Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics

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We present a 68-year-old male case, hemodialysis patient (body weight 56.8 kg) with Clostridium difficile (C. difficile) induced pseudomembranous colitis. The colitis was treated with orally administered vancomycin (VCM), 2.0 g/day, for 14 days leading to high serum levels. At this time, the VCM treatment was discontinued following negative stool cultures for C. difficile, and the serum VCM concentration was 58.7 μg/ml, the highest level in oral VCM case reports up to the present. Mean bioavailability was estimated as 16.8% during the VCM administration period in this patient, and it was assumed that the intestinal absorption of VCM was increased with severe colitis. As the serum VCM levels continued to decrease gradually, the symptoms of colitis improved. Nevertheless, the patient's colitis relapsed after oral levofloxacin treatment for bronchitis and high fever, although the serum VCM levels were still far greater than the minimum inhibitory concentration of C. difficile infection.
This finding suggests that VCM concentrations may remain insufficient in the colon despite the high serum levels. The high and persistent serum VCM concentrations in this patient may be due to the follow-ing: 1. increased absorption of VCM with severe colitis, 2. decreased excretion with renal impairment leading to VCM serum accumulation, and 3. too high a VCM dosage. We conclude that patients with both renal failure and severe intestinal disease may absorb and accumulate significant amounts of orally administered VCM. Therefore, a high dose oral VCM should be avoided in hemodialysis patients with severe pseudomembranous colitis.

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After notification of ICH-E5 guideline, the number of “bridging studies” has been increasing. By September 2002, 7 new chemical entities, for which a new drug application data package included data from a bridging study, have been approved by MHLW. Recently simultaneous global clinical development has been becoming more popular than bridging strategy for the development of new chemical entities in the world. Such a trend forces Japanese to join the worldwide clinical development and also to conduct single protocol multi-international sites studies. We have two experiences of one-protocol two international sites studies since 2001. From those experiences, three important points have been revealed in order to achieve a successful international clinical study: 1) To establish and to maintain a robust communication line, 2) To build reliability among study sites through the communication line, and 3) To prepare and to conduct the study by considering the clinical and cultural background of each individual study region.

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