Beringer Paul, Huynh Kitty My Tu, Kriengkauykiat Jane, Bi Luke, Hoem Nils, Louie Stan, Han Emily, Nguyen Thao, Hsu Donald, Rao Purush A, Shapiro Bertrand, Gill Mark
University of Southern California, School of Pharmacy, 1985 Zonal Ave., Los Angeles, California 90033, USA.
Antimicrob Agents Chemother. 2005 Dec;49(12):5013-7. doi: 10.1128/AAC.49.12.5013-5017.2005.
Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h(-1); P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h(-1); P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 +/- 6.0 mg/liter) far exceeded the maximum serum drug concentration ( approximately 50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.
铜绿假单胞菌引起的慢性肺部感染是囊性纤维化（CF）患者发病和死亡的主要原因。大环内酯类抗生素具有免疫调节和抗毒力活性。阿奇霉素在CF患者中的临床试验表明，其肺功能有显著改善，住院次数减少。本研究的目的是比较CF患者和对照组中阿奇霉素的药代动力学（PK）。该研究作为一项开放标签、平行、两阶段交叉研究进行，涉及12名健康志愿者和12名CF患者。第1阶段检测单次口服和静脉给药后的血清PK，而第2阶段检测多次口服给药后的细胞内PK。CF受试者与对照组相比，体重（53.1对71.0 kg；P<0.01）和体重指数（19.7对23.2；P<0.01）分别有显著差异。92%的CF患者存在胰腺功能不全并正在接受胰酶治疗。CF患者和对照组的吸收速率（达到最大血清药物浓度的时间，3.0对3.0小时；P = 0.78）和吸收程度（绝对生物利用度，34.2对42.8%；P = 0.37）相似。健康志愿者的药物向组织的分布（药物从中央室向外周室的转移速率，1.22对0.759 h(-1)；P = 0.03）和消除（从中央室的消除速率，0.693对0.492 h(-1)；P<0.01）分别比CF受试者更快。单核细胞浓度（15.2±6.0 mg/升）远远超过最大血清药物浓度（约50倍），表明有显著的细胞内蓄积。这些结果表明，服用胰酶的CF患者无需改变阿奇霉素的剂量。
