SGS Exprimo NV, Life Science Services, London, UK.
POG Pharmacometrics, London, UK.
Clin Pharmacokinet. 2021 Apr;60(4):541-561. doi: 10.1007/s40262-020-00960-5. Epub 2020 Dec 23.
In 4 decades, numerous nicotine replacement therapy products have been developed. Population pharmacokinetic models can support exposure-response modeling and inform nicotine replacement therapy product development, but only limited model-based cross-study population pharmacokinetic analyses for nicotine replacement therapy products have been published.
The aim of this retrospective analysis was to assess the population pharmacokinetics of nicotine across intravenous, oral, transdermal and oromucosal (mouth spray, chewing gum, lozenge and inhaler) routes and formulations in healthy smoking subjects.
Data on 930 unique subjects (46,016 observations) from 29 single- and repeated-dose studies with multiple formulations across intravenous, oral, transdermal and oromucosal routes of administration were included. Data from intravenous and extravascular routes of administration were modelled separately for run efficiency reasons. For developing extravascular models, clearance and disposition parameters and their inter-individual variabilities were fixed to the estimates for intravenously delivered nicotine. Detectable pre-dose nicotine concentrations were modelled as a hypothetical nicotine bolus into the central compartment at the start of wash-out. Modelling repeated-dose oral and buccal administrations required a time-dependent increase in clearance or decrease in bioavailability to describe the data adequately.
Disposition of intravenous nicotine was best described by a three-compartment model with initial and terminal half-lives of 7 min and 4.5 h, respectively, and the absorption of single oral doses was best described with a first-order absorption rate constant of 1.55 h. The data of buccal formulations were modelled with parallel oromucosal absorption and gastrointestinal absorption of a part of the dose that is swallowed. For transdermal nicotine, parallel zero- and first-order release from the patch and a transit-compartment absorption model best described the data. Key pharmacokinetic parameters were reliably estimated, with typical values for clearance (67 L/h for a 70-kg subject), volume of distribution (4.3 L/kg), oral bioavailability (40%) and transdermal bioavailability (76%) within expected ranges. The estimated fraction of the dose swallowed for buccal formulations ranged from 55% (gum) to 69% (lozenge).
Robust population pharmacokinetic models were developed for five nicotine replacement therapy product types and for intravenous and oral nicotine. These population pharmacokinetic models are used in exposure-response analyses and simulation-based nicotine replacement therapy product design.
在过去的 40 年中，已经开发出了许多尼古丁替代疗法产品。群体药代动力学模型可以支持暴露-反应建模并为尼古丁替代疗法产品的开发提供信息，但已发表的基于模型的尼古丁替代疗法产品的跨研究群体药代动力学分析仅限于有限的数量。
本回顾性分析旨在评估健康吸烟人群中通过静脉内、口服、透皮和口腔黏膜（口腔喷雾、咀嚼口香糖、含片和吸入器）途径和制剂给予尼古丁的群体药代动力学。
共纳入了 29 项单剂量和重复剂量研究的 930 个独特受试者（46016 次观察）的数据，这些研究涉及静脉内、口服、透皮和口腔黏膜途径的多种制剂。出于运行效率的原因，分别对静脉内和血管外途径给予的药物进行了建模。为了建立血管外模型，将清除率和处置参数及其个体间变异性固定为静脉内给予尼古丁的估计值。将可检测到的预剂量尼古丁浓度建模为在冲洗开始时在中央隔室中作为假设的尼古丁推注。为了充分描述重复口服和颊部给药的数据，需要以时间依赖性方式增加清除率或降低生物利用度。
静脉内给予尼古丁的处置最好用具有初始半衰期和终末半衰期分别为 7 分钟和 4.5 小时的三房室模型来描述，单口服剂量的吸收最好用 1.55 小时的一级吸收速率常数来描述。颊部制剂的数据用平行口腔黏膜吸收和吞咽部分剂量的胃肠道吸收来建模。对于透皮尼古丁，最好用贴剂的零级和一级释放以及转运室吸收模型来描述数据。关键药代动力学参数可靠地估算，对于 70 公斤体重的个体，典型的清除率（67 L/h）、分布容积（4.3 L/kg）、口服生物利用度（40%）和透皮生物利用度（76%）值在预期范围内。颊部制剂吞咽部分的估计剂量分数范围为 55%（口香糖）至 69%（含片）。
为五种尼古丁替代疗法产品类型以及静脉内和口服尼古丁建立了稳健的群体药代动力学模型。这些群体药代动力学模型用于暴露-反应分析和基于模拟的尼古丁替代疗法产品设计。
