Inhaled loxapine for agitation

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Approved by the FDA on December 21, 2012, loxapine inhalation powder is the newest agent commercialized for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults (Table 1).^1,2 Loxapine is a first-generation antipsychotic that garnered newfound interest because of its potential atypical properties.³ Loxapine’s reformulation allows for direct administration to the lungs, resulting in rapid absorption into systemic circulation. This formulation offers a different method to manage agitation, for which IM formulations of other antipsychotics have been approved.⁴

Inhaled loxapine is delivered using a handheld device that produces a thermally-generated condensation aerosol.^5,6 A single inhalation is sufficient to activate the controlled rapid heating (300 to 500°C in approximately 100 ms) of a thin layer of excipient-free loxapine on a metal substrate. Once vaporized, the medication cools down rapidly and aggregates into particles. The 1- to 3.5-micron aerosol particles of loxapine enter the respiratory track in 7

Table 1

Inhaled loxapine: Fast facts

How it works

As with all antipsychotics, loxapine is an antagonist at the dopamine D2 receptor. However, loxapine also has clinically relevant serotonin-2A antagonism.³ Pharmacologic effects for loxapine and its metabolites include biogenic amine transporter inhibitor activity, alpha adrenergic blocking effects, and histaminergic and muscarinic receptor affinity.^3,8

Clinical pharmacokinetics

In a phase I study of healthy volunteers, inhaled loxapine produced IV administration-type kinetics, with maximum plasma concentration achieved in approximately 2 minutes.⁶ Plasma exposure to loxapine was dose-proportional. Half-life for the 5- and 10-mg doses was approximately 6 hours. In these patients, exposure to loxapine’s metabolites as a percentage of exposure to the parent compound were 8.79% for 7-OH loxapine, 52.6% for 8-OH loxapine, and 3.96% for amoxapine (all produced as a result of metabolism via liver cytochrome P450 [CYP] enzymes CYP1A2, CYP2D6, and/or CYP3A4⁶). 7-OH loxapine has a 5-fold higher affinity for the dopamine D2 receptor compared with loxapine, and may contribute to the drug’s clinical effect.⁶

Based on loxapine levels observed in the pharmacokinetic study,⁶ loxapine is not extensively metabolized in the lungs. Peak plasma concentrations immediately after inhalation are higher than for oral loxapine, but concentration of loxapine and its metabolites after the initial distribution phase is similar to that of oral loxapine.⁶ Loxapine and its metabolites are excreted through the kidneys.

Efficacy

Three efficacy studies were completed (Table 2)^9-11; all were double-blind randomized controlled trials that compared inhaled loxapine, 5 or 10 mg, with placebo. Patients were required to be clinically agitated at baseline, with a score of ≥14 on the Positive and Negative Syndrome Scale Excited Component (PANSS-EC)—which consists of the PANSS items of tension, excitement, hostility, uncooperativeness, and poor impulse control; each item is rated from 1 (absent) to 7 (extreme)—and a score of ≥4 (moderate) on ≥1 item. Patients who were intoxicated or had a positive drug screen for psychostimulants were excluded. Lorazepam was allowed ≥2 hours after the study drug was administered. Change in the PANSS-EC was measured 10 minutes to 24 hours post-dose. The primary endpoint used to statistically test loxapine vs placebo was 2 hours post-dose.

In the initial phase II trial, loxapine 10 mg, but not 5 mg, was superior to placebo on the PANSS-EC at 2 hours.⁹ The authors described the 5-mg dose effect size as intermediate between placebo and the 10-mg dose, suggesting a possible dose response relationship. The 10-mg dose did separate from placebo as early as 20 minutes post-dose. The small number of patients enrolled is a limitation of this trial, but this was addressed in studies in the phase III program, which were considerably larger. For each of the 2 phase III trials—1 for patients with schizophrenia¹⁰ and the other for those with bipolar disorder (BD)¹¹—both doses of loxapine were superior to placebo starting at 10 minutes post-dose. The number needed to treat (NNT) for response—as defined by a Clinical Global Impressions-Improvement score of much improved or very much improved—for loxapine vs placebo is included in Table 2.^9-11 NNT for other outcomes, such as reduction on the PANSS-EC by at least 40% from baseline, demonstrated similar results.