Pfizer Inc, Groton, CT, USA.
Pfizer Inc, New York, NY, USA.
CPT Pharmacometrics Syst Pharmacol. 2021 Jul;10(7):769-781. doi: 10.1002/psp4.12645. Epub 2021 Jun 17.
Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12 and nausea/vomiting incidence) for varenicline in adolescent smokers were characterized using data from two phase 1 and one phase 4 studies. A one-compartment popPK model with first-order absorption and elimination adequately fitted the observed data. The effect of female sex on apparent clearance was significant. Apparent volume of distribution increased with body weight and decreased by 24%, 15%, and 14% for black race, "other" race, and female sex, respectively. The observed range of exposure in the phase 4 study was consistent with that expected for each dose and body-weight group from the results obtained in adolescent PK studies, supporting that varenicline dose and administration were appropriate in the study. The relationship between CAR9-12 and varenicline area under the concentration-time curve (AUC) from 0 to 24 hours (AUC ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC (p < 0.001) and was higher in females. Varenicline PK and ER for tolerability in adolescent smokers were comparable with adults, while ER for efficacy confirmed the negative results reported in the phase 4 study.
伐仑克林是一种已被批准用于成人戒烟的辅助药物。使用两项 1 期和一项 4 期研究的数据，对青少年吸烟者中伐仑克林的群体药代动力学（popPK）和暴露-反应（ER）（第 9-12 周持续戒烟率[CAR]和恶心/呕吐发生率）进行了描述。一个具有一级吸收和消除的单室 popPK 模型能够很好地拟合观察到的数据。女性对表观清除率的影响具有统计学意义。表观分布容积随体重增加而增加，黑种人、“其他”种族和女性的分布容积分别降低了 24%、15%和 14%。4 期研究中观察到的暴露范围与青少年 PK 研究中各剂量和体重组预期的暴露范围一致，支持研究中伐仑克林的剂量和给药方案是恰当的。第 9-12 周的持续戒烟率（CAR）与从 0 到 24 小时的浓度-时间曲线下面积（AUC）之间的关系无统计学意义（p=0.303）。恶心/呕吐的发生率随 AUC 增加而增加（p<0.001），且女性发生率更高。青少年吸烟者中伐仑克林的 PK 和耐受性 ER 与成人相当，而疗效 ER 证实了 4 期研究中报告的阴性结果。
