Tacrolimus and ciclosporin microemulsion in renal transplantation

Abstract

Author's reply Sir—Osemwegie Emovon and Barry Browne, as well as Arrigo Schieppati and colleagues claim that we compared subtherapeutic concentrations of ciclosporin with therapeutic concentrations of tacrolimus. This statement is not correct. The trough concentration range of ciclosporin we used in our study is that recommended throughout Europe in the manufacturer's datasheets. The concentrations were in the therapeutic range throughout the study (table), even in patients with acute rejections whose concentrations at the time of rejection were on average 231·5 ng/mL (SD 85·6).TableMean (SD) ciclosporin trough concentrations (ng/mL) in two trials of kidney transplantationMargreiter et alNashan et alBasiliximabPlaceboWeek 1277·9 (116·7)284·0 (232·3)293·1 (221·0)Week 2267·4 (105·5)268·6 (194·8)257·6 (215·1)Week 4262·0 (109·3)257·1 (207·9)260·8 (200·9)Month 3210·2 (67·0)189·7 (150·4)195·8 (166·6)Month 6192·8 (54·5)173·1 (125·6)157·6 (87·4) Open table in a new tab Moreover, ciclosporin trough concentrations were nearly identical to those noted in a Novartis-sponsored study (table), in which a rejection rate of 52·2% was noted in the ciclosporin group.1Nashan B Moore R Amlot P et al.Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients.Lancet. 1997; 350: 1193-1198Summary Full Text Full Text PDF PubMed Scopus (666) Google Scholar A study in the US showed an acute rejection rate of 49·1%.2Kahan BD Rajagopalan PR Hall M et al.Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody.Transplantation. 1999; 67: 276-284Crossref PubMed Scopus (463) Google Scholar These rates are similar to our ciclosporin rejection rate (51·3%). Thus, there no evidence of systematic overdosing the tacrolimus group or a systematic underdosing in the ciclosporin group. Schieppati and colleagues recommend maintaining ciclosporin blood concentrations between 330 and 430 ng/mL to keep acute rejection to a minimum. Any attempt to improve outcome after kidney transplantation is highly appreciated, but we think that patients need to be protected from such anachronistic concepts. Schieppati and colleagues also raise the issue of proper scientific conduct in clinical trials. Our trial fully adhered to guidelines from the International Conference on Harmonisation—Good Clinical Practice and European directives on good clinical practice. Because of the enormous logistics associated with large multicentre trials, they can obviously not be done without the support of the pharmaceutical industry. This is shown by the fact that, except for the first publication in 1970, many large multicentre studies in solid-organ transplantation have been sponsored by pharmaceutical companies. Jan Bruijn and Fokko van der Woude address the indications for biopsy and assessment of samples. In all large clinical trials in renal transplantation to date, rejection diagnosis has been based on biopsies that were clinically indicated. Our criteria for biopsy were discussed at various investigators' meetings and included a rise in serum creatinine of more than 20%, decline in urinary output, an increase in graft volume and vascular resistance, aggravation of hypertension, fever, tenderness of the graft, metabolic acidosis, or increased proteinuria. Biopsies were classified by the local histopathologists according to the Banff 93 criteria. Although intellectually more appealing, a central review seemed to be of limited clinical use, since treatment of rejection was based on histology. Furthermore, two previous trials that compared tacrolimus with the old formulation of ciclosporin revealed that the difference in the rate of biopsyproven rejection between the two groups remained essentially the same, irrespective of local or central reviewing.3Pirsch JD Miller J Deierhoi MH et al.A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation.Trasplantation. 1997; 63: 977-983Crossref PubMed Scopus (1018) Google Scholar, 4Mayer AD Dmitrewski J Squifflet J-P et al.Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection.Transplantation. 1997; 64: 436-443Crossref PubMed Scopus (629) Google Scholar Even if variability between centres cannot be ruled out, the conclusions drawn are fully warranted since within-observer variability may have affected both treatment groups in the same way: tacrolimus was more effective than ciclosporin in the prevention of acute rejection. Tacrolimus and ciclosporin microemulsion in renal transplantationIn their report of the European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation trial, Raimund Margreiter and colleagues (March 2, p 741)1 conclude that tacrolimus is significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation. Although we applaud the group's effort to address the important question of which calcineurin inhibitor is better after transplantation, we think the study design is fatally flawed. Full-Text PDF Tacrolimus and ciclosporin microemulsion in renal transplantationThe pharmaceutical company involved in the clinical trial design of Raimund Margreiter and colleagues' study1 produces tacrolimus, which the investigators conclude is better than ciclosporin microemulsion in preventing acute rejection after renal transplantation. Full-Text PDF Tacrolimus and ciclosporin microemulsion in renal transplantationRaimund Margreiter and colleagues1 base their conclusion on a prospective study involving 50 centres in seven European countries. Full-Text PDF