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Imeglimin Does Not Induce Clinically Relevant Pharmacokinetic Interactions When Combined with Either Metformin or Sitagliptin in Healthy Subjects.

Abstract：

BACKGROUND AND OBJECTIVES:Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics of either MET or SITA in healthy Caucasian men. METHODS:Healthy Caucasian men received either MET 850 mg twice daily with placebo (n = 16) or SITA 100 mg once daily with placebo (n = 16) on days 1-6, followed by MET 850 mg twice daily with IMEG 1500 mg twice daily or SITA 100 mg once daily with IMEG 1500 mg twice daily on days 7-12. Pharmacokinetic parameters were determined from blood and urine; levels of all compounds were evaluated using liquid chromatography with tandem mass spectrometry. RESULTS:Systemic exposure (AUC0-τ area under the plasma concentration-time curve over a dosing interval and maximum concentration) to MET was 14% and 10% lower, respectively, when administered with IMEG. Approximately 40% of MET was excreted unchanged in urine, decreasing to 34% when given with IMEG. The 90% confidence intervals for AUC0-τ and maximum concentration indicated no effect of co-administration on systemic exposure to MET. Mean AUC0-τ and maximum concentration of SITA were similar with or without IMEG. Median times to maximum concentration were 0.7 and 1.0 h and mean elimination half-lives were 8.2 and 8.7 h with and without IMEG, respectively. Systemic exposure to IMEG was similar to previous phase I studies. CONCLUSIONS:Co-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC0-τ and maximum concentration) and renal elimination were noted when MET was given with IMEG vs placebo. CLINICAL TRIAL REGISTRATION:EudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI).

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Fouqueray P,Perrimond-Dauchy S,Bolze S

doi

10.1007/s40262-020-00886-y

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

1261-1271

issue

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-020-00886-y

journal_volume

pub_type

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Imeglimin Does Not Induce Clinically Relevant Pharmacokinetic Interactions When Combined with Either Metformin or Sitagliptin in Healthy Subjects.