经鼻腔给予海洛因前药苯海佐因后在娱乐性药物使用者中的药代动力学和滥用潜力。

Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.

机构信息

KemPharm, Coralville, Iowa.

Worldwide Clinical Trials, Austin, Texas.

出版信息

Pain Med. 2018 Dec 1;19(12):2438-2449. doi: 10.1093/pm/pnx247.

DOI:10.1093/pm/pnx247

PMID:29092079

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6294406/

Abstract

OBJECTIVE

Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API.

DESIGN

Single-center, randomized, double-blind, crossover study.

SETTING

Clinical research site.

SUBJECTS

Healthy adult, nondependent, recreational opioid users.

METHODS

Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed.

RESULTS

Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax.

CONCLUSION

Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.

摘要

目的

开发一种不含对乙酰氨基酚的、即释型氢可酮产品仍然是一项未满足的医学需求；然而，新的阿片类镇痛药不应该引入新的滥用风险。苯氢可待因是氢可酮的前药，必须通过肠道中的酶代谢为氢可酮，以最佳发挥其药效。本研究评估了苯氢可待因活性药物成分（API）与酒石酸氢可酮（HB）API 相比的鼻内药代动力学和滥用潜力。

设计

单中心、随机、双盲、交叉研究。

地点

临床研究基地。

受试者

健康的、非依赖的、娱乐性阿片类药物使用者。

方法

受试者（51 名完成者）随机接受 13.34mg 鼻内苯氢可待因 API 和 15.0mg 鼻内 HB API（氢可酮的等摩尔剂量）。在每个给药间隔内采集血样，并获得药物喜好评分（在双极视觉模拟量表上评估）。评估鼻内刺激和安全性。

结果

苯氢可待因 API 的氢可酮血浆峰浓度（Cmax）低 36.0%，氢可酮总暴露量（AUClast 和 AUCinf）分别低 20.3%和 19.5%（均 P<0.0001）。与 HB API 相比，苯氢可待因 API 的所有部分 AUC 值均较低，在给药后一小时内，氢可酮暴露量减少了≥75%（均 P<0.0001）。苯氢可待因 API 氢可酮的中位 Tmax 延迟了 1 小时以上。与 HB API 相比，苯氢可待因 API 的药物喜好评分（Emax）显著降低（P=0.004），45%的受试者药物喜好 Emax 降低了≥30%。