A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

Abstract

Objective: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). Methods: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart + oral placebo, two doses of inhaled placebo + oral placebo, or two doses of inhaled placebo + oral moxifloxacin (400 mg; positive control), with ≥ 3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. Results: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. Conclusions: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review

“…Another great advantage of inhaled loxapine is the lack of the effect on cardiac repolarization. In fact, Cassella et al [ 48 ] showed that two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation, thus confirming the previous results of Spyker et al [ 47 ], who demonstrated that there was no apparent QT prolongation associated with the therapeutic dose of inhaled loxapine. Also, in clinical studies of agitated patients with psychiatric disorders, inhaled loxapine did not cause QTc prolongation or torsade de pointes [ 49 , 52 , 53 , 54 , 55 ].…”

“…Several studies on healthy volunteers have been conducted in order to assess the pharmacokinetics and tolerability of inhaled loxapine [ 46 , 47 , 48 , 49 , 50 ] ( Table 2 ). The administration of inhaled loxapine results in a rapid absorption, with a Tmax of two minutes, reaching a mean maximum plasma concentration ( C max) of 257 ± 219 ng/mL [ 26 , 29 ].…”

“…In fact, inhaled loxapine quickly reduces acute agitation in patients with schizophrenia or bipolar disorder, through a non-invasive route of administration with an onset of the effect within ten minutes [ 59 ]. Moreover, inhaled loxapine is generally well-tolerated, and the most common AEs are dysgeusia, throat irritation, and mild sedation [ 48 , 52 , 53 , 54 ], that do not usually require intervention.…”

“…Moreover, the delivery of inhaled loxapine directly into the lung has several potential advantages. These include a rapid onset of the anti-agitation effect (within a couple of minutes, generally 10), and a less invasive and needle-free systemic delivery of drugs [ 48 , 52 , 53 , 54 , 55 , 56 ]. Furthermore, the inhaled formulation of loxapine avoids transit through the gastrointestinal system and, therefore, the hepatic first-pass metabolism achieves a bioavailability of 9.1 mg of the 10 mg dose [ 25 ].…”

<p>Examining the safety, efficacy, and patient acceptability of inhaled loxapine for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults</p>

“…EPS, including akathisia, were uncommon and statistically non-significant when compared to placebo, unlike what can be seen with intramuscular haloperidol 37. Inhaled loxapine does not prolong the QTc interval 21,28,40…”