# Statistical and Clustering Analysis of Safety Profiles of FDA-Approved Protein Kinase Inhibitors
## 3 Results
### Average Spectrum of AEs for the Approved Protein Kinase Inhibitors  
To obtain a comprehensive view of the AEs associated with PKIs, we aggregated data across all the drugs in the analyzed set. We define a prototypical protein kinase inhibitor (P-PKI) to represent a standard compound that serves to illustrate the general AE patterns and frequencies of PKIs.  
The dataset revealed one AE PT occurring in more than 1 in 10 patients (\(\geq\)10%, very common): death. Additionally, there were 53 AEs occurring in 1 to 10 out of 100 patients (1% to 10%, common) and 400 AE PTs occurring in 1 to 10 out of 1000 patients (0.1% to 1%, uncommon). A graphical representation of the very common and common AE PTs for P-PKI, along with their frequency of occurrence, is shown in Figure 2.  
Death being the most reported AE indicates a high-risk factor associated with the P-PKI treatment. This high rate can be also explained by the use of chemotherapeutic agents in late-stage cancer patients where the underlying disease itself has a high mortality rate. High frequencies of diarrhea (7.68%), nausea (5.58%), and vomiting (3.06%) indicate  
Figure 2: Very common and common AE PTs of the P-PKIs together with their frequency of occurrence.  
the antiproliferative/cytotoxic effects of the drugs on rapidly dividing cells in the gastrointestinal tract. Decreased white blood cell count (1.78%), neutropenia (1.49%), decreased platelet count (1.44%), and anemia (1.72%) are suggestive of bone marrow suppression.  
The frequency of infection (1.04%) seems to be correlated with the frequency of neutropenia and a direct result of the compromised immunity. However, the frequencies of infection-related AE PTs were not significantly different between the analyzed sets.  
Analysis of outlier values for the 54 AEs classified as very common or common in the P-PKI safety profile identified 235 high outliers. Each of these values significantly exceeded the typical frequency range for specific AEs across the entire PKI drug set.  
The highest number of outliers was recorded for hypertension, with 11 occurrences, followed by falls, with 9, and palmar-plantar erythrocytesesthesia syndrome and neoplasm progression, each with 8. Several conditions, including constipation, alopecia, increased blood pressure, thrombocytopenia, joint swelling and dose omission issues, had seven occurrences each. Asthenia had the lowest count, with just one outlier. Some of the most common AEs in the P-PKI profile, like death, diarrhea, fatigue, nausea, and drug ineffective, showed few outliers, indicating low variability in their occurrence.  
Analysis by drug indicated that abemaciclib, imatinib, netarsudil, pexidartinib, and selumetinib had no recorded outliers, suggesting these drugs have a safety profile that can be considered representative for the whole group. Conversely, tucatinib had the highest number of outliers (17), indicating that it behaves atypically compared to the group in multiple safety aspects. Other drugs with significant outliers include neratinib and nintendanib, each with 12, and ripretinib with 10.