伐尼克兰戒烟的临床药代动力学和药效学综述。,Clinical Pharmacokinetics

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伐尼克兰戒烟的临床药代动力学和药效学综述。
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2010-12-01 , DOI: 10.2165/11537850-000000000-00000
Hélène M Faessel ₁ , R Scott Obach , Hans Rollema , Patanjali Ravva , Kathryn E Williams , Aaron H Burstein

Affiliation

Varenicline tartrate (Chantix®/Champix®) 是 α(4)β(2) 烟碱型乙酰胆碱受体的选择性部分激动剂，被批准用作戒烟辅助剂。成人的常用口服剂量为 1 毫克，每天两次，持续 12 周，初始滴定周。多项临床药理学研究对伐尼克兰在 18-55 岁成年吸烟者、≥65 岁老年吸烟者和非吸烟者、12-17 岁青少年吸烟者和肾功能受损受试者中的药代动力学进行了表征。伐尼克兰在单剂量和多剂量给药至 3 mg/天后表现出线性药代动力学。口服后吸收几乎完全，全身利用度高。口服生物利用度不受食物或一天中时间给药的影响；最大血浆药物浓度通常在给药后 3-4 小时内出现。伐尼克兰的蛋白结合率低（≤ 20%），且与年龄和肾功能无关。伐尼克兰几乎完全以原形在尿液中排泄，主要通过肾小球滤过，通过人体有机阳离子转运蛋白 hOCT-2 具有活性肾小管分泌的某些成分。伐尼克兰不进行显着代谢，也不被肝微粒体细胞色素 P450 (CYP) 酶代谢。与约 24 小时的消除半衰期一致，在重复给药 4 天内达到稳态条件。吸烟者和非吸烟者在伐尼克兰的代谢或排泄方面没有显着差异。在体外，伐尼克兰不会抑制或诱导主要 CYP 酶的活性。当伐尼克兰与窄治疗指数药物华法林或地高辛、戒烟药物安非他酮或透皮尼古丁以及肾分泌药物西咪替丁或二甲双胍共同给药时，未观察到具有临床意义的药代动力学药物相互作用。一项针对成年吸烟者多项研究的基于模型的综合伐尼克兰药代动力学分析进一步表明，肾功能是导致伐尼克兰全身暴露个体间差异的临床重要因素。虽然轻度至中度肾功能不全的受试者无需调整剂量，但重度肾功能不全的受试者需要将剂量减至 1 mg/天。在考虑肾功能后，年龄、性别或种族对伐尼克兰的药代动力学没有明显影响。青少年的伐尼克兰药代动力学通常与成人相当；体重效应会导致体型较小（体重 ≤ 55 公斤）的个体接触更多，但已被成人推荐剂量的一半所抵消。（然而，重要的是要注意伐尼克兰目前未被批准用于 18 岁以下的吸烟者）。将个体特异性药物暴露与临床反应相关联的暴露-反应分析一致表明，成年吸烟者的治疗结束戒烟率随着伐尼克兰暴露量的增加而线性增加；每天两次 1 毫克的剂量方案与更大的暴露量和在治疗开始后 1 年内实现稳定戒烟的可能性增加可靠相关。恶心是伐尼克兰临床试验中最常报告的单一不良事件，其发生率与性别有关，并随着伐尼克兰暴露而增加。总之，伐尼克兰可预测的药代动力学特性和直接的处置特征简化了其在临床实践中的应用。

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A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation.

Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α(4)β(2) nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18-55 years, elderly smokers and nonsmokers aged ≥ 65 years, adolescent smokers aged 12-17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3-4 hours after dosing. Protein binding of varenicline is low (≤ 20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steady-state conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤ 55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in varenicline clinical trials, with an incidence that was sex-related and increased with varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice.

更新日期：2019-11-01

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