3 weeks later, the same data were presented to the American Surgical Association (on April 5, 1990) and a manuscript was published 5 months later on the eve of the multicentre trials.