An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN‐D0501 in healthy subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Transient receptor potential vanilloid 1(TRPV1) receptor antagonists have the potential to be used in a wide variety of indications. Whilst many compounds have been evaluated pre‐clinically, published clinical data are sparse. A possible dose‐limiting effect of TRPV1 antagonists is their potential to cause hyperthermia. WHAT THIS STUDY ADDS • This study reports the safety and pharmacokinetic data for XEN‐D0501, a novel TRPV1 antagonist, in healthy subjects including effects on body temperature. AIMS XEN‐D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder. This study investigated the safety and pharmacokinetics of repeat‐dose XEN‐D0501 in healthy subjects. METHODS The study was conducted in two parts. Part 1 was a double‐blind, randomized, placebo‐controlled, two‐way crossover study in three cohorts of 12 young male subjects. Each subject received XEN‐D0501 and placebo (in random order) twice daily for 13 days, with a final single dose on day 14. Doses of 1, 2.5 and 5 mg XEN‐D0501 were investigated. Part 2 was an open‐label, randomized, two‐way crossover study in male and female subjects (45 to 65 years). Subjects received single doses of 5 mg XEN‐D0501 under fasted and fed conditions in random order. Blood sampling and safety assessments were conducted throughout the study. RESULTS XEN‐D0501 was rapidly absorbed ( t max generally 0.5–4 h post dose). XEN‐D0501 exposure increased less than proportionally to dose over the range studied and exhibited minimal accumulation with twice daily dosing. Food had no clinically relevant effects on the pharmacokinetics of XEN‐D0501. There were no severe or serious adverse events and all doses were well tolerated. A dose‐related increase in body temperature was seen with XEN‐D0501 which attenuated over time. Differences from placebo in mean maximum core body temperatures were 0.22°C, 0.5°C and 0.74°C following 1 mg, 2.5 mg and 5 mg twice daily XEN‐D0501. The observed increase in body temperature was not considered to be of clinical concern. CONCLUSIONS XEN‐D0501 appeared safe and well tolerated at doses up to 5 mg twice daily for 14 days in healthy subjects.