Pharmacokinetic properties and safety profile of histamine dihydrochloride injection in Chinese healthy volunteers: a phase I, single-center, open-label, randomized study.
OBJECTIVE
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.


RESULTS
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, t½ was 0.50 and 1.02 hours; Tmax was 0.15 and 0.14 hours; mean Cmax was 26.59 and 71.01 nmol/L; AUC0-t was 8.35 and 20.43 nmol/h/L; AUC0-∞ 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, t½ was 0.58 and 0.66 hours; Tmax was 0.28 and 0.26 hours; mean Cmax was 17.01 and 23.54 nmol/L; AUC0-t was 7.72 and 17.08 nmol/h/L; AUC0-∞ 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.


CONCLUSIONS
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.
Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Jiapeng
J
Li
Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China.
Xiaojun
X
Huang
Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Qian
Q
Wang
Drug Clinical Trial Institute, Peking University People's Hospital, Beijing, China.
Shan
S
Jing
Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China.
Hao
H
Jiang
Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Zhongna
Z
Wei
Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Yannan
Y
Zang
Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Yang
Y
Liu
Department of Pharmacy, Peking University People's Hospital, Beijing, China. Electronic address: lb.zhao@163.com.
Libo
L
Zhao
Department of Pharmacy, Peking University People's Hospital, Beijing, China. Electronic address: phaseistudy@163.com.
Yi
Y
Fang
Department of Pharmacy, Peking University People's Hospital, Beijing, China.
Wanyu
W
Feng
D000328:Adult; D044466:Asian People; D002681:China; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006632:Histamine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D017442:Histamine Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry / Q000379:methods
D017442:Histamine Agonists; D006632:Histamine
Chinese; healthy volunteers; histamine dihydrochloride; pharmacokinetics; safety