In Vitro Investigation, Pharmacokinetics, and Disposition of Imeglimin, a Novel Oral Antidiabetic Drug, in Preclinical Species and Humans

Chevalier, Clémence; Fouqueray, Pascale; Bolze, Sébastien

doi:10.1124/dmd.120.000154

Cited by 24 publications

(27 citation statements)

References 11 publications

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“…Imeglimin has shown an inhibitory effect in glucose production in both isolated rat liver cells and rat liver slices. 4,5 Moreover, imeglimin elicited a reduction in glucose produced by the isolated cells in a concentration-dependent pattern, with reductions ranging from 9% (for 0.25 mmol/L) to 80% (for 1.5 mmol/L), which is comparable to the results of metformin in its highest dosages. 7 In liver slices, the inhibition of glucose production was also apparent; in a dose-dependent pattern, the reduction ranged from 14% (for 2.5 mmol/L) to 84% (for 10 mmol/L).…”

Section: Inhibition Of Hepatic Glucose Productionmentioning

confidence: 65%

“…4 Imeglimin demonstrates a moderate intestinal absorption (50-80%) through the mechanism of active paracellular absorption; however, increased dosages of oral imeglimin have resulted in decreased intestinal absorption, likely due to the saturation of the active transport mechanism. 5 Consequently, the distribution of the drug through the bloodstream is fast, and plasma protein binding is low. Furthermore, there is no evidence of cytochrome P450 inhibition or induction.…”

Section: Pharmacokinetics: Chemical Propertiesmentioning

confidence: 99%

“…Furthermore, there is no evidence of cytochrome P450 inhibition or induction. 5 Imeglimin is excreted through the kidneys and mostly remains unchanged. 6 A recent study by Chevalier et al has indicated that it is safe and well tolerated in patients with moderate hepatic impairment, as the increase in maximum plasma concentration and the area under the curve (AUC) of concentration/time was not reported as clinically significant.…”

Section: Pharmacokinetics: Chemical Propertiesmentioning

confidence: 99%

“…7 In liver slices, the inhibition of glucose production was also apparent; in a dose-dependent pattern, the reduction ranged from 14% (for 2.5 mmol/L) to 84% (for 10 mmol/L). 5 On a molecular level, imeglimin achieved these results by downregulating phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in isolated hepatocytes from rats, and by inhibiting lactic acidosis via the mitochondrial-dependent pathway. 3,4 Stimulation of skeletal muscle glucose uptake…”

Section: Inhibition Of Hepatic Glucose Productionmentioning

confidence: 99%

See 3 more Smart Citations

Imeglimin: A New Promising and Effective Weapon in the Treatment of Type 2 Diabetes

Doupis¹,

Baris²,

Avramidis³

2021

touchREVIEWS in Endocrinology

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Section: Inhibition Of Hepatic Glucose Productionmentioning

confidence: 65%

Section: Pharmacokinetics: Chemical Propertiesmentioning

confidence: 99%

Section: Pharmacokinetics: Chemical Propertiesmentioning

confidence: 99%

Section: Inhibition Of Hepatic Glucose Productionmentioning

confidence: 99%

See 2 more Smart Citations

Imeglimin: A New Promising and Effective Weapon in the Treatment of Type 2 Diabetes

Doupis¹,

Baris²,

Avramidis³

2021

touchREVIEWS in Endocrinology

View full text Add to dashboard Cite

“…In contrast, administration of similar doses of Metformin in both animal models resulted in significant increases in mean plasma lactate levels and decreases in pH along with occurrences of overt lactic acidosis according to standard clinical definitions (Pang & Boysen, 2007). Although a precise cause of death was not established, it is important to note that several deaths occurred only with Metformin, in particular at higher dose levels, whereas no deaths—either related to lactic acidosis events or not—occurred with Imeglimin despite doses and plasma concentrations reached in the models are far greater those used in clinical settings (Clemence et al, 2020). Moreover, we confirmed that plasma exposure levels to both drugs were similar in the two models.…”

