Opportunities for and Challenges of Pulmonary Drug Delivery in the Management of Acute Exacerbations of CNS Disorders

Abstract

Advances in pulmonary (PM) drug delivery through inhalation devices have enabled effective treatments for acute exacerbations of central nervous system (CNS) episodes, addressing previously unmet medical needs. While PM formulations of loxapine and levodopa are approved for agitation and off periods in Parkinson's disease (PD), respectively, there remains an unmet need for rapid-acting therapies for other acute exacerbations of neurologic disorders. In this review, the potential of PM delivery to address this gap in the management of acute CNS disorders is critically assessed, focusing on Staccato^® loxapine for agitation, Inbrija^® (levodopa) for PD, the investigational drug inhaler device Staccato^® alprazolam for epilepsy, and other investigational drug inhaler devices. PM delivery benefits from bypassing first-pass metabolism, utilizing inhalation devices to enable rapid drug delivery to the densely perfused alveolar space, arterial bloodstream, and brain. However, challenges include lung tissue sensitivity, low dose volume (compared with oral and intravenous administration), and difficulties with administration during certain acute episodes. Pharmacokinetic, efficacy, and safety data from approved or investigational PM therapies for agitation, PD, epilepsy, migraine, and insomnia present inhalation as a promising option for patients requiring acute episode management by facilitating fast absorption and onset of action and generally good tolerability. In particular, for epilepsy, on-demand medication that may be administered by patients or caregivers early at seizure onset may translate to improved patient outcomes. To enhance PM management of acute exacerbations of CNS disorders, further research and user training for optimal PM administration are required.

Fig. 1

Pathway from drug inhalation to systemic circulation and CNS. Upon inhalation, drug particles travel through the conducting airways to the alveolar region. In addition to passive diffusion, drug absorption through the alveolar and capillary epithelia to systemic circulation can be facilitated by active transporters or by paracellular diffusion via tight junctions or aqueous pores. CNS, central nervous system

Fig. 2

Inhaler devices and their respective inner mechanisms currently approved for PM delivery of treatments for acute exacerbations of CNS conditions. CNS, central nervous system; PM, pulmonary. Adapted from Refs. [20, 21, 38, 72, 135]

Fig. 3

Plasma drug concentrations over time of benzodiazepines used to treat acute seizures, or being investigated for this purpose, via different routes of administration. IV midazolam administration (2.5 min infusion) is included as a reference point (dashed line). *This study was investigator-initiated and undertaken using a solution of midazolam not designed for buccal administration.The PK data presented in these figures are based on the closest available data to the maximum approved single dose (per their respective labels) or maximum dose investigated in the most recent PK study as appropriate (see supplementary information for additional details regarding the rationale for each of the selected study data for inclusion). This figure is intended to collate data from independent studies in one source, and therefore direct comparison should be made cautiously as data are obtained from different clinical studies and with different PK sampling time, which may influence the accuracy of the reported mean plasma-concentration time profile. a Mean plasma concentrations (ng/mL) over time (min) of benzodiazepines delivered through pulmonary, intranasal, oromucosal, intramuscular, and rectal routes of administration. b, c mean plasma concentrations as a proportion of the respective maximum concentration over 120 min (b) or over 30 min (c) of benzodiazepines delivered through pulmonary, intranasal, oromucosal, intramuscular, and rectal routes of administration. Data from [, , –112]. APZ, alprazolam; BF, buccal film; DZP, diazepam; IV, intravenous; MDZ, midazolam; OS, oromucosal solution; PK, pharmacokinetic