Pharmacokinetic and Pharmacodynamic Effects of Oral CXA‐10 a Nitro Fatty Acid After Single and Multiple Ascending Doses in Healthy and Obese Subjects

摘要

10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics ( ), pharmacodynamics ( ), safety, and tolerability of oral ‐10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of ‐10. After single and multiple ascending doses, ‐10 demonstrated dose‐proportional increases in plasma exposure. ‐10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In ‐10‐202, a consistent decrease from baseline was observed with ‐10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, ‐1, and ‐6. In ‐10‐203, after coadministration with ‐10, geometric mean peak plasma concentration (C ) and area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval ( ) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of ‐10. Adverse events ( s) were dose‐related, and the most frequently reported s (>10% of subjects) were diarrhea, abdominal pain, and nausea. ‐10 was safe and well‐tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of ‐10 75–300 mg once daily.