SAT0082 A randomised, double-blind, placebo-controlled, oral single dose, dose escalation trial, investigating the safety, tolerability and pharmacokinetics of svt-2016 in healthy male subjects. preliminary report

Background As a pivotal enzyme in the inflammatory response, inhibition of cyclooxygenase is an established mechanism of action for many anti-inflammatory agents. Non-selective inhibition of COX reduces pain, fever and inflammation but is often associated with gastrointestinal or renal injury. In the past decade, the existence of multiple isoforms of COX has become established.1 Selective inhibitors of COX-2 are thought to reduce pain, fever and inflammation without causing the gastrointestinal or renal injury associated with inhibition of COX-1.2 SVT-2016 is a new COX-2 inhibitor being developed for the treatment of pain and inflammation associated with osteoarthritis and rheumatoid arthritis. Objectives Evaluate the safety and tolerability of rising doses (16 mg, 32 mg and 64 mg) of SVT-2016, in healthy male volunteers. In addition, the pharmacokinetics (PK) of SVT-2016 following a single oral dose was examined. Methods Three groups of 6 healthy male volunteers, aged 23–43 years, were exposed to a single oral dose of SVT-2016 or matching placebo (Group 1: 16 mg SVT-2016, Group 2: 32 mg SVT-2016 and Group 3: 64 mg SVT-2016). For each group, subjects were randomised to receive either SVT-2016 or matching placebo (2:1 active to placebo). All volunteers provided informed written consent prior to participation. The study was approved by the Simbec Independent Ethics Committee. Following administration of SVT-2016, blood samples were taken for the determination of plasma SVT-2016 levels at the following time points: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post dose. Vital signs were measured and a 12-lead ECG performed throughout the 48 h post dose. Continuous ECG monitoring took place until 4 h after dosing. Laboratory safety tests were conducted prior to dosing and at 24 h and 48 h post dose. Adverse events were monitored throughout the study. Validated LCMS method was used for the determination of plasma SVT-2016 concentrations. Results There were no clinically significant changes in vital signs, ECG or laboratory safety tests during the study. A total of three adverse events were recorded (2 events of mild headache and 1 event of mild dizziness). No serious or severe adverse events were recorded. All events were considered to be mild in severity. The pharmacokinetic profile obtained following a single oral dose of SVT-2016 demonstrates that, SVT-2016 was absorbed in a dose dependent manner, Cmax increasing with increasing dose level administered. This peak plasma concentration occurs at approximately 1.7 h (range: 1.5 h ? 1.9 h) following administration of SVT-2016, suggesting a rapid onset of action. The elimination half-life of SVT-2016 appears to increase with increasing dose level and would support the suitability of this compound for the treatment of patients with osteoarthritis and rheumatoid arthritis. Conclusion SVT-2016 was considered to be safe and well tolerated at the dose levels investigated. The PK obtained favour the development of SVT-2016 as a novel COX-2 inhibitor for the treatment of pain and inflammation associated with osteoarthritis and rheumatoid arthritis. To further examine the safety, tolerability and PK of SVT-2016, it is proposed that further dose levels be investigated. References Xie WL, et al. Proc Natl Acad Sci USA 1991;88:2692–6 Wallace JL. TiPS 1999;20:4–6