Indications:Unspecified number of patients with ulcerative colitis.
TypeofStudy:Letters to the editor
FreeText:Comment on Sandimmun and reply. The study (Van Assche et al, Gastroenterology 125, 1018-1024, 2003) commented on in this letter was a randomized, double-blind trial comparing 2 intravenous (iv) doses of Sandimmun (4 mg/kg versus 2 mg/kg) in patients with severe ulcerative colitis (UC). The comment reflects on the following points: 1) The title was somewhat misleading: the basis of the study was not the use of different doses, but the attainment of 2 different blood level ranges (150-250 and 250-350 ng/mL) to find out the best safety profile during the 7-day infusion therapy. A comparison of the frequency of adverse events in the "4 mg/kg group" with that observed in the first famous Sandimmun study in severe UC conducted by Lichtiger et al who gave 4 mg/kg by continuous infusion, obtaining blood levels of 339 and 653 ng/mL, reveals appreciable differences in the frequencies of hypertension (9/38 versus 4/11) and of paresthesia (3/38 versus 4/11). Thus, the most important consideration is to keep the Sandimmun blood level within the narrow therapeutic range. 2) The authors of the letter doubt whether patients with severe UC should really be treated by iv infusions of Sandimmun instead of oral capsules of Sandimmun Neoral, although Van Assche et al stated that most patients with severe UC feel sick and may not be able to comply with taking Neoral capsules. The comment, in contrast, stresses the favorable pharmacokinetic parameters of Neoral . The authors own results showed that an oral dose of 4 mg/kg may also be effective and provide a good safety profile. They saw complete remission in 12/14 patients after 1 month, and only 1 patient was operated on during the 6-month follow-up. After the 7-day infusion period, Van Assche et al used an oral dose of 8 mg/kg over 3 months but did not publish any data on this oral phase of their study. 3) The comment emphasizes that the best safety and efficacy profile during Neoral therapy can be achieved by using 2 blood sampling times. The 0 and 2-hour (post-dosing) values provide a close correlation with the AUC whereas monitoring the 0-hour blood level alone is of very low predictive value. By using a markedly lower dose of Neoral as described earlier (dose not stated), the authors of the letter could achieve a therapeutic blood level of between 800 and 1200 ng/mL 2 hours post-dosing. The 0-hour level was the same (150-300 ng/mL) as that measured in Van Assche s "2 mg/kg intravenous group" or after the oral administration of 8 mg/kg. The letter draws the conclusion that there is no theoretical advantage in continuous iv infusion versus oral therapy. 4) In contrast to other findings, Van Assche et al suggested that smoking had an unfavorable effect on their severe UC group. The authors of the comment assume that the continuous iv administration of Sandimmun probably prevented the continuation of smoking and that therefore the abrupt withdrawal of nicotine may have been responsible for the poorer outcome in patients who used to smoke. In their reply, van Assche et al state that the authors of the comment had only open-label experience with Neoral in severe UC. Since no controlled trials with Neoral in this indication have been published it was and still is logical to investigate the optimal dosing of iv Sandimmun in severe UC. Moreover, the use of Neoral in non-controlled trials may introduce a selection bias toward patients with less severe UC symptoms. The therapeutic blood level margins discussed in the comment were developed to prevent organ rejection in transplant patients. Van Assche et al saw no better outcome in those of their UC patients who had blood Sandimmun levels at the upper end of the margin for transplant patients. Optimal therapeutic blood levels are not yet known for UC. The bioavailability of Neoral is "notoriously unpredictable". Van Assche et al agree that Neoral can be investigated as an initial therapy for severe UC but only in a randomized controlled trial with iv Sandimmun as the active comparator.
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