MP21-07 SAFETY, TOLERABILITY AND PHARMACOKINETICS OF SINGLE AND MULTIPLE ASCENDING DOSES OF THE EP2/EP3 RECEPTOR AGONIST ONO-8055, A POTENTIAL NEW THERAPY FOR UNDERACTIVE BLADDER, IN HEALTHY SUBJECTS

Abstract

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology II1 Apr 2015MP21-07 SAFETY, TOLERABILITY AND PHARMACOKINETICS OF SINGLE AND MULTIPLE ASCENDING DOSES OF THE EP2/EP3 RECEPTOR AGONIST ONO-8055, A POTENTIAL NEW THERAPY FOR UNDERACTIVE BLADDER, IN HEALTHY SUBJECTS Christopher Chapple, Mark Bruce, Tomoya Ohno, Tomohiro Kuwayama, and Stephen Deacon Christopher ChappleChristopher Chapple More articles by this author , Mark BruceMark Bruce More articles by this author , Tomoya OhnoTomoya Ohno More articles by this author , Tomohiro KuwayamaTomohiro Kuwayama More articles by this author , and Stephen DeaconStephen Deacon More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.959AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Underactive bladder (UAB) is a syndrome involving a dysfunctional bladder condition in which patients are unable to produce an effective voiding contraction. ONO-8055 is a potent prostaglandin EP2 and EP3 receptor agonist that has been demonstrated to contract the bladder and relax the urethra in vitro. This study was a first in human investigation into the safety, tolerability and pharmacokinetics (PK) of ONO-8055 in healthy subjects. METHODS This was a single-centre 5-part study in 145 healthy subjects. ONO-8055 was given as single and multiple oral ascending doses to healthy young (Y) and elderly (E) males (M) and females (F). Part A (single ascending dose, 0.5-1000μg, 72YM), Part C (multiple ascending dose, 41 subjects, 100–700μg twice daily [BID] for 7 days in YM, 300–500μg for 13 days in Y/E F), Part D (gender effect, single 300μg dose, 8F) and Part E (age effect, single 300μg dose, 16 E M/F) had a double-blind, placebo-controlled and parallel group design. Part B (food effect, single 300μg dose, 8 YM) had an open-label crossover design. 111 subjects were exposed to ONO-8055 (80 YM, 6 EM, 12 YF and 13 EF). RESULTS There were no serious adverse events (AEs). The majority of AEs reported were gastrointestinal (GI) related, were of mild intensity (93%) and resolved. There were 2 severe AEs - diarrhoea at 300μg BID and frequent bowel movements at 500μg BID both in EF. Overall, the most frequent AE reported was diarrhoea (ONO-8055: 26.1%; Placebo: 17.6%). GI AEs mainly involved loose stools and to a lesser extent increased frequency of stools, and appeared to have a possible dose relationship. Females appeared to be more susceptible to GI AEs than males. There were no clinically significant changes in laboratory tests, vital signs or ECGs. Cmax and AUCinf were dose proportional with single doses up to 8μg and less than proportional 25–1000μg. There was no evidence of deviation from dose proportionality for Cmax or AUCinf with multiple dosing (100–700μg). Steady state was achieved by Day 5. AUCinf was 23% higher in fed vs fasted state (p<0.05). A high fat meal delayed median Tmax (by ∼2.5h, p<0.001). There was no significant effect of age or gender on PK. CONCLUSIONS ONO-8055 was generally well tolerated following single doses up to 1000μg and multiple doses up to 700 μg BID. Overall there were no safety or PK concerns that would preclude further development of ONO-8055 for UAB. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e235 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Chapple More articles by this author Mark Bruce More articles by this author Tomoya Ohno More articles by this author Tomohiro Kuwayama More articles by this author Stephen Deacon More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...