Background & Aims
Introduction: Otenaproxesul is a non-abusable, novel anti-inflammatory compound, designed for the management of acute pain. Unique to the molecule is a hydrogen sulfide releasing mechanism intended to enhance analgesic benefits while minimizing GI ulcerating effects typical of NSAIDs. In this study otenaproxesul was tested for safety and tolerability in an open-label three arm phase 1b PK trial.
Methods
Materials and Methods: Thirty-six subjects were recruited in one of the three treatment arms: Group A: a single 600 mg treatment, Groups B and C received 5-day treatment courses of otenaproxesul starting with a loading dose and followed by select, two-tiered tapering dose regimens. Treatment was administered every 12 hours as per the following regimens, Group B: (200, 100, 100, 100, 50, 50, 25, 25, 25, and 25) mg; Group C: (400, 200, 200, 200, 100, 100, 50, 50, 50, and 50) mg. Each arm included 4 male and 8 female healthy volunteers, 18 to 59 years of age. 80.6 % of study participants were Caucasian. Participants fasted 10 hours before and 4 hours post first dose administration and 2 hours before and after each subsequent treatment administration. Blood samples were collected for PK analyses at specified time intervals.
Results
Results: All participants completed the study. There were no SAEs, and all reported AEs were mild, not clinically significant and had resolved by the end of the study. Otenaproxesul’s concentration-time curves displayed linear, dose-proportional pharmacokinetics for both plasma drug concentrations and overall drug exposure.
Conclusions
Conclusions: Otenaproxesul was shown to be safe and well tolerated across all treatment regimens. The well-behaved and predictable PK characteristics afford flexibility for the design of safe, acute pain treatment regimens. Investigation of the otenaproxesul’s efficacy in patients undergoing abdominoplasty or bunionectomy is warranted.
References
1.Potent anti-inflammatory effects of an H2 S-releasing naproxen (ATB-346) in a human model of inflammation James R W Glanville 1, Parinaaz Jalali 1, Julia D Flint 1, Amit A Patel 1, Alexander A Maini 1, John L Wallace 2, Ali A Hosin 1, Derek W Gilroy 1 FASEB J . 2021 Oct;35(10):e21913. doi: 10.1096/fj.201902918RR. PMID: 34555204 DOI: 10.1096/fj.201902918RR
2.A proof-of-concept, Phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide-releasing anti-inflammatory drug John L Wallace 1 2, Peter Nagy 3 4, Troy D Feener 5, Thibault Allain 5, Tamás Ditrói 3, David J Vaughan 2, Marcelo N Muscara 6, Gilberto de Nucci 7, Andre G Buret 3 4 Br J Pharmacol . 2020 Feb;177(4):769-777. doi: 10.1111/bph.14641. PMID: 30834513 PMCID: PMC7024706 DOI: 10.1111/bph.14641
3.Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter John L Wallace 1, Rui Wang 2 Nat Rev Drug Discov . 2015 May;14(5):329-45. doi: 10.1038/nrd4433. Epub 2015 Apr 7. PMID: 25849904 DOI: 10.1038/nrd4433
Presenting Author
Joseph Stauffer
Poster Authors
Topics
- Evidence, Clinical Trials, Systematic Review, Guidelines, and Implementation Science