Preclinical development of inhalable D-cycloserine and ethionamide to overcome pharmacokinetic interaction and enhance efficacy against mycobacterium tuberculosis

Abstract

We compared the pharmacokinetics and efficacy of a combination of D-cycloserine (DCS) and ethionamide (ETO) via oral and inhalation routes in mice. The plasma half-life (t1/2) of oral ETO at a human-equivalent dose decreased from 4.63 0.61 h to 1.64 0.40 h when DCS was coadministered. The area under the concentration-time curve from 0 h to time t (AUC0 –t) was reduced to one-third. Inhalation overcame the interaction. Inhalation, but not oral doses, reduced the lung CFU/g of Mycobacterium tuberculosis H37Rv from 6 to 3 log10 in 4 weeks, indicating bactericidal activity.