Robinson Cynthia Y, Rubino Christopher M, Farr Stephen J
Senior Scientific Advisor, Clinical Development, Zogenix, Inc., San Diego, California.
Vice President, Pharmacometrics, Institute for Clinical Pharmacodynamics, Latham, New York; Adjunct Assistant Research Professor, School of Pharmacy and Pharmaceutical Sciences, SUNY University at Buffalo, Buffalo, New York.
J Opioid Manag. 2015 Sep-Oct;11(5):405-15. doi: 10.5055/jom.2015.0290.
To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies.
Both studies were multicenter clinical studies.
In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone- ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites.
Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods.
Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steadystate mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies.
The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.
在两项独立的2期临床研究受试者中评估单一实体氢可酮缓释（ER）制剂的单剂量和稳态药代动力学。
两项研究均为多中心临床研究。
在研究1中，115例术后疼痛（拇囊炎切除术）患者接受单剂量10、20、30或40mg氢可酮-ER、10mg氢可酮/325mg对乙酰氨基酚速释（IR）或安慰剂。在研究2中，37例骨关节炎疼痛患者每日两次接受10、20、30或40mg氢可酮-ER，共7天。单剂量给药后（研究1）或给药7天后（研究2），在给药后长达24小时定期采集静脉血样，检测氢可酮及其主要代谢物的浓度。
采用非房室分析方法估算标准药代动力学参数。
与IR制剂的2.9小时相比，单剂量氢可酮-ER后，所有剂量水平的氢可酮-ER的Tmax均延长至约6小时。与氢可酮/对乙酰氨基酚-IR对照剂相比，所有剂量的氢可酮-ER制剂在整个12小时给药间隔内均能提供氢可酮的长效缓释，且稳态时峰谷波动减小。单剂量和稳态平均Cmax和AUClast值均显示出合理的剂量比例关系。在两项研究中，去甲氢可酮和氢吗啡酮的血浆浓度分别为氢可酮浓度的32%-38%和<2.1%。
氢可酮持续的血浆浓度支持每日两次给药，给药间隔为12小时。
