Safety, Tolerability, and Pharmacokinetics of RT234 (Vardenafil Inhalation Powder): A First-in-Human, Ascending Single- and Multiple-Dose Study in Healthy Subjects

Abstract

Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration ''as needed'', to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH). Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs). Results: RT234 was generally safe and well tolerated at single doses of 0.2-2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The t max occurred at the time that the first blood sample following completion of dosing. After C max was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra Ò ) than after administration of any dose level of RT234. During repeated dose administration of RT234, C max was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t 1/2 values were comparable after single-and repeated-dose administration. Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

Future Perspectives of Pulmonary Arterial Hypertension: A Review of Novel Pipeline Treatments and Indications

“…A phase I study, RT234-CL101, has been completed for RT234 [ 106 ], which compared the pharmacokinetic profiles of RT234 and oral vardenafil in healthy volunteers. The maximum concentration of vardenafil was reached rapidly (time to C max [ T max ] = 2 min), there were no serious treatment-emergent AEs, and the drug was well tolerated.…”

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design

“…Vardenafil is a high-affinity inhibitor of PDE5 (half-maximal inhibitory concentration [IC 50 ] 0.091 ± 0.031) [ 11 ], which, in combination with its slow dissociation rate, allows for lower concentrations of the drug to be used, reducing the chance of adverse effects. Furthermore, direct delivery to the lungs via RT234 reduces systemic exposure to the drug, as observed in RT234-CL101 [ 13 ]. This is supported by the results of the RT234-CL201 phase IIa study, in which the pulmonary vascular resistance/systemic vascular resistance ratio was reduced and stable mean systemic arterial pressure and systemic vascular resistance were maintained [ 23 ].…”

“…RT234-CL202 is the first trial to test the acute effect of an inhaled PDE5i on exercise parameters in patients with PAH and is therefore the first to address the unmet need for a PRN therapy for PAH. This trial will extend the results of the phase I and IIa studies, which established that RT234 is ideally suited for use as a PRN treatment for PAH because it exhibits pulmonary selectivity, is rapidly absorbed and cleared [ 13 ], and is well tolerated by patients with PAH on background therapies [ 23 ]. Although these trials demonstrated that RT234 has an acceptable safety profile and improves hemodynamic parameters in patients with PAH, this phase IIb trial will specifically investigate the safety and efficacy of RT234 when used to acutely improve VO 2 during exercise.…”

“…Plasma samples will be collected at visits 3 and 4 before RT234 dosing; at 3, 15, and 30 minutes post dose; immediately at the end of the exercise period; and at 45, 75, 120, 180, and 240 minutes post dose. Vardenafil concentrations will be measured in the PK samples as described previously [ 13 ]. Estimators of PK parameters will include T max , C max , area under the curve from time 0 to the last measurable concentration (AUC 0–Last ), AUC from time 0 to infinity (AUC 0–Inf ), and half-life (t 1/2 ).…”

“…1 )). A phase I study, RT234-CL101, has been completed for RT234 [ 13 ], which compared the pharmacokinetic (PK) profiles of RT234 and oral vardenafil in healthy volunteers. The maximum concentration (C max ) of vardenafil was reached rapidly (time to C max [T max ] = 2 minutes), there were no serious treatment-emergent adverse events (TEAEs), and the drug was well tolerated.…”