Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

Abstract

The use of ethionamide (ETH) in treating multi-drug resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray dried particles might minimize systemic exposure and side effects. Methods Spray dried ETH particles were optimized for performance in a dry powder aerosol generator (DPAG) and exposure chamber. ETH particles were administered by the IV, oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage and lung tissues were measured and subjected to non-compartmental pharmacokinetic analysis. Results DPAG dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At Tmax, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas, following insufflation lung concentrations were 5-fold higher than in plasma. AUC(0-t), and CL were similar after IV administration and insufflation. AUC(0-t) after oral administration was 6–7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). Conclusion Pulmonary ETH delivery would potentially enhance efficacy for TB treatment given the high lung concentrations and bioavailability

Inhalable Fucoidan Microparticles Combining Two Antitubercular Drugs with Potential Application in Pulmonary Tuberculosis Therapy

“…According to the World Health Organisation (WHO), there were 10.4 million new TB cases globally and 1.3 million TB-related deaths in 2016 [1]. Global TB control is very difficult due to many factors, including late diagnosis and patient nonadherence to long-term treatments, which leads to a high incidence of extensive resistance to effective antitubercular drugs [2]. Besides drug resistance, the current therapy faces serious challenges, such as multi-drug interactions—especially with antiretroviral agents in cases of TB and HIV co -infection—long-term treatment, and antibiotic toxicity, which lead to adverse effects, resulting in patient non-compliance [3].…”

The Treatment of Tuberculosis

“…19,32 Several drugs have been prepared as inhaled dosage forms. [60][61][62][63][64] The challenges to this approach include delivery into the damaged areas of the lung, extra-pulmonary organisms, patient acceptance, adherence, and proper technique, and cost. All of these problems can be overcome, some more easily than others.…”

“…Given that TB typically presents as a chronic pneumonia, it is tempting to consider direct chemotherapy in the lungs, thus sparing systemic toxicity 19,32 . Several drugs have been prepared as inhaled dosage forms 60–64 . The challenges to this approach include delivery into the damaged areas of the lung, extra‐pulmonary organisms, patient acceptance, adherence, and proper technique, and cost.…”

Preclinical Development of Inhalable d -Cycloserine and Ethionamide To Overcome Pharmacokinetic Interaction and Enhance Efficacy against Mycobacterium tuberculosis

“…A further benefit of administering inhalations may lie in the fact that ETO is a prodrug that is converted into its active sulfoxide metabolites by the enzyme FMO2, available predominantly in host lung tissue. Hence, bacteria residing in the lungs would be exposed to the high concentration of the active metabolite (6). Pulmonary delivery of ETO alone has been recently reported (6).…”

“…Hence, bacteria residing in the lungs would be exposed to the high concentration of the active metabolite (6). Pulmonary delivery of ETO alone has been recently reported (6). A fixed-dose inhaled combination of the two drugs might therefore be useful (7).…”