Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

Daniel A Spyker, Robert A Riesenberg, James V Cassella, Daniel A Spyker, Robert A Riesenberg, James V Cassella

Abstract

This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412.

Keywords: ADASUVE; Staccato; agitation; inhaled loxapine; multiple dose; pharmacodynamics; pharmacokinetics.

© 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Staccato drug‐device combination product.
Figure 2
Figure 2
Subject disposition (safety population).
Figure 3
Figure 3
Plasma concentrations of loxapine by dose regimen, first 12 h. Mean ± 1 SD by dose group, all PK subjects (N = 24).
Figure 4
Figure 4
Dose proportionality based on AUCinf for all 8 dose groups. Slope (90%CI) = 0.818 (0.762–0.875) across the 8 doses. (Regression [95%CI], R2 = 0.911, N = 60). + from single dose study, □ from this study.
Figure 5
Figure 5
Safety summaries, change from baseline by last dose administered. Arithmetic mean [90% confidence interval] (safety population). A: Sitting systolic BP (mmHg); B: Sitting diastolic BP (mmHg); C: Sitting heart rate (/min); D: VAS sedation (mm); E: PR interval (msec); F: QTcF, Fridericia corrected QT (msec).

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Source: PubMed

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