药物代谢动力学和安全性研究：新型抗人巨细胞病毒药物乐特韦在肾功能损害患者中的应用。
Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment.
机构信息
AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
clinphase, Hanau, Germany.
出版信息
Br J Clin Pharmacol. 2017 Sep;83(9):1944-1953. doi: 10.1111/bcp.13292. Epub 2017 May 5.
AIMS
Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment.
METHODS
This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min 1.73m ), moderate (30-59 ml min 1.73m ) and severe (<30 ml min 1.73m ) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses.
RESULTS
All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUC and C ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUC 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; C 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R = 0.0662, P = 0.2249 and R = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R = 0.3548, P = 0.0021 and R = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups.
CONCLUSIONS
Renal impairment increased exposure to letermovir, although age was a confounding factor.
目的
人巨细胞病毒仍然是免疫功能低下患者的一个重大问题，而现有的病毒聚合酶靶向治疗与显著的毒性有关。因此，病毒端粒酶复合物抑制剂勒特莫韦正在开发中。我们评估了勒特莫韦在肾功能损害患者中的药代动力学。
方法
这是一项 I 期、开放标签、非随机试验。根据改良肾脏病饮食研究方程估计的肾小球滤过率（estimated glomerular filtration rate，eGFR）将 24 名受试者分为三组：肾功能正常（eGFR≥90ml/min·1.73m ）、中度损害（30-59ml/min·1.73m ）和重度损害（<30ml/min·1.73m ）。所有受试者均每日口服 120mg 勒特莫韦，连续 8 天，采集血样进行药代动力学分析。
结果
所有 24 名入组的受试者均完成了试验。与肾功能正常受试者相比，中度和重度肾功能损害分别使游离勒特莫韦分数增加了 11%和 26%。肾功能损害（AUC 和 C ）增加，与肾功能正常受试者相比，总勒特莫韦的 AUC 分别增加了 192%（143-258%）和 142%（83-243%），C 分别增加了 125%（87-182%）和 106%（75-151%）。清除率与肾功能正常受试者相比有所下降。相关性分析表明，肾功能下降与游离勒特莫韦浓度增加呈相关性（R = 0.5076，P<0.0001）。清除率与肾功能下降（R = 0.0662，P=0.2249 和 R = 0.1861，P=0.0353，总清除率和游离清除率）和年龄增加（R = 0.3548，P=0.0021 和 R = 0.3166，P=0.0042，总清除率和游离清除率）均存在相关性。多剂量 120mg 勒特莫韦在各组中均具有良好的耐受性。
结论
肾功能损害增加了勒特莫韦的暴露量，尽管年龄是一个混杂因素。
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