Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea.

BACKGROUND: Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of Neisseria gonorrhoeae (N. gonorrhoeae). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study. In this narrative review of previously shown data, we summarise how a translational approach based on in vitro PK/PD and population PK modelling and simulation data was undertaken to select a dosing regimen for the ongoing phase III gepotidacin study in participants with uncomplicated urogenital gonorrhoea. METHODS: For dose selection, prior in vitro minimum inhibitory concentrations (MICs) and PK/PD data were available. PK modelling was conducted to determine a dose that would limit plasma concentrations to less than 14 µg/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining ≥90% probability of target attainment (PTA) for efficacy and resistance suppression against N. gonorrhoeae isolates with gepotidacin MICs ≤1 µg/mL. RESULTS: Two 3000 mg gepotidacin doses, administered 10-12 hours apart, resulted in PTA of ≥97.5% and ≥91.7% for gepotidacin MICs ≤1 µg/mL for the ratio of the area under the free drug plasma concentration-time curve over 24 hours to the MIC (fAUC0-24/MIC) efficacy, and resistance suppression targets of 40 and 46, respectively, but limited the occurrence of maximum plasma concentrations ≥14 µg/mL. CONCLUSIONS: Two gepotidacin 3000 mg oral doses 10-12 hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MIC N. gonorrhoeae isolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses.

Design and Conduct Considerations for First-in-Human Trials.

A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations. An emphasis is placed on FIH trial design considerations, including starting dose selection, study size and population, dose escalation scheme, and implementation of adaptive designs. In light of the recent revision of the European Medicines Agency (EMA) guideline on FIH trials to promote safety and mitigate risk, we also discuss new measures introduced in the guideline that impact FIH trial design.