A Phase I Study Investigating the Local Tolerability and Pharmacokinetics of Isoniazid (INH) Inhalation by Wet Nebulization in Patients With Tuberculosis

Rationale: To halt the global tuberculosis (TB) crisis, and particular the ongoing threat of drug-resistant TB (DR-TB), it is essential to reduce transmission. This could be done by shortening the period that patients with pulmonary TB secrete viable bacilli, and are therefore contagious to others, by prompt initiation of effective treatment. Pulmonary administration of anti-TB drugs might play an important role since it yields higher local concentrations and lower systemic concentrations compared to systemic (oral or parenteral) administration. Isoniazid (INH) has very high bactericidal activity and is one of the most effective drugs in the treatment of TB. Although the occurrence of mutations leading to resistance to INH at systemic concentrations has hindered the use of this drug, INH can still be effective when administered in a high concentration at the site of infection even in case of drug resistance. This cannot easily be achieved by oral dosing because of the associated risk of systemic toxicity. However, pulmonary administration of INH may be a solution. The concept of inhalable antimicrobials is not new; for example it is a well-established therapy for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients. INH has been used by inhalation before in patients with TB but only up to a dose of 200 mg/day. In this protocol, a local tolerability and pharmacokinetic study of higher doses of INH inhalations will be performed by wet nebulization in patients with TB. The hypothesis is that single doses up to 1200 mg INH are safe. Future studies will demonstrate that high intrapulmonary concentrations enhance the initial reduction of the bacterial load in both drug-susceptible TB (DS-TB) as well as TB with reduced susceptibility to INH. If proven, this novel inhalation-based approach may lead to a massive decline in further spread of (drug resistant) TB. Objectives: The primary objective of this study is to investigate the local tolerabilit