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

Abstract

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator 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 T_max, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC_(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC_(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.

Keywords: bioavailability; ethionamide; pharmacokinetics and pulmonary absorption; porous particles; tuberculosis.

Figure 1

SEM micrograph of spray dried ETH PPs. Bar = 10 μm. This micrograph corresponds to PPs containing 50% ETH, but the morphology of PPs containing 20% ETH is similar and therefore not shown.

Figure 2

AVERAGE plasma concentration versus time curves (log scale) for all treatments administered by various routes and with different doses. Treatments include: intravenous ethionamide USP (IV; 6 mg/kg), oral ethionamide USP (Oral; 6 mg/kg), ethionamide large porous particles (ETH-PPs; 6 mg/kg), and ethionamide large porous particles delivered by nose-only exposure (ETH-PPs; 5 mg/kg). * = IV different from oral (P<0.05); # = insufflation different from oral (P<0.05). (Average ± standard deviation, n = 4–8).