Gatti G, Papa P, Torre D, Andreoni M, Poggio A, Bassetti M, Marone P
1st Department of Infectious Diseases, University of Genoa, Genoa, San Matteo Hospital, Pavia, Italy.
Antimicrob Agents Chemother. 1998 Aug;42(8):2017-23. doi: 10.1128/AAC.42.8.2017.
Rifabutin pharmacokinetics were studied by the population approach (NONMEM) with 40 human immunodeficiency virus-infected patients receiving rifabutin at different doses for prophylaxis or therapy of mycobacterial infections. A two-compartment open model with first-order absorption was used as the structural pharmacokinetic model. Parameter estimates were the absorption rate constant (0. 201/h), clearance/bioavailability (CL/F; 60.9 liters/h), volume of the central compartment/bioavailability (231 liters), intercompartmental clearance (60.3 liters/h), and volume of the peripheral compartment/bioavailability (Vp/F; 1,050 liters). The distribution and elimination half-lives were 1.24 and 25.4 h, respectively. The covariates tested for influence on CL/F and Vp/F were sex, age, weight, height, body surface area, tobacco smoking, drug addiction, alanine aminotransferase levels, creatinine clearance, total protein, bilirubin, numbers of CD4(+) cells, presence of diarrhea, cachexia index, rifabutin use (prophylaxis versus therapy), rifabutin dose, study site, and the concomitant administration of clarithromycin, fluconazole, phenobarbital, ciprofloxacin, azithromycin, or benzodiazepines. The only statistically significant effects on rifabutin pharmacokinetic parameters were a 27% decrease in Vp/F due to the concomitant administration of azithromycin and a 39% increase in Vp/F due to tobacco smoking. Such effects may be considered clinically unimportant. Our results confirm the lack of a correlation of rifabutin pharmacokinetic parameters with parameters of disease progression and gastrointestinal function. Also, the lack of a correlation with covariates which were previously found to be significant, such as concomitant fluconazole and clarithromycin use, may suggest that the effect of such covariates may be less important in the real clinical setting, in which several concomitant factors may influence pharmacokinetic parameters, with an overall effect of no apparent correlation.
采用群体药代动力学方法（NONMEM）对40例接受不同剂量利福布汀预防或治疗分枝杆菌感染的人类免疫缺陷病毒感染患者进行了利福布汀药代动力学研究。采用具有一级吸收的二室开放模型作为结构药代动力学模型。参数估计值为吸收速率常数（0.201/h）、清除率/生物利用度（CL/F；60.9升/小时）、中央室容积/生物利用度（231升）、隔室间清除率（60.3升/小时）和外周室容积/生物利用度（Vp/F；1050升）。分布半衰期和消除半衰期分别为1.24小时和25.4小时。检测的对CL/F和Vp/F有影响的协变量包括性别、年龄、体重、身高、体表面积、吸烟、药物成瘾、丙氨酸转氨酶水平、肌酐清除率、总蛋白、胆红素、CD4(+)细胞数量、腹泻情况、恶病质指数、利福布汀的使用（预防与治疗）、利福布汀剂量、研究地点以及克拉霉素、氟康唑、苯巴比妥、环丙沙星、阿奇霉素或苯二氮䓬类药物的联合使用。对利福布汀药代动力学参数唯一具有统计学显著意义的影响是，联合使用阿奇霉素导致Vp/F降低27%，吸烟导致Vp/F升高39%。这些影响在临床上可能被认为不重要。我们的结果证实利福布汀药代动力学参数与疾病进展参数和胃肠功能参数缺乏相关性。此外，与先前发现具有显著意义的协变量（如联合使用氟康唑和克拉霉素）缺乏相关性，可能表明这些协变量在实际临床环境中的影响可能较小，在实际临床环境中，多种伴随因素可能影响药代动力学参数，总体效果是无明显相关性。
