Intrapulmonary Pharmacokinetics of S-013420, a Novel Bicyclolide Antibacterial,in Healthy Japanese Subjects

S-013420 (EDP-420) is a novel bicyclolide (bridged bicyclic macrolide) antibacterial currently under development for the treatment of respiratory tract infections. The objective of the present study was to determine the plasma and intrapulmonary pharmacokinetic parameters of orally administered S-013420 in healthy volunteers. Twenty-eight healthy Japanese male subjects who never smoked were randomly allocated to seven groups of four subjects each who underwent bronchoalveolar lavage (BAL) at different times after dosing (2, 4, 6, 8, 10, 12, or 24 h). Blood samples were also taken at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h after dosing. The S-013420 concentrations in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs) were measured by using a combined high-performance liquid chromatography-mass spectrometric technique. A pharmacokinetic analysis of the plasma, ELF, and AM S-013420 concentration profiles was performed. S-013420 was rapidly absorbed in plasma, and the mean time to the maximum concentration in plasma was 2.27 h. S-013420 was rapidly distributed to the ELF and was slowly distributed to AMs. The areas under the concentration-time curves from time zero to 24 h (AUC_0-24) for S-013420 were 20.3 times higher in ELF than in plasma and 244.6 times higher in AMs than in plasma. The mean maximum concentration in plasma was higher in ELF than in plasma and was much higher in AM than in plasma. Furthermore, pharmacodynamic calculations were done by using the AUC_0-24/MIC₉₀ ratio for common pneumonia pathogens (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis). The AUC_0-24 for plasma/MIC₉₀s for these four organisms were 41.8, 83.6, 1.3, and 20.9, respectively. The AUC_0-24 for ELF/MIC₉₀s were 849.6, 1,699.2, 26.6, and 424.8, respectively. Considering the good efficacy shown in a subsequent phase 2 study (S. Kohno, K. Yamaguchi, Y. Tanigawara, A. Watanabe, A. Aoki, Y. Niki, and J. Fujita, Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L-485), the good distribution of S-013420 in AMs and ELF observed in the present study is predictive of the good efficacy of S-013420 against respiratory pathogens.During the development of antibacterial agents, knowledge of the drug concentrations in infected lesions is important for predicting the effectiveness of antimicrobial chemotherapy. In order to support the use of a drug for clinical indications such as respiratory tract infections, the bronchoalveolar lavage (BAL) technique can be utilized to investigate the distribution of the drug in the lungs of humans. The BAL technique allows measurement of the concentration of drug both in the epithelial lining fluid (ELF) and within alveolar macrophages (AMs). Measurement of the latter is especially important for macrolides, which can accumulate intracellularly at high concentrations.Several investigations measuring the distributions of clarithromycin (CAM) (10, 11, 13, 15), azithromycin (AZM) (11, 13, 15, 20), and telithromycin (TEL) (5, 12) in the lungs of healthy subjects have been reported. Those studies have shown that macrolides have high degrees of distribution in ELF and AMs.S-013420 (EDP-420) is a novel bicyclolide (bridged bicyclic macrolide) antibacterial and has been shown to have potent activity against various pathogens. It is notable that the drug has strong activity against multidrug-resistant Streptococcus pneumoniae, including penicillin G- and erythromycin-resistant strains, which have become a worldwide public health problem (4).The spectrum of activity of S-013420 covers both common and atypical respiratory pathogens. Maki et al. (8) showed that S-013420 has in vitro activity against S. pneumoniae, Streptococcus pyogenes, and methicillin-susceptible Staphylococcus aureus (MIC₉₀s ≤ 0.063 to 0.25 μg/ml). This activity was greater than the activities of CAM and AZM (MIC₉₀s = 1 to >64 μg/ml) and comparable to the activity of TEL. The anti-Haemophilus influenzae activity of S-013420 (MIC₉₀ = 8 μg/ml) was comparable to that of CAM and less than that of TEL (MIC₉₀ = 4 μg/ml). Tsuji et al. investigated the in vivo activity of S-013420 against experimental animal infection models (18). In an animal model of infection with erythromycin-resistant S. pneumoniae, S-013420 was more effective than CAM and AZM and was as effective as TEL. S-013420 (30 mg/kg of body weight) reduced the number of viable cells of a strain of H. influenzae to the same extent that CAM did.In general, ketolide analogues such as TEL are well known to have a low potential to induce resistance. S-013420 has also been demonstrated to have a low potential to induce resistance (19). These excellent antibacterial characteristics of S-013420 are the result of the inhibition of protein synthesis by binding to two sites in domain V and one site in domain II, a total of three sites, of the 23S rRNA for the 50S subunit of the bacterial ribosome.For macrolide antibiotics, the ratio of area under the concentration-time curve (AUC) to the MIC, calculated by pharmacokinetic (PK) analysis, is well-known to correlate with efficacy against infections (3). The AUC for ELF/MIC is the most favorable parameter for predicting the ability of macrolides to eradicate respiratory pathogens.In the present study, we investigated the pharmacokinetics of S-013420, including its lung distribution, using BAL multiple times for up to 24 h after the administration of a single oral dose of a S-013420 suspension to healthy volunteers. By means of in vitro PK and pharmacodynamic (PD) modeling with an H. influenzae strain (MIC = 8 μg/ml), the AUC from time zero to 24 h (AUC_0-24)/MIC required to achieve 90% maximum bactericidal activity was calculated in order to predict the appropriate dosages for use in a subsequent phase 2 clinical trial (7).