Pharmacokinetics of Trastuzumab and Its Efficacy and Safety in HER2-positive Cancer Patients

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2024 Aug 23

PMID 39177768

Authors

Xinyu Luo

Nan Wang

Yue Xing

Xinyue Gao

Yang Yu

Tong Liu

Shuai Jiang

Mei Dong

Affiliations

Soon will be listed here.

Abstract

Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients.

References

Boekhout A, Beijnen J, Schellens J . Trastuzumab. Oncologist. 2011; 16(6):800-10. PMC: 3228213. DOI: 10.1634/theoncologist.2010-0035. View

Diaby V, Tawk R, Sanogo V, Xiao H, Montero A . A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer. Breast Cancer Res Treat. 2015; 151(1):27-40. PMC: 4530780. DOI: 10.1007/s10549-015-3383-6. View

Yakes F, Chinratanalab W, Ritter C, King W, Seelig S, Arteaga C . Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 2002; 62(14):4132-41. View

Lane H, Beuvink I, Motoyama A, Daly J, Neve R, Hynes N . ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol. 2000; 20(9):3210-23. PMC: 85615. DOI: 10.1128/MCB.20.9.3210-3223.2000. View

Molina M, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J . Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001; 61(12):4744-9. View

Kute T, Stehle Jr J, Ornelles D, Walker N, Delbono O, Vaughn J . Understanding key assay parameters that affect measurements of trastuzumab-mediated ADCC against Her2 positive breast cancer cells. Oncoimmunology. 2012; 1(6):810-821. PMC: 3489736. DOI: 10.4161/onci.20447. View

Klos K, Zhou X, Lee S, Zhang L, Yang W, Nagata Y . Combined trastuzumab and paclitaxel treatment better inhibits ErbB-2-mediated angiogenesis in breast carcinoma through a more effective inhibition of Akt than either treatment alone. Cancer. 2003; 98(7):1377-85. DOI: 10.1002/cncr.11656. View

Quartino A, Hillenbach C, Li J, Li H, Wada R, Visich J . Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous "manual syringe" injection or intravenously in women with HER2-positive early breast cancer. Cancer Chemother Pharmacol. 2015; 77(1):77-88. PMC: 4706584. DOI: 10.1007/s00280-015-2922-5. View

Yang J, Zhao H, Garnett C, Rahman A, Gobburu J, Pierce W . The combination of exposure-response and case-control analyses in regulatory decision making. J Clin Pharmacol. 2013; 53(2):160-6. DOI: 10.1177/0091270012445206. View

10.

Bruno R, Washington C, Lu J, Lieberman G, Banken L, Klein P . Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother Pharmacol. 2005; 56(4):361-9. DOI: 10.1007/s00280-005-1026-z. View

11.

Leveque D, Gigou L, Bergerat J . Clinical pharmacology of trastuzumab. Curr Clin Pharmacol. 2008; 3(1):51-5. DOI: 10.2174/157488408783329931. View

12.

Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987; 235(4785):177-82. DOI: 10.1126/science.3798106. View

13.

Nahta R, Esteva F . Herceptin: mechanisms of action and resistance. Cancer Lett. 2006; 232(2):123-38. DOI: 10.1016/j.canlet.2005.01.041. View

14.

Dubska L, Andera L, Sheard M . HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway: an unexpected effect on TRAIL-induced apoptosis. FEBS Lett. 2005; 579(19):4149-58. DOI: 10.1016/j.febslet.2005.06.047. View

15.

Junttila T, Akita R, Parsons K, Fields C, Lewis Phillips G, Friedman L . Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009; 15(5):429-40. DOI: 10.1016/j.ccr.2009.03.020. View

16.

Baselga J, Carbonell X, Castaneda-Soto N, Clemens M, Green M, Harvey V . Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol. 2005; 23(10):2162-71. DOI: 10.1200/JCO.2005.01.014. View

17.

Leyland-Jones B, Gelmon K, Ayoub J, Arnold A, Verma S, Dias R . Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003; 21(21):3965-71. DOI: 10.1200/JCO.2003.12.109. View

18.

Maximiano S, Magalhaes P, Pereira Guerreiro M, Morgado M . Trastuzumab in the Treatment of Breast Cancer. BioDrugs. 2016; 30(2):75-86. DOI: 10.1007/s40259-016-0162-9. View

19.

Terrell-Hall T, Nounou M, El-Amrawy F, Griffith J, Lockman P . Trastuzumab distribution in an and model of brain metastases of breast cancer. Oncotarget. 2017; 8(48):83734-83744. PMC: 5663550. DOI: 10.18632/oncotarget.19634. View

20.

Murthy R, Borges V, Conlin A, Chaves J, Chamberlain M, Gray T . Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018; 19(7):880-888. DOI: 10.1016/S1470-2045(18)30256-0. View