多剂呼吸道合胞病毒（RSV）融合蛋白抑制剂 JNJ-53718678 在住院 RSV 感染婴儿中的药代动力学、安全性和抗病毒作用：一项随机 1b 期研究。

Pharmacokinetics, Safety, and Antiviral Effects of Multiple Doses of the Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitor, JNJ-53718678, in Infants Hospitalized With RSV Infection: A Randomized Phase 1b Study.

机构信息

Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, University of Santiago, La Coruña, Spain.

Quantitative Sciences, Janssen Research and Development, Beerse, Belgium.

出版信息

Clin Infect Dis. 2020 Dec 17;71(10):e594-e603. doi: 10.1093/cid/ciaa283.

DOI:10.1093/cid/ciaa283

PMID:32201897

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7744997/

Abstract

BACKGROUND

This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to ≤24 months.

METHODS

Patients categorized by age (cohort 1: ≥6 to ≤24 months; cohort 2: ≥3 to < 6 months; cohort 3: > 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction.

RESULTS

Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng × hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL.

CONCLUSIONS

In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed.

CLINICAL TRIALS REGISTRATION

NCT02593851.

摘要

背景

这项 1b 期研究评估了呼吸道合胞病毒（RSV）特异性融合抑制剂 JNJ-53718678（JNJ-8678）在年龄>1 至≤24 个月的住院 RSV 感染患者中的药代动力学、安全性和抗病毒作用。

方法

根据年龄将患者分为（队列 1：≥6 至≤24 个月；队列 2：≥3 至<6 个月；队列 3：>1 至<3 个月），每天口服 JNJ-8678 或安慰剂一次，持续 7 天。剂量增加遵循数据审查委员会的建议（队列 1：2/6/8/9mg/kg；队列 2：1.5/4.5/6mg/kg；队列 3：1/3/5mg/kg）。队列 1 包括 9mg/kg 剂量，因为较低剂量未达到目标暴露量。采用群体药代动力学模型评估稀疏的药代动力学样本。通过不良事件（AE）、实验室检查和心电图评估安全性。为了评估抗病毒作用，使用逆转录定量聚合酶链反应（qRT-PCR）随时间定量检测鼻拭子中的 RSV RNA 病毒载量。

结果

患者接受 JNJ-8678（n=37）或安慰剂（n=7）治疗。队列 1-3 中，最高剂量的药代动力学参数相似（第 7 天给药后 24 小时内的血浆浓度-时间曲线下面积（AUC）：分别为 35840、34980 和 39627ng×hour/mL）。报告了 2 例 3 级 AE（均为细支气管炎；1 例 JNJ-8678，1 例安慰剂），均报告为严重 AE；所有其他 AE 均为 1 级或 2 级。还报告了 2 例其他严重 AE（鼻炎[JNJ-8678]；肺炎[安慰剂]）。无死亡、4 级 AE 或导致停药的 AE。与安慰剂相比，JNJ-8678 治疗组第 3 天 RSV 病毒载量从基线的中位变化为-1.98 对数 10 拷贝/mL 至-0.32 对数 10 拷贝/mL。