Hongxian Pang1,2, Wei Xue2, Aixin Shi3, Min Li2, Yang Li2, Guoying Cao2, Bei Yan2, Fan Dong2, Wei Xiao4, Guorong He5, Guanhua Du5, Xin Hu2, Gang Cheng6. 1. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, People's Republic of China. 2. Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Department of Pharmacy, Beijing Hospital, No.1 Dahua Road, Beijing, 100730, People's Republic of China. 3. Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Department of Pharmacy, Beijing Hospital, No.1 Dahua Road, Beijing, 100730, People's Republic of China. aixins0302@126.com. 4. State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical CO.LTD, Jiangsu, People's Republic of China. 5. Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People's Republic of China. 6. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, People's Republic of China. chenggang63@hotmail.com.
Abstract
BACKGROUND AND OBJECTIVES:Baicalein, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, is a neuroprotective agent under development to treat Parkinson's disease. This study investigated the pharmacokinetics, safety and tolerability of baicalein after a multiple-ascending-dose protocol in healthy Chinese volunteers. METHODS: In this single-center, double-blind, placebo-controlled, parallel-group study, participants were randomized to receive baicalein (n = 8 per dose regimen) or placebo (n = 2 per dose regimen). Dosing regimens were 200, 400, and 800 mg once daily on days 1 and 10, twice daily on days 3-9. Plasma, urine, and feces samples were assayed for baicalein and its predominant metabolite baicalin using validated HPLC-MS/MS methods. Pharmacokinetic parameters were computed using standard non-compartmental analysis. Dose proportionality was assessed with a method combining equivalence criterion and power model. Drug safety and tolerability were assessed by monitoring adverse events and laboratory parameters. RESULTS:Thirty-three of 36 enrolled participants completed the study. A total of 44 adverse events occurred in 23 participants. A steady-state concentration of analytes in plasma was achieved on day 8 after repeated dosing. Analytes concentrations and exposure increased with increasing dose. The dose proportionality constant (β) for AUCss of baicalein and baicalin was 0.922 (90 % confidence interval, 0.650-1.195) and 0.942 (90 % confidence interval, 0.539-1.345), respectively. The accumulation index varied from 1.66 to 2.07 for baicalein and from 1.68 to 2.45 for baicalin. CONCLUSION: In dose range of 200-800 mg, multiple-dose oral baicalein administration was safe and well tolerated, dose proportionality was inconclusive, and no serious accumulation of baicalein was observed.
RCT Entities:
BACKGROUND AND OBJECTIVES:Baicalein, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, is a neuroprotective agent under development to treat Parkinson's disease. This study investigated the pharmacokinetics, safety and tolerability of baicalein after a multiple-ascending-dose protocol in healthy Chinese volunteers. METHODS: In this single-center, double-blind, placebo-controlled, parallel-group study, participants were randomized to receive baicalein (n = 8 per dose regimen) or placebo (n = 2 per dose regimen). Dosing regimens were 200, 400, and 800 mg once daily on days 1 and 10, twice daily on days 3-9. Plasma, urine, and feces samples were assayed for baicalein and its predominant metabolite baicalin using validated HPLC-MS/MS methods. Pharmacokinetic parameters were computed using standard non-compartmental analysis. Dose proportionality was assessed with a method combining equivalence criterion and power model. Drug safety and tolerability were assessed by monitoring adverse events and laboratory parameters. RESULTS: Thirty-three of 36 enrolled participants completed the study. A total of 44 adverse events occurred in 23 participants. A steady-state concentration of analytes in plasma was achieved on day 8 after repeated dosing. Analytes concentrations and exposure increased with increasing dose. The dose proportionality constant (β) for AUCss of baicalein and baicalin was 0.922 (90 % confidence interval, 0.650-1.195) and 0.942 (90 % confidence interval, 0.539-1.345), respectively. The accumulation index varied from 1.66 to 2.07 for baicalein and from 1.68 to 2.45 for baicalin. CONCLUSION: In dose range of 200-800 mg, multiple-dose oral baicalein administration was safe and well tolerated, dose proportionality was inconclusive, and no serious accumulation of baicalein was observed.
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