Abstract Neurological conditions, such as multiple sclerosis, Parkinson?s disease, dementia, spina bifida, diabetes, stroke, and spinal cord injury (SCI), can result in loss of voluntary voiding of urine and require intermittent bladder catheterization for voiding. Catheter use is associated with increased incidence of health problems, predominately repeated urinary tract infections, sepsis, urethral trauma and hospitalization. Dignify Therapeutics is developing a novel drug treatment, DTI-100, to provide an ?on-demand, rapid-onset, short-duration, drug-induced, voiding therapy? for those who cannot void voluntarily. Results from our STTR Phase I grant award demonstrated that both intranasal (IN) solutions and sublingual orally disintegrating tablets (ODTs) that contain DTI-100 exhibit pharmacokinetic (PK) and pharmacodynamic (PD) characteristics that support additional studies to select between these two formulations for subsequent clinical development. Although both formulations induced voiding in rats, ODT dosing was not as potent or effective as IN dosing, presumably due to the highly keratinized oral mucosa of the rat compared to other species. Because of this, and because a ?non-rodent? species is required for use in safety studies prior to entering clinical trials, this STTR Phase II application proposes to evaluate IN and sublingual ODT formulations in rabbits and dogs, two species which are acceptable to the FDA for safety studies. The ultimate goal of this application is to pick a ?final formulation? for pharmaceutical development and select a suitable species for preclinical safety studies to enable our IND application to the FDA. In Phase II, DTI-100 will be administered to rabbits and dogs using the most promising formulations from our Phase I rat studies to compare PK and PD responses across species. Specific Aim (SA) 1 will complete one- year formulation stability tests that were initiated in Phase I. Formulation optimization by modification of excipients is also performed in SA1 if results with Phase I formulations in rabbits and dogs are inferior to those from rats. SA2 compares the IN and ODT formulations for PK profile and PD effects (isovolumetric pressure recording and voiding cystometry) in acute spinal and spinal intact, anesthetized rabbits. SA3 compares IN and ODT formulations for PK and PD effects in dogs. Voiding parameters are measured in anesthetized (isovolumetric pressure recording and voiding cystometry) and conscious (voiding onset and duration, voided volume, voiding efficiency) dogs. Based on their respective abilities to best meet the PK and PD of our ?ideal? target product profile, an IN or ODT formulation will be selected and used for subsequent IND-enabling preclinical safety studies.
NIH ExPorter
NIH ExPorter