Section: Discussionmentioning

confidence: 99%

Reduced lactic acidosis risk with Imeglimin: Comparison with Metformin

Theurey

Vial

Fontaine

et al. 2022

Physiological Reports

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The global prevalence of type 2 diabetes (T2D) is expected to exceed 642 million people by 2040. Metformin is a widely used biguanide T2D therapy, associated with rare but serious events of lactic acidosis, in particular with predisposing conditions (e.g., renal failure or major surgery). Imeglimin, a recently approved drug, is the first in a new class (novel mode of action) of T2D medicines. Although not a biguanide, Imeglimin shares a chemical moiety with Metformin and also modulates mitochondrial complex I activity, a potential mechanism for Metformin‐mediated lactate accumulation. We interrogated the potential for Imeglimin to induce lacticacidosis in relevant animal models and further assessed differences in key mechanisms known for Metformin's effects. In a dog model of major surgery, Metformin or Imeglimin (30–1000 mg/kg) was acutely administered, only Metformin‐induced lactate accumulation and pH decrease leading to lactic acidosis with fatality at the highest dose. Rats with gentamycin‐induced renal insufficiency received Metformin or Imeglimin (50–100 mg/kg/h), only Metformin increased lactatemia and H+ concentrations with mortality at higher doses. Plasma levels of Metformin and Imeglimin were similar in both models. Mice were chronically treated with Metformin or Imeglimin 200 mg/kg bid. Only Metformin produced hyperlactatemia after acute intraperitoneal glucose loading. Ex vivo measurements revealed higher mitochondrial complex I inhibition with Metformin versus slight effects with Imeglimin. Another mechanism implicated in Metformin's effects on lactate production was assessed: in isolated rat, liver mitochondria exposed to Imeglimin or Metformin, only Metformin (50–250 µM) inhibited the mitochondrial glycerol‐3‐phosphate dehydrogenase (mGPDH). In liver samples from chronically treated mice, measured mGPDH activity was lower with Metformin versus Imeglimin. These data indicate that the risk of lactic acidosis with Imeglimin treatment may be lower than with Metformin and confirm that the underlying mechanisms of action are distinct, supporting its potential utility for patients with predisposing conditions.

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Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function

Kitamura

Yumizaki

Kondo

et al. 2023

The Journal of Clinical Pharma

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Imeglimin is a diabetic drug excreted mainly in the urine; therefore, the impact of renal impairment on its pharmacokinetics (PK) is of interest. We assessed the PK and safety of imeglimin in Japanese patients with impaired renal function. This was an uncontrolled, open-label, single-dose, phase 1 study. Participants were classified into 4 groups by their estimated glomerular filtration rate (mL/min/1.73 m 2 ) as follows: ≥90, normal renal function; and 60 to <90, mild; 30 to <60, moderate; and 15 to <30, severe renal impairment. All participants received imeglimin 1000 mg except those with severe renal impairment, who received imeglimin 500 mg. PK parameters were estimated using noncompartmental analysis, and those after multiple administrations were projected using a noncompartmental superposition method. In total, 24 Japanese participants (6 in each group) were enrolled and completed the study.The mean plasma imeglimin concentration reached the maximum at 2-4 hours after administration and then rapidly decreased.The geometric mean maximum observed plasma concentration and area under the plasma concentration-time curve values were higher in the impaired renal function groups versus normal renal function group. Most imeglimin was excreted in urine by 24 hours after administration. Renal clearance decreased with decreasing renal function. Projected maximum observed plasma concentration and area under the plasma concentration-time curve over the dosing interval after multiple dosing were greater in the renal impairment groups versus normal renal function group. No adverse events were observed. Considering increased plasma exposure along with decreased renal clearance, dose adjustment is required in patients with moderate and severe renal impairment with estimated glomerular filtration rate of 15 to <45 mL/min/1.73 m 2 .

show abstract

In Vitro Investigation, Pharmacokinetics, and Disposition of Imeglimin, a Novel Oral Antidiabetic Drug, in Preclinical Species and Humans

Cited by 24 publications

References 11 publications

Imeglimin: A New Promising and Effective Weapon in the Treatment of Type 2 Diabetes

Imeglimin: A New Promising and Effective Weapon in the Treatment of Type 2 Diabetes

Reduced lactic acidosis risk with Imeglimin: Comparison with Metformin

Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function

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