Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants

Author(s):  
Jennifer E. Hibma ◽  
Melissa O’Gorman ◽  
Sunil Nepal ◽  
Sylvester Pawlak ◽  
Katherine Ginman ◽  
...  
Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 715-718
Author(s):  
Abigail R. Bland ◽  
Nensi Shrestha ◽  
Rhonda J. Rosengren ◽  
John C. Ashton

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin <i>N</i>-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo.


2020 ◽  
Vol 50 (12) ◽  
pp. 1470-1474
Author(s):  
Beina Hui ◽  
Jingping Zhang ◽  
Xiaobo Shi ◽  
Fangfang Xing ◽  
Yang W Shao ◽  
...  

Abstract Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.


2016 ◽  
Vol 23 (8) ◽  
pp. 602-614 ◽  
Author(s):  
Trang H Au ◽  
Courtney C Cavalieri ◽  
David D Stenehjem

Clinical pharmacists are important contributors to the care of patients with cancer; it is therefore critical for oncology clinical pharmacists to stay current with new anticancer therapies. This review summarizes the epidemiology and pathogenesis of non-small cell lung cancer, including the most common genetic alterations, as well as the mechanism of action, clinical development, pharmacodynamics and pharmacokinetics of the anaplastic lymphoma kinase inhibitor ceritinib for the treatment of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer. Targeted therapies based on the presence of specific mutations are an important development in the treatment of non-small cell lung cancer. However, acquired resistance to the first anaplastic lymphoma kinase-inhibitor approved by the U.S. Food and Drug Administration, crizotinib, is observed in almost half of patients treated with it. Ceritinib is an oral anaplastic lymphoma kinase-inhibitor that has demonstrated more potent antitumor activity than crizotinib in preclinical models. It was granted accelerated approval in 2014 to treat anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer patients who have progressed on or are intolerant to crizotinib. Ceritinib represents an important alternative second-line therapy for patients with metastatic non-small cell lung cancer who have traditionally limited treatment options.


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