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METHODS article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1432944
This article is part of the Research Topic Drug Metabolism and Transport: The Frontier of Personalized Medicine Volume II View all 11 articles
A validated UPLC-MS/MS method for quantification of pyrotinib and population pharmacokinetic study of pyrotinib in HER2-positive breast cancer patients
Provisionally accepted- 1 Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
- 2 Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
Objective: Pyrotinb has been approved for the treatment of HER2-positive advanced or metastatic breast cancer in China. However, the plasma concentration of pyrotinb in different patients varies greatly, and in the course of treatment, if patients have intolerable adverse reactions, the drug dosage will be reduced or even stopped. This study set out to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the determination of pyrotinb in human plasma, analyze the population pharmacokinetics (PPK) of pyrotinib and assess the influence of patient variables on PK of pyrotinib in patients with HER2 positive breast cancer.Method: An UPLC-MS/MS method was developed to measure pyrotinib in human plasma. Utilizing a gradient elution procedure and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 μm), sample separation was accomplished in 5.5 minutes.Pyrotinb extraction via protein precipitation was used as a sample pre-treatment technique. In total, 50 patients provided 158 plasma samples, which were identified and used in the PPK investigation. The non-linear mixed-effects modeling (NONMEM) approach was used to assess the plasma concentrations and covariates information. For the final PPK model evaluation, external evaluation, non-parametric bootstrap, visual predictive check (VPC), and goodness-of-fit (GOF) were used.The UPLC-MS/MS method for determining plasma concentration of pyrotinib in patients had good selectivity and linearity in the range of 1-1000 ng/mL. Pyrotinib concentration profile in HER2-positive breast cancer patients was well described by a single-compartment PPK model with first-order absorption and elimination. The formulas for the final estimated values of overall parameters of CL/F and Vd/F and Ka are respectively:No dosage adjustment was advised, despite the possibility that the total protein levels could have a substantial impact on the apparent distribution volume of pyrotinib with limited magnitude.In this study, an UPLC-MS/MS method was established to determine the concentration of pyrotinib in human plasma. A population pharmacokinetic model of pyrotinib in HER2 positive breast cancer patients suggested that low serum total protein reduced the clearance rate of pyrotinib in patients. Clinical medical staff should pay attention to the liver function of patients with abnormal serum total protein and be alert to the occurrence of adverse drug reactions.
Keywords: Pyrotinib, tyrosine kinase inhibitor, population pharmacokinetics, HER2-positive breast cancer, NONMEM
Received: 15 May 2024; Accepted: 02 Sep 2024.
Copyright: © 2024 Zhu, Xu, Zhao, Qie, Gao, Gao, Feng, Bai, Feng and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Haopeng Zhao, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
Hongxin Qie, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
Xiaonan Gao, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
Rui Feng, Department of Pharmacy, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
MingXia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
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