Verzenio® (Abemaciclib)

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Abemaciclib: Mechanism of Diarrhea

El mecanismo de la diarrea con abemaciclib no se ha dilucidado.

Detailed Information

The mechanism of diarrhea with abemaciclib has not been elucidated. There are nonclinical reports that no effects on the GI tract were observed in mouse models lacking CDK4, CDK6, and cyclin D and that no effects on tissues such as esophagus and intestine were observed in adult mice lacking CDK4.1,2

In nonclinical toxicity studies, pathological findings of proliferative changes in crypt cells and villous atrophy were observed in the intestinal mucosa of rats administered abemaciclib.3 Conclusions made in the Thibault et al manuscript are, in part, consistent with Lilly data regarding abemaciclib and morphologic changes in the GI tract of rats, mice and dogs.4 These findings are different from histological findings typically observed with cytocidal anticancer agents or radiation, which include necrosis of crypt cells and loss of microvilli or intestinal mucosal epithelia.5-8

References

1. Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 2004;18:2699-2711. http://dx.doi.org/10.1101/gad.1256504

2. Barrière C, Santamaría D, Cerqueira A, et al. Mice thrive without Cdk4 and Cdk2. Mol Oncol. 2007;1(1):72-83. http://dx.doi.org/10.1016/j.molonc.2007.03.001

3. Thibault S, Hu W, Hirakawa B, et al. Intestinal toxicity in rats following administration of CDK4/6 inhibitors is independent of primary pharmacology. Mol Cancer Ther. 2019;18(2):257-266. http://dx.doi.org/10.1158/1535-7163.MCT-18-0734

4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5. Slavin RE, Dias MA, Saral R. Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols: a clinical-pathologic study of 33 patients. Cancer. 1978;42(4):1747-1759. https://doi.org/10.1002/1097-0142(197810)42:4<1747::AID-CNCR2820420413>3.0.CO;2-T

6. Khan SA, Wingard JR. Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr. 2001;2001(29):31-36. https://doi.org/10.1093/oxfordjournals.jncimonographs.a003437

7. Boussios S, Pentheroudakis G, Katsanos K, Pavlidis N. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann Gastroenterol. 2012;25(2):106-118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959393/

8. Stacey R, Green JT. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther Adv Chronic Dis. 2014;5(1):15-29. https://doi.org/10.1177/2040622313510730

Glossary

CDK = cyclin-dependent kinase

GI = gastrointestinal

Lilly = Eli Lilly and Company

Fecha de la última revisión: 2019 M11 22


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