亚洲成人侵袭性真菌感染高危人群中静脉用泊沙康唑的 1b/3 期药代动力学和安全性研究。

Phase 1b/3 Pharmacokinetics and Safety Study of Intravenous Posaconazole in Adult Asian Participants at High Risk for Invasive Fungal Infections.

机构信息

Hematology Department, The First Affiliated Hospital of Soochow University, 296 Shizi Street, Cang Lang Qu, Suzhou, 215006, Jiangsu, China.

Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 30020, China.

出版信息

Adv Ther. 2022 Apr;39(4):1697-1710. doi: 10.1007/s12325-021-02012-1. Epub 2022 Feb 15.

DOI:10.1007/s12325-021-02012-1

PMID:35167031

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8989837/

Abstract

INTRODUCTION

Antifungal prophylaxis in patients at high risk for invasive fungal infections (IFIs), such as those with acute myeloid leukemia or myelodysplastic syndromes, continues to be underused in Asia, despite the fact that it reduces IFI-related death and increases IFI-free survival. We characterized the pharmacokinetics (PK) and safety of the intravenous (IV) formulation of posaconazole in adult Asian participants at high risk for IFI.

METHODS

Participants received posaconazole IV 300 mg twice on day 1, posaconazole IV 300 mg once daily on days 2-10, and posaconazole IV 300 mg once daily or oral suspension 200 mg 3 times daily for up to 18 days for a maximum of 28 days. There were two PK sampling groups: intensive and sparse. Sparse trough PK sampling was collected from all participants on days 3, 6, 10, 15, 22, and 28/end of treatment. The intensive PK group had additional sampling performed over 24 h on day 10. Primary end points were steady state average concentration (C) and percentage of participants with C ≥ 500 ng/mL. Safety was assessed up to day 30/end of treatment.

RESULTS

Seventy participants with acute myelogenous leukemia were enrolled, 30 in the intensive PK group and 40 in the sparse PK group; 57 participants completed the study, 26 in the intensive PK group and 31 in the sparse PK group. On day 10, arithmetic mean C was 2986 ng/mL [coefficient of variation (%CV), 36%; range, 1409-5930 ng/mL]; 100% of participants in the intensive PK group (n/N = 27/27) had C ≥ 500 ng/mL. Arithmetic mean (%CV) C was 2474 (50.4%) and 2466 ng/mL (42.4%) in the intensive and sparse PK groups on day 10, respectively. Safety was similar to that of previous posaconazole formulations.

CONCLUSION

In Asian participants at high risk for IFIs, IV posaconazole achieved the target exposure associated with efficacy that was previously established for supporting global registration of posaconazole for IV administration and was generally well tolerated.

CLINICAL TRIAL REGISTRATION

ClinicalTrials.gov, NCT03336502.

摘要

简介

尽管抗真菌预防治疗可降低侵袭性真菌感染（IFI）相关死亡率并提高IFI 无病生存率，但在亚洲，高危IFI 患者（如急性髓系白血病或骨髓增生异常综合征患者）的抗真菌预防治疗仍未得到充分应用。本研究旨在评估高危 IFI 亚洲成年参与者应用泊沙康唑静脉制剂的药代动力学（PK）和安全性。

方法

参与者接受泊沙康唑静脉滴注 300mg，每日 2 次，第 1 天共 2 次，第 2-10 天每日 1 次，第 11-18 天每日 1 次，或泊沙康唑口服混悬液 200mg，每日 3 次，共 28 天。有 2 个 PK 采样组：密集采样组和稀疏采样组。所有参与者在第 3、6、10、15、22 和 28 天（或治疗结束时）进行稀疏谷浓度 PK 采样。密集采样组在第 10 天进行额外的 24 小时采样。主要终点为稳态平均浓度（C）和 C≥500ng/mL 的参与者比例。安全性评估至第 30 天（或治疗结束时）。

结果

共纳入 70 例急性髓系白血病患者，其中 30 例入密集 PK 组，40 例入稀疏 PK 组；57 例患者完成了研究，其中 26 例入密集 PK 组，31 例入稀疏 PK 组。第 10 天，泊沙康唑的算术平均 C 为 2986ng/mL[变异系数（%CV）为 36%；范围为 1409-5930ng/mL]；密集 PK 组 27/27（100%）的参与者 C≥500ng/mL。第 10 天，密集 PK 组和稀疏 PK 组的泊沙康唑算术平均（%CV）C 分别为 2474（50.4%）和 2466ng/mL（42.4%）。安全性与先前泊沙康唑制剂相似。