Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors
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Published:2021-06-02
Issue:3
Volume:88
Page:451-464
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ISSN:0344-5704
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Container-title:Cancer Chemotherapy and Pharmacology
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language:en
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Short-container-title:Cancer Chemother Pharmacol
Author:
Pilla Reddy VenkateshORCID, Fretland Adrian J., Zhou Diansong, Sharma Shringi, Chen Buyun, Vishwanathan Karthick, McGinnity Dermot F., Xu Yan, Ware Joseph A.
Abstract
Abstract
Purpose
Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown.
Methods
A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data.
Results
While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin.
Conclusion
Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.
Funder
Acerta Pharma, a member of the AstraZeneca Group
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Cancer Research,Pharmacology,Toxicology,Oncology
Reference48 articles.
1. National Comprehensive Cancer Network (2020) NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas v3.2020. https://www.nccn.org/professionals/physician_gls/default_nojava.aspx. Accessed 7 May 2021 2. National Comprehensive Cancer Network (2020) NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma version 2.2021. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed 7 May 2021 3. Denker S, Bittner A, Na IK, Kase J, Frick M, Anagnostopoulos I, Hummel M, Schmitt CA (2019) A Phase I/II first-line study of R-CHOP plus B-cell receptor/NF-κB-double-targeting to molecularly assess therapy response. Int J Hematol Oncol. 8(4):ljh20. https://doi.org/10.2217/ijh-2019-0010 4. Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, Goldlust IS, Yasgar A, McKnight C, Boxer MB, Duveau DY, Jiang JK, Michael S, Mierzwa T, Huang W, Walsh MJ, Mott BT, Patel P, Leister W, Maloney DJ, Leclair CA, Rai G, Jadhav A, Peyser BD, Austin CP, Martin SE, Simeonov A, Ferrer M, Staudt LM, Thomas CJ (2014) High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA 111(6):2349–2354. https://doi.org/10.1073/pnas.1311846111 5. Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W (2019) Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol 37(15):1285–1295. https://doi.org/10.1200/jco.18.02403
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