Clinical Pharmacokinetics of Telithromycin, the First Ketolide Antibacterial
Clinical Pharmacokinetics of Telithromycin, the First Ketolide Antibacterial
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第一种酮内酯类抗菌药泰利霉素的临床药代动力学
DOI：
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发表时间：
2005
影响因子：
4.5
通讯作者：
V. Bhargava
中科院分区：
文献类型：
--
作者：
Jun Shi;G. Montay;V. Bhargava
泰利霉素是第一个酮内酯，它是一类与大环内酯类相关的新型抗菌剂，其结构修饰允许与细菌核糖体 RNA 双重结合，从而保留对具有大环内酯-林可酰胺-链霉素 B 耐药性的肺炎链球菌的活性。感染患者的临床经验表明，口服泰利霉素800mg，每日1次，连用5～10天，可有效治疗社区获得性上、下呼吸道感染。泰利霉素在人体中的吸收率估计≥90%。在进入体循环之前，泰利霉素经历首过代谢（主要通过肝脏）。其绝对生物利用度为57%，且不受食物影响。静脉滴注后泰利霉素的分布容积为2.9L/kg。泰利霉素 60-70% 与血清蛋白结合，并广泛扩散到一系列目标生物组织中，在整个给药间隔内达到针对主要呼吸道病原体的最低抑制浓度 (MIC) 以上的浓度。进入体循环后，泰利霉素通过多种途径消除（7%通过胆汁和/或肠道排泄，13%通过肾脏排泄，37%通过肝脏代谢）。泰利霉素通过细胞色素P450 (CYP) 3A4和非CYP途径代谢。与母体药物相比，所鉴定的代谢物显示出最小的抗菌活性。健康受试者每日一次服用泰利霉素 800mg，血浆峰浓度为 2.27 μg/mL。泰利霉素的血浆浓度随时间呈双相下降，多剂量给药后初始处置半衰期为 2.9 小时，最终消除半衰期约为 10 小时。每日一次给药后 2-3 天内即可达到稳态血浆浓度。正如对特殊患者群体（例如肝或肾功能不全患者）的研究结果表明，由于通过多种途径消除，当其中一种消除途径受损时，暴露量会小幅增加。对于严重肾功能不全的患者，建议减少剂量。伊曲康唑和酮康唑等强效抑制剂抑制 CYP3A4 导致泰利霉素血浆浓度-时间曲线下面积分别增加 54% 和 95%。泰利霉素抑制 CYP3A4 途径的潜力与克拉霉素相似。泰利霉素每日一次给药可能会限制药物相互作用的可能性以及临床上暴露量的显着增加。在 III 期临床试验中，泰利霉素 800mg 每日一次剂量已被证明可对社区获得性肺炎患者的肺炎链球菌、流感嗜血杆菌和金黄色葡萄球菌提供接近最大的抗菌活性。 总之，泰利霉素具有良好表征和可重复的药代动力学特征，其药代动力学/药效学关系支持 800mg 每日一次的口服给药方案。
Telithromycin is the first ketolide, which is a new class of antibacterial agents related to the macrolides that have structural modifications permitting dual binding to bacterial ribosomal RNA so that activity is retained against Streptococcus pneumoniae with macrolide-lincosamide-streptograminB resistance. Clinical experience in infectious patients has shown that oral telithromycin 800mg once daily for 5–10 days is effective for the treatment of community-acquired upper and lower respiratory tract infections. Absorption of telithromycin in humans is estimated to be ≥90%. Prior to entering the systemic circulation, telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg. Telithromycin is 60–70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation, telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism).Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent drug. In healthy subjects receiving telithromycin 800mg once daily, the peak plasma concentration achieved is 2.27 μg/mL. Plasma concentrations of telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2–3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of CYP3A4 by potent inhibitors such as itraconazole and ketoconazole results in a 54% and 95% increase in telithromycin area under the plasma concentration-time curve, respectively. The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin. The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the telithromycin 800mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia.In conclusion, telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800mg once daily.
影响因子：
3.6
作者：
E. Schuetz;W. T. Beck;J. Schuetz
通讯作者：
E. Schuetz;W. T. Beck;J. Schuetz
影响因子：
158.5
作者：
LINDENBAUM, J;RUND, DG;SAHA, JR
通讯作者：
SAHA, JR