TY - JOUR
T1 - Pharmacokinetics of Gepotidacin in Renal Impairment
AU - Hossain, Mohammad
AU - Tiffany, Courtney
AU - Raychaudhuri, Aparna
AU - Nguyen, Dung
AU - Tai, Guoying
AU - Alcorn, Harry
AU - Preston, Richard A.
AU - Marbury, Thomas
AU - Dumont, Etienne
N1 - Funding Information:
Funding for this study was provided by GlaxoSmithKline (NCT02729038). This work was also supported in whole or in part with federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Other Transaction Authority Agreement No. HHSO100201300011C. Editorial support (development of the first draft, assembling tables and figures, collating author comments, and referencing) was provided by Guissou Dabiri, PhD, and was funded by GSK.
Funding Information:
Funding for this study was provided by GlaxoSmithKline (NCT02729038). This work was also supported in whole or in part with federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Other Transaction Authority Agreement No.?HHSO100201300011C. Editorial support (development of the first draft, assembling tables and figures, collating author comments, and referencing) was provided by Guissou Dabiri, PhD, and was funded by GSK. The authors would like to thank the participants and clinical staff of this study for their participation.
Publisher Copyright:
© 2020 GlaxoSmithKline. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - end-stage renal disease
KW - gepotidacin
KW - pharmacokinetics
KW - physiologically based pharmacokinetic modeling
KW - renal impairment
KW - safety
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U2 - 10.1002/cpdd.807
DO - 10.1002/cpdd.807
M3 - Article
C2 - 32429000
AN - SCOPUS:85085658946
VL - 9
SP - 560
EP - 572
JO - Clinical Pharmacology in Drug Development
JF - Clinical Pharmacology in Drug Development
SN - 2160-763X
IS - 5
ER -