Pharmacokinetics of EDP-420 after Multiple Oral Doses in Healthy Adult Volunteers and in a Bioequivalence Study

Abstract

EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI.Macrolides are currently used as a first-line treatment for respiratory tract infections (RTIs), including community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis, pharyngitis/tonsillitis, and otitis media (5, 37). The extensive clinical usage of macrolides has resulted in the rapid emergence of macrolide resistance, particularly among streptococci, staphylococci, and enterococci (1, 13, 38). Thus, there is an urgent need to develop new antibiotics with activity against a broad spectrum of pathogens (especially resistant strains) commonly encountered in community-acquired RTIs. The design of EDP-420 (formerly known as EP-013420, or S-013420) was undertaken in response to this unmet medical need.EDP-420 represents a novel structural class of bridged bicyclolide antibacterial agents (36) (the structure is shown in Fig. 1). It exhibits potent in vitro activities against RTI pathogens, including multidrug-resistant streptococci and the atypical pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila) (4, 10, 19, 24, 27-32, 34, 39). In vivo, EDP-420 has also demonstrated efficacy against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Mycobacterium avium in mouse protection tests, against S. pneumoniae and Haemophilus influenzae in a rat lung infection model, and against penicillin-and quinoloneresistant pneumococci in a rabbit meningitis model (2-4, 22, 23, 25, 32-34). The nonclinical pharmacok...

Pharmacokinetic/Pharmacodynamic Modeling for Concentration-Dependent Bactericidal Activity of a Bicyclolide, Modithromycin

“…The KC 50 /MIC values in this study were generally higher than those for β‐lactams, suggesting that this parameter could be an index of dose dependency for the efficacy, as suggested by Yano et al The KC 50 values of modithromycin ranged from 0.159 to 473 μg/mL. Plasma C max following a 100–1200‐mg single oral dose in the US phase 1 study ranged from 196 to 1076 μg/mL, indicating KC 50 values were achievable in in vivo plasma.…”

“…For S. aureus SR20405 and H. influenzae SR24169, PK parameter sets P1–P4, which were determined based on PK parameters estimated from plasma concentrations of modithromycin following a 400‐mg single oral dose in Phase 1 study conducted in US, were used. For S. pneumoniae SR26132, PK parameter set P5, which was determined based on PK parameters estimated from plasma concentrations of modithromycin following a 300‐mg single oral dose in Phase 1 study conducted in Japan, was used.…”

In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

“…The time-concentration curves of S-013420 exposed to H. influenzae were basically derived from the PK profile of S-013420 after administration of a 400-mg single oral dose obtained from a phase I study conducted in the United States (15). The AUC 0-24 , C max , and half-life (t 1/2 ) of this PK profile were 8.61 g-h/ml, 0.506 g/ml, and 17.8 h, respectively.…”

Recent Advances in the Medicinal Chemistry of Novel Erythromycin- Derivatized Antibiotics

“…Compared with telithromycin, EDP-420 also showed excellent pharmacokinetic properties in mice, rat and dog with longer half-life and higher concentration in lung. Disclosed clinical data [58,59] showed that EDP-420 was well tolerated in healthy human volunteers with long half-life and high systemic exposure. EDP-420 also exhibited excellent activities against Mycobacterium avium [60,61] and penicillin-resistant and quinolone-and penicillin-resistant pneumococci [62].…”