PDF(Pubmed)
Abstract：
UNASSIGNED: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine.
UNASSIGNED: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity.
UNASSIGNED: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms.
UNASSIGNED: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.
UNASSIGNED: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity.
UNASSIGNED: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms.
UNASSIGNED: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.
摘要：
■伊博加因是一种致幻药物，可用于治疗阿片类药物使用障碍（OUD）。伊波加因及其代谢产物的药代动力学（PKs）与其对副作用和阿片类药物戒断严重程度的临床影响之间的关系尚不清楚。我们旨在研究接受ibogaine支持的排毒的OUD患者的这些关系。
■该研究在14名患有OUD的受试者中进行。他们接受了10mg/kg盐酸伊波加因的单剂量。伊博加因的血浆PKs，noribogaine,并在24小时内获得了葡萄糖醛酸降维卡因。进行细胞色素P450同工酶2D6（CYP2D6）基因分型。通过非线性混合效应模型分析PKs，并与校正的QT间期（QTc）延长相关，小脑共济失调,和阿片类药物戒断的严重程度。
■伊波加因的PK是高度可变的，并且与CYP2D6基因型显著相关（p<0.001）。伊波加因的基本清除率（CYP2D6活性评分（AS）为0）为0.82L/h。对于AS的每个点，这增加了30.7L/h。伊波加因血浆浓度与QTc之间的关系最好通过乙状Emax模型来描述。Spearman相关性对伊波加因具有QTc（p=0.109）和小脑效应（p=0.668）的利波加因具有显着的相关性（p<0.03）；两者均与阿片类药物戒断症状的严重程度相关。
■伊波加因的清除率与CYPD2D6基因型密切相关。伊博加因的心脏副作用（QTc时间）和小脑效应很可能更多是由伊博加因而不是去利博加因驱动。未来的研究应旨在探索更低的剂量和/或应用基于CYP2D6基因型的个体化给药。
■该研究在14名患有OUD的受试者中进行。他们接受了10mg/kg盐酸伊波加因的单剂量。伊博加因的血浆PKs，noribogaine,并在24小时内获得了葡萄糖醛酸降维卡因。进行细胞色素P450同工酶2D6（CYP2D6）基因分型。通过非线性混合效应模型分析PKs，并与校正的QT间期（QTc）延长相关，小脑共济失调,和阿片类药物戒断的严重程度。
■伊波加因的PK是高度可变的，并且与CYP2D6基因型显著相关（p<0.001）。伊波加因的基本清除率（CYP2D6活性评分（AS）为0）为0.82L/h。对于AS的每个点，这增加了30.7L/h。伊波加因血浆浓度与QTc之间的关系最好通过乙状Emax模型来描述。Spearman相关性对伊波加因具有QTc（p=0.109）和小脑效应（p=0.668）的利波加因具有显着的相关性（p<0.03）；两者均与阿片类药物戒断症状的严重程度相关。
■伊波加因的清除率与CYPD2D6基因型密切相关。伊博加因的心脏副作用（QTc时间）和小脑效应很可能更多是由伊博加因而不是去利博加因驱动。未来的研究应旨在探索更低的剂量和/或应用基于CYP2D6基因型的个体化给药。
