Bioanalysis of tucatinib and metabolite, and a five-way cross-validation to support clinical pharmacokinetic analysis: Supplementary data

Tucatinib, a tyrosine kinase inhibitor of HER2, is approved in multiple regions for metastatic breast
cancer and is being evaluated in metastatic colorectal and gastric cancers. During clinical development,
quantification of tucatinib plasma concentrations for pharmacokinetic analysis was performed using
MS/MS analysis by three laboratories using five different methods. Cross-validation was required to
confirm data across laboratories were comparable. A five-way cross-validation procedure was developed
where bioanalysis performed by one laboratory and method was used as a ‘base’ against which the other
methods were validated. This cross-validation method provides an alternative to multiple head-to-head
comparisons between two methods, and enabled combination of data from multiple tucatinib clinical
trials for a single population pharmacokinetic analysis.

妥卡替尼（Tucatinib）是一种靶向人表皮生长因子受体2（HER2）的酪氨酸激酶抑制剂，已在多个地区获批用于转移性乳腺癌的治疗，目前正针对转移性结直肠癌与胃癌开展临床研究与评估。在临床研发阶段，为开展药代动力学分析，需对妥卡替尼的血浆浓度进行定量检测，三家实验室采用五种不同方法通过串联质谱（MS/MS）完成了该项定量检测工作。为确保不同实验室间的检测数据具有可比性，需开展交叉验证。研究人员开发了一种五组交叉验证流程：以单家实验室采用单种方法得到的生物分析结果作为“基准”，对其余四种方法的检测结果进行验证。该交叉验证方法可替代两两方法间的多组头对头比对，同时支持整合多项妥卡替尼临床试验的数据，以开展单群体药代动力学分析。