Population pharmacokinetics of buprenorphine and naloxone sublingual combination in Chinese healthy volunteers and patients with opioid use disorder: Model-based dose optimization

• Main Authors: Meng Gu (Author), Anning Li (Author), Wenyao Mak (Author), Fang Dong (Author), Nuo Xu (Author), Jingye Zhang (Author), Yufei Shi (Author), Nan Zheng (Author), Zhijia Tang (Author), Qingfeng He (Author), Canjun Ruan (Author), Wei Guo (Author), Xiaoqiang Xiang (Author), Chuanyue Wang (Author), Bing Han (Author), Xiao Zhu (Author)
• Format: Book
• Published: Frontiers Media S.A., 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

The sublingual combination of buprenorphine (BUP) and naloxone (NLX) is a new treatment option for opioid use disorder (OUD) and is effective in preventing drug abuse. This study aimed to explore rational dosing regimen for OUD patients in China via a model-based dose optimization approach. BUP, norbuprenorphine (norBUP), and NLX plasma concentrations of 34 healthy volunteers and 12 OUD subjects after single or repeated dosing were included. A parent-metabolite population pharmacokinetics (popPK) model with transit compartments for absorption was implemented to describe the pharmacokinetic profile of BUP-norBUP. In addition, NLX concentrations were well captured by a one-compartment popPK model. Covariate analysis showed that every additional swallow after the administration within the observed range (0-12) resulted in a 3.5% reduction in BUP bioavailability. This provides a possible reason for the less-than-dose proportionality of BUP. There were no differences in the pharmacokinetic characteristics between BUP or NLX in healthy volunteers and OUD subjects. Ethnic sensitivity analysis demonstrated that the dose-normalized peak concentration and area-under-the-curve of BUP in Chinese were about half of Puerto Ricans, which was consistent with a higher clearance observed in Chinese (166 L/h vs. 270 L/h). Furthermore, Monte Carlo simulations showed that an 8 mg three-times daily dose was the optimized regimen for Chinese OUD subjects. This regimen ensured that opioid receptor occupancy remained at a maximum (70%) in more than 95% of subjects, at the same time, with NLX plasma concentrations below the withdrawal reaction threshold (4.6 ng/mL).

Item Description

1663-9812
10.3389/fphar.2023.1089862