Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
Clinical Hospital for Infectious Diseases, Mirogojska, Zagreb, Croatia.
Int J Antimicrob Agents. 2015 Nov;46(5):576-81. doi: 10.1016/j.ijantimicag.2015.07.015. Epub 2015 Sep 3.
Cadazolid is under development as an oral treatment for Clostridium difficile infection (CDI), which is the most common infectious cause of antibiotic-associated diarrhoea. Low systemic cadazolid exposures were previously reported in healthy subjects following both single and multiple oral dosing. The main objective of this study was to investigate systemic cadazolid exposure in patients with severe CDI with potential disrupted lining of the gastrointestinal tract. A single 3000 mg oral dose of cadazolid was administered to six patients with microbiologically-confirmed severe CDI. Plasma and faeces were collected up to 144 h post-dose for determination of cadazolid concentrations. Safety assessments were conducted over the 144-h investigational period. Cadazolid was well tolerated in patients with severe CDI, with no reported drug-related adverse events. Cadazolid systemic exposure following a single 3000 mg oral dose was very low, with a peak plasma concentration (C(max)) of 2.64 ng/mL and an area under the concentration-time curve (AUC(0-144)) of 125 ng×h/mL. The median peak daily faecal cadazolid concentration was 5675 times the C. difficile MIC(90) of 0.25 mg/L. In subjects with severe CDI, cadazolid systemic exposure was very low following a single high oral dose. Cadazolid plasma concentrations were similar in magnitude to those previously reported for healthy subjects, whereas total systemic exposure was ca. 5-6 times higher, but was still low. Peak daily faecal cadazolid concentrations were 5675 times the 0.25 mg/L C. difficile MIC(90), and on Day 4 five of the six patients presented a daily faecal cadazolid concentration ≥1651 times the MIC(90) [ClinicalTrial.gov ID: NCT02053181].
卡他唑韦正在开发为一种治疗艰难梭菌感染（CDI）的口服药物，CDI 是抗生素相关性腹泻最常见的感染原因。先前报道健康受试者单次和多次口服给药后系统内卡他唑韦暴露水平较低。本研究的主要目的是研究胃肠道内衬受损的严重 CDI 患者的系统卡他唑韦暴露情况。6 例经微生物学证实的严重 CDI 患者单次口服 3000mg 卡他唑韦。给药后 144 小时内采集血浆和粪便以测定卡他唑韦浓度。在 144 小时的研究期间进行了安全性评估。严重 CDI 患者对卡他唑韦的耐受性良好，无药物相关不良反应报告。单次 3000mg 口服剂量后，卡他唑韦的全身暴露量非常低，Cmax 为 2.64ng/ml，AUC（0-144）为 125ng×h/ml。中位每日粪便卡他唑韦峰浓度是艰难梭菌 MIC90（0.25mg/L）的 5675 倍。在严重 CDI 患者中，单次高剂量口服后卡他唑韦的全身暴露量非常低。卡他唑韦的血浆浓度与先前报道的健康受试者相似，而总全身暴露量约为 5-6 倍，但仍较低。每日粪便卡他唑韦峰浓度是艰难梭菌 MIC90（0.25mg/L）的 5675 倍，在第 4 天，6 例患者中有 5 例每日粪便卡他唑韦浓度≥MIC90（0.25mg/L）的 1651 倍[临床试验编号：NCT02053181]。
