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Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug-drug interactions via CYP3A metabolism and transporters.
Barth, Aline; Perry, Caroline R; Shabbir, Shaila; Zamek-Gliszczynski, Maciej J; Thomas, Sebin; Dumont, Etienne F; Brimhall, Darin B; Nguyen, Dung; Srinivasan, Meenakshi; Swift, Brandon.
Afiliação
  • Barth A; Global Blood Therapeutics, South San Francisco, California, USA.
  • Perry CR; GSK, Collegeville, Pennsylvania, USA.
  • Shabbir S; GSK, Stevenage, UK.
  • Zamek-Gliszczynski MJ; GSK, Collegeville, Pennsylvania, USA.
  • Thomas S; GSK, Collegeville, Pennsylvania, USA.
  • Dumont EF; Boston Pharmaceuticals, Cambridge, Massachusetts, USA.
  • Brimhall DB; PPD, Las Vegas, Nevada, USA.
  • Nguyen D; GSK, Collegeville, Pennsylvania, USA.
  • Srinivasan M; GSK, Collegeville, Pennsylvania, USA.
  • Swift B; GSK, Durham, North Carolina, USA.
Clin Transl Sci ; 16(4): 647-661, 2023 04.
Article em En | MEDLINE | ID: mdl-36642822
Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug-drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P-glycoprotein (P-gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co-administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P-gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two-drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration-time curve (AUC). A weak DDI (AUC increase 48%-50%) was observed for gepotidacin co-administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1-methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P-gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (<2-fold AUC increase). There were no new safety-risk profile findings. These results will inform the safe and efficacious clinical use of gepotidacin when co-administered with other drugs.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Itraconazol / Citocromo P-450 CYP3A Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Itraconazol / Citocromo P-450 CYP3A Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article