Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects
| Autor: | Liyan Miao, Sheng Ma, Shiping Ma, Yicong Bian, Xiao Liu, Chenrong Huang, Hua Zhang, Zheming Gu, Yating Xiong, Zhenwen Yu, Pangke Yan, Yongyi Jiao |
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| Rok vydání: | 2020 |
| Předmět: |
Metabolic Clearance Rate
Sedation Metabolite Administration Oral Urine Pharmacology 030226 pharmacology & pharmacy Excretion Feces 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Humans Medicine Pharmacology (medical) 030212 general & internal medicine Adverse effect Anesthetics ADME business.industry Healthy Volunteers chemistry Pharmacodynamics Administration Intravenous medicine.symptom business |
| Zdroj: | British Journal of Clinical Pharmacology. 87:93-105 |
| ISSN: | 1365-2125 0306-5251 |
| DOI: | 10.1111/bcp.14363 |
| Popis: | Aims This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. Methods A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. Results The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. Conclusion HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose. |
| Databáze: | OpenAIRE |
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