Tissue Distribution of [ ¹⁴ C]-Lefamulin into the Urogenital Tract in Rats

Abstract

Lefamulin, a semisynthetic pleuromutilin antibiotic approved in the United States, Canada, and Europe for intravenous and oral treatment of community-acquired bacterial pneumonia, is highly active in vitro against bacterial pathogens that cause sexually transmitted infections (STIs), including multidrug-resistant strains of Neisseria gonorrhoeae , Chlamydia trachomatis , and Mycoplasma genitalium . This nonclinical study used quantitative whole-body autoradiography (QWBA) and qualitative tape-transfer microautoradiography (MARG) to investigate lefamulin distribution into urogenital tract tissues down to a cellular level in male and female rats.

Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections

“…Frontiers in Pharmacology frontiersin.org urogenital tract tissues than in plasma in a rat model (Wicha et al, 2022). When simulating treatment based on free lefamulin concentrations in human plasma, successful eradication of the WHO reference strains WHO F, WHO X, and WHO V required a single oral dose of 1.2, 2.8, and 9.6 g, respectively.…”

“…When simulating this treatment and lefamulin 750 mg orally every 12 h (highest single oral dose with proven tolerability) based on free lefamulin concentrations in human plasma, only WHO F was eradicated, and both WHO X and WHO V persisted (Figure 3). Considering lefamulin concentrations in relevant STI tissues as a source control of gonococcal infections, with ≥5-10 times higher concentrations of lefamulin (Wicha et al, 2022), WHO X and WHO V were also eradicated without any lefamulin resistance emergence in the successful treatment arms (Figure 4). The absence of human PK data from the main infection sites for gonorrhea, such as the anogenital tract and oropharynx, represents the main limitation of the present study and most similar STI studies, which is a problem not only for novel antimicrobials, such as lefamulin, but also for currently recommended antimicrobials.…”

“…Lefamulin was administrated to mimic an adult human PK plasma concentration–time profile following a single oral dose of lefamulin (PK parameters for lefamulin 600 mg oral dose (fasted) were used: 12% fraction of free lefamulin in plasma, 9 h t 1/2 , and a 2-h infusion time, and linearly adjusted for other doses) (NAB-BC-3781-1107; ClinicalTrials.gov identifier NCT02557789). Furthermore, because the lefamulin concentration in the main STI tissues (urogenital tissues) in rats has been shown to be ≥ 5–10 times higher than the concentration in plasma ( Wicha et al, 2022 ), 5 and 10 times the free lefamulin concentration in human plasma was also simulated. One HFIM cartridge per examined strain and experiment was used as an untreated growth control.…”

“…Dose–fractionation experiments ( n = 2) simulated, based on free lefamulin concentrations in human plasma, lefamulin oral daily dose of 1.2 g (approved oral treatment for CABP) and 1.5 g (because 750 mg is the highest single oral dose proven safe) against WHO F; 1.2–4.0 g against WHO X; and 1.2 and 1.5 g against WHO V; administered as one-half of the total dose given at 0 h and at 12 h (q12 h) repeatedly for 7 days, and 2.4–3.6 g against WHO X as one-third the total dose administered at 0, 8, and 16 h (q8 h) repeatedly for 7 days. Additionally, dose–fractionation experiments that simulated lefamulin oral dose regimens based on free lefamulin concentrations in urogenital tissues of rats were conducted, which have been shown to be ≥ 5–10 times higher than in plasma ( Wicha et al, 2022 ). These dose–fractionation experiments ( n = 2) included lefamulin daily dose of 1.2 g against WHO F and WHO X and lefamulin of 1.2 and 1.5 g for WHO V, administered as one-half of the total dose given at 0 h and at 12 h (q12 h) repeatedly for 7 days.…”

“…By performing lefamulin dose–range and dose–fractionation studies, we examined the dynamic rate of lefamulin N. gonorrhoeae killing and emergence of any lefamulin-resistant N. gonorrhoeae populations. We also evaluated the PD based on free (protein-unbound) lefamulin concentrations in human plasma and in urogenital tract tissues (main gonorrhea infection sites), which was estimated based on a rat model ( Wicha et al, 2022 ).…”