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Background: Loxapine inhalation powder delivered by a hand-held device as a thermally generated aerosol (ADASUVE) was recently approved in the United States and European Union for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. As smokers comprise a large subpopulation of these patients, and many antipsychotic drugs require dose adjustments for smokers, the objective of this study was to compare the pharmacokinetics of inhaled loxapine administered to smokers and nonsmokers., Methods: Pharmacokinetics and sedation pharmacodynamics using a visual analog scale were studied in 35 male and female adult subjects (18 nonsmokers and 17 smokers) following a single dose of 10 mg of inhaled loxapine. Blood samples were drawn at predose, 30 seconds, 1, 2, 3, 10, 30, and 60 minutes, and 2, 6, 12, and 24 hours after dosing. Loxapine and 8-OH-loxapine were analyzed using reverse-phase liquid chromatography coupled with a tandem mass spectrometer. Pharmacokinetic parameters assessed included Cmax, Tmax, AUCinf, and T1/2 for loxapine and 8-OH-loxapine. Geometric mean ratios (GMRs) were determined for smokers to nonsmokers., Results: Loxapine Cmax was similar in smokers and nonsmokers with a GMR of 99.0%. The median loxapine Tmax was 1.88 and 1.01 minutes for nonsmokers and smokers, respectively. Loxapine AUCinf and AUClast values in nonsmokers were comparable with smokers (GMRs of 85.3% and 86.7%, respectively). A slight decrease in the observed mean terminal half-life values was observed for smokers (6.52 hours for smokers and 7.30 hours for nonsmokers)., Conclusions: Sedation profiles and visual analog scale scores at each time point were similar for nonsmokers and smokers. It was concluded that inhaled loxapine does not require dosage adjustment based on smoking behavior.

The antipsychotic drugs risperidone, paliperidone, olanzapine, quetiapine, aripiprazole, clozapine, haloperidol, and chlorpromazine have been reported to have various degrees of interaction (substrate or inhibitor) with the multidrug resistance transporter, P-glycoprotein (P-gp). An interaction of the antipsychotic drug loxapine with P-gp was recently reported, but an IC50 value was not determined. Loxapine (as the succinate salt) was evaluated as a P-gp substrate, and inhibitor of P-gp mediated transport of digoxin in vitro in Caco-2 cells. Loxapine was not a substrate for P-gp but did exhibit weak-to-moderate inhibition (IC50 = 9.1 μM). Since the typical steady state maximal plasma concentrations of loxapine in clinical use have been reported to be in the nanomolar range, pharmacokinetic interactions due to the inhibition of P-gp activity are not expected.

A highly pure aerosol of the antipsychotic drug, loxapine, can be thermally generated through vaporization from a thin coating of loxapine on a stainless steel substrate with the formation of a condensation aerosol. Because loxapine can exist in two polymorphic forms, the morphological time course from loxapine drug substance to coating on the substrate (intermediate product) and ultimately to the aerosol was investigated using differential scanning calorimetery, X-ray diffraction (XRD), Fourier transform infrared, and Raman spectroscopy. Monoclinic and orthorhombic crystalline forms of loxapine were confirmed by single crystal and powder XRD. A mixture of both loxapine crystalline polymorphs was formed on the substrate, independent of the initial loxapine crystalline morphology, and demonstrated to be stable. The loxapine aerosols generated from the thermal aerosolization process were demonstrated to be amorphous, regardless of the initial polymorph of loxapine active pharmaceutical ingredient used. In humans, the amorphous aerosol was reported to be rapidly absorbed and the particle size resulted in rapid delivery to the deep lung., (Copyright © 2010 Wiley-Liss, Inc.)