Simon Nicolas, Moirand Romain, Dematteis Maurice, Bordet Régis, Deplanque Dominique, Rolland Benjamin
Aix Marseille Univ, APHM, INSERM, IRD, SESSTIM, Hop Sainte Marguerite, Service de Pharmacologie Clinique, CAP-TV, Marseille, France.
Univ Rennes, INSERM, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), CIC 1414, Unité d'Addictologie, Rennes, France.
Front Psychiatry. 2018 Aug 23;9:385. doi: 10.3389/fpsyt.2018.00385. eCollection 2018.
Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300 mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: <60 mg/d; 2: 60-120 mg/d; 3: >120 mg/d-180 mg/d; and 4: >180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34-2), clearance (Cl/F) 11.6 L/h (10.8-12.3) and volume of distribution (Vd/F) 72.8 L (66.5-80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19-65), 21% (16-27), and 22% (11-36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21-26). No serious adverse event was reported. : EudraCT #2013-003412-46.
巴氯芬是一种γ-氨基丁酸B型（GABA-B）受体激动剂，它在治疗酒精使用障碍（AUD）方面引起了一些关注，偶尔使用剂量高达300mg/d。我们进行了第一项关于巴氯芬在AUD受试者中的全面药代动力学研究，口服日剂量高达300mg。60名接受市售巴氯芬治疗AUD的受试者参加了一项前瞻性1期研究。参与者被分为四个剂量组（1组：<60mg/d；2组：60-120mg/d；3组：>120mg/d-180mg/d；4组：>180mg/d），并使用非线性混合效应模型对巴氯芬进行了全面的药代动力学分析。在逐步建模中评估了不同临床和生物学协变量的影响。57名参与者完成了研究（共收集到522个观察浓度）。消旋巴氯芬呈现出线性药代动力学特征，符合一室模型，且无影响临床或生物学的因素。巴氯芬的药代动力学参数为（自助法95%置信区间）：吸收常数（Ka）1.64 1/h（1.34-2）、清除率（Cl/F）11.6 L/h（10.8-12.3）和分布容积（Vd/F）72.8 L（66.5-80.4），半衰期为4.4小时。Ka、Cl/F和Vd/F的个体间变异（IIV）分别为44%（19-65）、21%（16-27）和22%（11-36）。残余变异为24%（21-26）。未报告严重不良事件。：欧盟临床试验注册号#2013-003412-46。
