sitagliptin-phosphate and Carcinoma--Non-Small-Cell-Lung

Osimertinib is recommended as the first-line treatment of advanced non-small cell lung cancer (NSCLC) in adults. The most commonly reported adverse events for osimertinib are skin effects, diarrhea, nausea, decreased appetite, fatigue, paronychia, and stomatitis. Severe thrombocytopenia is rarely reported. We present a case of severe thrombocytopenia in a 70-year-old NSCLC patient caused by osimertinib combined with sitagliptin. After remission of thrombocytopenia, the patient was well tolerated with osimertinib re-administration in the absence of sitagliptin. We speculated that declined platelet count might be related to the interaction between osimertinib and sitagliptin by acting with a synergistic effect on platelets. Osimertinib rechallenge can be considered after discontinuing drugs that may contribute to platelet decline if possible, and making a careful assessment of complete blood count and risk of bleeding.

Topics: Adult; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Sitagliptin Phosphate; Thrombocytopenia

Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-2

Topics: Afatinib; Animals; Carcinoma, Non-Small-Cell Lung; Diarrhea; ErbB Receptors; Lung Neoplasms; Quality of Life; Rats; Sitagliptin Phosphate