Pharmacokinetic Determinants of Ponatinib-Induced Vascular Toxicity: A Possible Role of Perivascular Adipose Tissue

Tyrosine kinase inhibitors (TKIs) have revolutionised chronic myeloid leukaemia treatment but cause cardiovascular toxicities through incompletely understood mechanisms. This study characterised the pharmacokinetics of imatinib, nilotinib and ponatinib, focusing on perivascular adipose tissue (PVAT) accumulation and vascular toxicity in C57BL/6 mice. Ponatinib showed unique pharmacokinetics with high apparent mean residence time (5.22 h vs. 1.51 h for imatinib, and 3.20 h for nilotinib) and high apparent distribution volume (2891.33 mL/kg vs. 683.75 mL/kg for imatinib, and 74.84 mL/kg for nilotinib). Importantly, ponatinib had exceptionally high tissue-to-plasma ratio in aorta with PVAT (8.44 vs. 0.37 for imatinib, and 0.14 for nilotinib). Chronic ponatinib treatment (10 mg/kg, 4 weeks) severely impaired endothelium-dependent vasodilation assessed by magnetic resonance imaging in vivo (thoracic aorta -7.4 ± 1.1% vs. controls 5.1 ± 1.3%). Ponatinib accumulated in aorta with PVAT after chronic treatment and directly impaired adipocyte maturation in in vitro experiments. In isolated aorta, ponatinib reduced vascular nitric oxide (NO) release. In conclusion, endothelial dysfunction and impaired NO-dependent function induced by ponatinib were related to a unique profile of ponatinib distribution compared with other TKIs, along with direct effects on adipocyte maturation. Our results suggest that after chronic treatment, ponatinib accumulation in PVAT leads to the impairment of the vasoprotective function of PVAT, contributing to endothelial dysfunction induced by ponatinib.