AUTHOR=Gu Meng , Li Anning , Mak Wenyao , Dong Fang , Xu Nuo , Zhang Jingye , Shi Yufei , Zheng Nan , Tang Zhijia , He Qingfeng , Ruan Canjun , Guo Wei , Xiang Xiaoqiang , Wang Chuanyue , Han Bing , Zhu Xiao 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1089862

DOI=10.3389/fphar.2023.1089862

ISSN=1663-9812

ABSTRACT=<p>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 <italic>via</italic> 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 <inline-formula id="inf1"><mml:math id="m1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">L</mml:mi><mml:mo>/</mml:mo><mml:mi mathvariant="normal">h</mml:mi></mml:mrow></mml:math></inline-formula> vs. 270 <inline-formula id="inf2"><mml:math id="m2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">L</mml:mi><mml:mo>/</mml:mo><mml:mi mathvariant="normal">h</mml:mi></mml:mrow></mml:math></inline-formula>). 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 <inline-formula id="inf3"><mml:math id="m3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">n</mml:mi><mml:mi mathvariant="normal">g</mml:mi><mml:mo>/</mml:mo><mml:mi mathvariant="normal">m</mml:mi><mml:mi mathvariant="normal">L</mml:mi></mml:mrow></mml:math></inline-formula>).</p>