Pharmacokinetic Properties and Safety Profile of Histamine Dihydrochloride Injection in Chinese Healthy Volunteers: A Phase I, Single-center, Open-label, Randomized Study

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• 作者：Jiapeng Li ; MS¹ ; Xiaojun Huang ; MD² ; Qian Wang ; BN¹ ; Shan Jing ; MD³ ; Hao Jiang ; MD² ; Zhongna Wei ; MS¹ ; Yannan Zang ; MS¹ ; Yang Liu ; MS¹ ; Libo Zhao ; PhD¹ ; ^{lb.zhao@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yi Fang ; PhD¹ ; ^{phaseistudy@163.com" class="auth_mail" title="E-mail the corresponding author} ; Wanyu Feng ; PhD¹
• 关键词：Chinese ; healthy volunteers ; histamine dihydrochloride ; pharmacokinetics ; safety
• 刊名：Clinical Therapeutics
• 出版年：2015
• 出版时间：1 October 2015
• 年：2015
• 卷：37
• 期：10
• 页码：2352-2364
• 全文大小：258 K

文摘

Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell−derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs).

Methods

In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs.

Findings

No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t_½ was 0.50 and 1.02 hours; T_max was 0.15 and 0.14 hours; mean C_max was 26.59 and 71.01 nmol/L; AUC_0−t was 8.35 and 20.43 nmol/h/L; AUC_0−∞ was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t_½ was 0.58 and 0.66 hours; T_max was 0.28 and 0.26 hours; mean C_max was 17.01 and 23.54 nmol/L; AUC_0−t was 7.72 and 17.08 nmol/h/L; AUC_0−∞ was 9.01 and 19.62 nmol/h/L; accumulated amount excreted in urine within 24 hours was 331.7 and 583.21 nmol; and maximum urine excretion rates were 53.29 and 133.53 nmol/h, respectively.

Implications

Both single-dose 0.5 mg and 1.0 mg HDC were well tolerated in Chinese HVs, and the pharmacokinetic profile of HDC in Chinese HVs was characterized in this study. A single dose of 1.0 mg HDC had a more rapid but similar extent of absorption, a wider distribution, and a little more rapid elimination in Chinese HVs compared with Western HVs. Findings from this study support additional clinical trials for HDC using in Chinese patients. Chinese Clinical Trial Registry identifier: ChiCTR-ONC-13003954.