Pharmacokinetics of Gepotidacin in Renal Impairment

Abstract

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. In this phase 1, nonrandomized, open-label, parallel-group, multicenter, multipart study, the pharmacokinetics, safety, and tolerability of a single intravenous (IV) dose of gepotidacin 750 mg over 2 hours were evaluated in subjects with normal renal function, in those with moderate and severe renal impairment, and in end-stage renal disease (ESRD) on and not on dialysis. Administration of IV gepotidacin 750 mg was safe and generally tolerated in the study subjects. Dosing in severe renal impairment with and without hemodialysis resulted in significant increases in plasma drug levels and decreases in clearance. The geometric mean elimination half-life (t½ ) was minimally impacted (range 9.45 to 11.5 hours) in all the renal-impairment groups relative to normal renal function. Regardless of renal function, urine gepotidacin concentrations remained considerably high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma concentrations. The t½ in saliva was not impacted in the moderate-impairment and ESRD subjects and was comparable to t½ in plasma. Over a 4-hour dialysis, approximately 6% of the gepotidacin dose was removed. Overall, subjects with severe renal impairment and ESRD with and without hemodialysis may require adjustment in dose or dosing frequency.

Trial registration: ClinicalTrials.gov NCT02729038.

Keywords: end-stage renal disease; gepotidacin; pharmacokinetics; physiologically based pharmacokinetic modeling; renal impairment; safety.

Conflict of interest statement

M.H., C.T., A.R., D.N., G.T., and E.D. were employees of GSK and hold company stock. H.A., R.P., and T.M. were the study investigators funded by GSK during the conduct of the study. All authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors.

© 2020 GlaxoSmithKline. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Relationship between gepotidacin clearance and renal function. CL indicates clearance; EGFR, estimated glomerular filtration rate; ESRD, end‐stage renal disease; R2, R2 (correlation coefficient).

Figure 2

Mean gepotidacin urine concentrations by renal function (semilogarithmic scale). Lower limit of quantification (LLOQ) = 1.00 μg/mL represented by dashed line; E coli MIC = 4 μg/mL, represented by solid line. All values below LLOQ were set to 0. Subjects with ESRD on hemodialysis received gepotidacin 750 mg starting 2 hours before initiation of the last hemodialysis (period 1; ESRD before hemodialysis) and starting 2 hours after completion of the last hemodialysis (period 2; ESRD after hemodialysis). ESRD indicates end‐stage renal disease; MIC, minimal inhibitory concentration.

Figure 3

Scatterplot of gepotidacin saliva and unbound plasma AUC0‐∞ by renal function (log‐log plot). Plasma parameters are presented as protein‐corrected values (67% protein correction factor): unbound plasma parameters = total plasma parameter × 0.67. Saliva parameters represent unbound drug parameters because saliva drug concentrations do not require correction for protein binding. AUC indicates area under the concentration‐time curve; ESRD, end‐stage renal disease.

Figure 4

Plot of gepotidacin total plasma, unbound plasma, and saliva concentrations in normal subjects and subjects with moderate renal impairment.