Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants

Abstract

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic in late-phase development for uncomplicated urinary tract infection and uncomplicated urogenital gonorrhea. Two clinical studies were conducted to assess the pharmacokinetics (PK) and interethnic comparisons of oral gepotidacin (free-base and to-be-marketed mesylate formulations) administered as single doses ranging from 1500 to 3000 mg in fed and fasted states, and as 2 × 3000-mg doses given 12 hours apart under fed conditions in healthy participants of Japanese ancestry. Dose proportionality was observed in plasma exposures, and comparable area under the concentration-time curve (AUC) and maximum concentration were observed in fed and fasted states. Interethnic comparisons for Japanese versus non-Japanese participant data showed slightly higher plasma maximum concentration (7%-30%) yet similar plasma AUCs; slightly lower urine AUCs (11%-18%) were observed. The slightly higher plasma exposures in healthy Japanese versus White participants in the same study were attributed to lower mean body weights (64 kg versus ≈80 kg). Adverse events were primarily gastrointestinal, and when administered with food, gastrointestinal tolerability was improved. Overall, the gepotidacin PK and safety-risk profiles in healthy Japanese support potential evaluation of the global clinical doses in future studies.

SWOT and Root Cause Analyses of Antimicrobial Resistance to Oral Antimicrobial Treatment of Cystitis

“…The primary weaknesses of OAT are inter-individual variability in the clinical outcomes and AMR owing to inter-individual variability in pharmacokinetics [25,29,30,[96][97][98] and hepatobiliary vs. renal clearance [20] delaying the achievement of the minimum inhibitory concentration (MIC) in urine [23,87]. The oral bioavailability of OAT differs with race [32,99], food intake [97], inter-individual variability in the gastric emptying time [100], posture (supine or ambulatory) [101,102], and the general health status of the patient [103]. MIC is the lowest antimicrobial concentration required to prevent the visible growth of the test strain of a microbe after a definite incubation period under strictly controlled in vitro conditions [104].…”

“…It is noteworthy that the antimicrobial effect of OAT on cystitis takes effect only after the absorbed dose fraction runs the gauntlet of pharmacokinetics to be filtered from the plasma by the kidneys into urine (Figure 2) [20,23,26,30,32,35,87,105]. The variability in the pharmacokinetics of OAT stems from variable absorption of drug from the gut [23,106], first pass metabolism of drug in the liver before its systemic distribution and renal excretion (Figure 2) for an intermittent ureteric delivery of OAT into urine.…”

“…Based on the frequent voiding of patients with cystitis, one can infer that the concentration build-up reported for healthy volunteers [23] may not materialize in patients with cystitis as their frequent voiding prevents concentration buildup (Figure 2). Moreover, kidney function as indexed by creatinine clearance [24,32,34,35,107] exerts a critical impact on the urine levels of OAT to cause a characteristic delay in the MIC [28]. The delay in the urinary MIC [24,32,34,107] of OAT in the wake of the initial conditions (different from parenteral administration) is a threat for the emergence and prevalence of AMR, which can be countered by AMS practices.…”

“…Moreover, kidney function as indexed by creatinine clearance [24,32,34,35,107] exerts a critical impact on the urine levels of OAT to cause a characteristic delay in the MIC [28]. The delay in the urinary MIC [24,32,34,107] of OAT in the wake of the initial conditions (different from parenteral administration) is a threat for the emergence and prevalence of AMR, which can be countered by AMS practices. AMS represents an opportunity for the future sustained growth of newer OAT targeting resistant uropathogens.…”

“…While there has been a lot of discussion on the role of the genetic [21,22] and phenotypic attributes of adaptable uropathogens [31] in AMR development, this review is focused on oral antimicrobial treatments (OATs), specifically their interaction with the human body (pharmacokinetics), delaying the achievement of MIC in urine [32,33], and the potential consequences. Uropathogens exposed to below-MIC levels in urine bestow The infection of the urothelium can only occur after uropathogens successfully compete for available nutrients with the commensal microbiome [13] by employing mechanisms of commensalism [14], mutualism, and parasitism [15,16].…”