A review of formulations and preclinical studies of inhaled rifampicin for its clinical translation

Abstract

Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans.

Keywords: Animal models; Inhalation; Preclinical development; Rifampicin; Tuberculosis.

Fig. 1

Devices for direct aerosol delivery to small animals. A Device for intra-tracheal liquid instillation; B Microsprayer^® Aerosolizer for liquid aerosol delivery; C dry powder insufflator. B and C were manufactured by Penn-Century, Inc

Fig. 2

A small animal laryngoscope (left) and a prototype rat intubation platform (right)

Fig. 3

Exposure systems for passive pulmonary drug administration to laboratory animals

Fig. 4

Assessment of in vivo properties of aerosol drug formulations developed for anti-TB therapy