Use of receptor and nonreceptor tyrosine kinase inhibitors and Parkinson disease risk

There are currently no disease-modifying therapies for Parkinson disease (PD), although various targets for disease modification have been explored. Expression and binding of receptor tyrosine kinases (rTKs) and nonreceptor tyrosine kinases (nrTKs) have been implicated in PD pathogenesis, and their inhibition is a promisingneuroprotective strategy. This population-based, case-control study of US Medicare beneficiaries included 207,532 incident PD patients and 975,177 comparable, population-based control subjects from 2016 to 2018. This study investigated associations between Medicare Part D prescription fills prior to PD diagnosis for 7 rTK inhibitors (erlotinib, sorafenib, pazopanib, imatinib, sunitinib, nintedanib, and dasatinib) and 4 nrTK inhibitors (nilotinib, ibrutinib, ruxolitinib, and tofacitinib) and PD risk. Logistic regression estimated relative risks (RR) and 95% confidence intervals (CIs) adjusted for age, sex, race, smoking, and healthcare utilization. All medications were inversely associated with incident PD. The rTK inhibitors erlotinib (RR = 0.53, 95% CI: 0.38-0.74), sorafenib (RR = 0.43, 95% CI: 0.25-0.74), imatinib (RR = 0.60, 95% CI: 0.47-0.75), pazopanib (RR = 0.58, 95% CI: 0.39-0.86), nintedanib (RR = 0.66, 95% CI: 0.50-0.88), sunitinib (RR = 0.60, 95% CI: 0.39-0.93), and dasatinib (RR = 0.53, 95% CI: 0.35-0.82) had the strongest inverse associations. Among nrTK inhibitors, ibrutinib (RR = 0.62, 95% CI: 0.51-0.75) had a marked inverse association. Given the chemotherapeutic mechanisms of these medications, and the known cancer-PD inverse relationship, we performed a sensitivity analysis adjusting for relevant cancer subtypes, yielding a similar inverse association. Overall, the use of rTK and nrTK inhibitors was associated with a lower risk of developing PD, although there may be differential impact of this medication class depending on specific inhibition pathways.