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 tmax occurred at the time that the first blood sample following completion of dosing. After Cmax 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®) than after administration of any dose level of RT234. During repeated dose administration of RT234, Cmax 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 t1/2 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.

Keywords: inhalation; pharmacokinetics; pulmonary arterial hypertension; vardenafil.

Conflict of interest statement

The authors declare they have no competing financial interests.

Figures

FIG. 1.

Study design. (a) Part 1: SAD, single ascending doses; (b) Part 2: MAD, multiple ascending doses.

FIG. 2.

Mean plasma vardenafil concentrations versus nominal time after administration of single ascending inhalation doses to healthy subjects. Color images are available online.

FIG. 3.

Plasma vardenafil Cmax and AUC values versus RT234 dose. AUC, area under the curve. Color images are available online.

FIG. 4.

Mean plasma vardenafil concentrations versus time after administration of single doses of 0.6 mg RT234 or 20 mg oral vardenafil (Levitra®) to healthy subjects Color images are available online.

FIG. 5.

Scatter plot of plasma vardenafil concentrations versus time from all subjects receiving repeated doses. Color images are available online.

FIG. 6.

Observed and model-predicted plasma vardenafil concentrations versus time from all subjects receiving repeated doses. Color images are available online.