SAFETY AND PHARMACOKINETICS OF VARDENAFIL INHALATION POWDER (RT234) FOLLOWING ORAL INHALATION IN HEALTHY ADULT VOLUNTEERS

Abstract

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Vardenafil Inhalation Powder (RT234) is being developed for use as an as-needed treatment of episodic symptoms of Pulmonary Arterial Hypertension (PAH), to acutely improve exercise capacity, performance, and disease-associated symptom impacts. To evaluate the pharmacokinetics (PK) and safety of RT234, a Phase 1 single-center, open label, randomized clinical study in healthy human adult subjects was performed in two parts, a crossover single ascending dose (SAD), followed by a multiple ascending dose (MAD) study. METHODS: SAD: Single ascending doses of 0.2, 0.6, 1.2, and 2.4 mg of vardenafil hydrochloride were administered via oral inhalation with the RS01 monodose dry powder inhaler (Plastiape, Osnago, Italy) (N=6/group). The 0.6 mg dose group was compared to a 20 mg oral tablet of Levitra in a crossover design. Safety, tolerability and pharmacokinetics were assessed. MAD: The 2.4 mg dose was then administered for up to four times daily over a period of 9 days (N=8). SAD: Single ascending doses of 0.2, 0.6, 1.2, and 2.4 mg of vardenafil hydrochloride were administered via oral inhalation with the RS01 monodose dry powder inhaler (Plastiape, Osnago, Italy) (N=6/group). The 0.6 mg dose group was compared to a 20 mg oral tablet of Levitra in a crossover design. Safety, tolerability and pharmacokinetics were assessed. MAD: The 2.4 mg dose was then administered for up to four times daily over a period of 9 days (N=8). RESULTS: SAD: RT234 was well tolerated with all treatment emergent adverse events (TEAEs) mild to moderate in intensity. Headache and dizziness the most commonly reported TEAEs. Brief, asymptomatic decreases in systolic, diastolic, and mean arterial pressure were noted. These changes were not associated with reflex tachycardia or AEs of dizziness, and were not considered clinically significant. Vardenafil was rapidly absorbed in a dose proportional manner, with a Tmax at the first timepoint, 5 minutes post-administration. After Cmax, the plasma concentration declined rapidly in an exponential fashion. MAD: Treatment-related TEAEs were similar in the SAD and MAD cohorts. No clinically significant accumulation was observed in the MAD study. Mean half-life values were comparable to that measured in the SAD portion of the study. CONCLUSIONS: Vardenafil Inhalation Powder (RT234), was found to be safe and well tolerated when orally inhaled in normal human volunteers. This study indicates that vardenafil, administered via oral inhalation, is rapidly absorbed into the bloodstream, and when combined with vardenafil’s known long binding time at the catalytic receptor on the phosphodiesterase-5 enzyme, is well-suited for further clinical development as an as-needed therapeutic in PAH. CLINICAL IMPLICATIONS: Safety and Pharmacokinetics of Vardenafil Inhalation Powder (RT234) are ideal for further development as an as-needed therapy for PAH. A Phase 2a clinical study is underway. DISCLOSURES: No relevant relationships by Michael Eldon, source=Web Response Employee relationship with Respira Therapeutics, Inc. Please note: >$100000 Added 03/23/2020 by Mari Maurer, source=Web Response, value=Salary Consultant relationship with Respira Therapeutics Please note: $20001 - $100000 Added 03/26/2020 by Ed Parsley, source=Web Response, value=Consulting fee Employee relationship with Respira Therapeutics Please note: >$100000 Added 03/22/2020 by Jeffry Weers, source=Web Response, value=Salary