Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase‐4 inhibitor, evogliptin (<scp>DA</scp>‐1229)

Oh, Jaeseong; Kim, Andrew Hyoung Jin; Lee, Seung Hwan; Cho, Hyun-Jeong; Kim, Yon Su; Bahng, Mi Young; Yoon, Seo Hyun; Cho, Joo Youn; Jang, In Jin; Yu, Kyung‐Sang

doi:10.1111/dom.12813

Cited by 15 publications

(17 citation statements)

References 18 publications

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“…Thus, urinary markers mentioned in this study could be affected by the renal function of individuals, even without the effect of uremic toxins. However, we had previously observed a significant difference in CYP3A activity among patients with renal impairment grouped by eGFR when the activity was assessed by 6β-OH-cortisol/cortisol and 6β-OH-cortisone/cortisone 10. Thus, we wanted to validate this result in a relatively larger cohort and in comparison with plasma markers for CYP3A activity.…”

Section: Discussionmentioning

confidence: 88%

“…Previous studies have hypothesized that indoxyl sulfate may interfere with transcriptional activation and down-regulate gene expression through pro-inflammatory cytokines, which could directly inhibit the activity of CYP and drug transporters 59. Additionally, we previously observed a significant difference in hepatic CYP3A activity according to the severity of renal impairment in phase I clinical trials of a CYP3A substrate, evogliptin, where metabolic markers were measured in samples collected before administration of evogliptin 10. Thus, drug-induced toxicity may occur in patients with renal impairment, not only because drug elimination by the kidneys is reduced, but also because plasma indoxyl sulfate could interfere with enzymes involved in hepatic drug metabolism 11…”

Section: Introductionmentioning

confidence: 91%

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Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

et al. 2018

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BackgroundThe renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of 4β-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers.MethodsSixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers (6β-OH-cortisol/cortisol, 6β-OH-cortisone/cortisone, 4β-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the 4β-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test.ResultsThere was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary 6β-OH-cortisol/cortisol and 6β-OH-cortisone/cortisone as well as plasma 4β-OH-cholesterol and 4β-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate.ConclusionHepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 91%

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

et al. 2018

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“…Blood sampling for measuring unbound evogliptin was conducted 4.5 and 24 h after study drug administration. Blood sampling points were determined by considering the time to reach peak concentration ( T max ) and the elimination half‐life ( t 1/2 ) of evogliptin 9–14 . Plasma concentrations of total and free evogliptin were analysed using liquid chromatography–tandem mass spectrometry (LC–MS/MS).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and safety of evogliptin in hepatically impaired patients

Hong

Jin

Kim

et al. 2020

Brit J Clinical Pharma

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Aims Evogliptin is a potent and selective dipeptidyl peptidase‐4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment. Methods An open‐label, parallel‐group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8). Results Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (Cmax) and area under the concentration–time curve values from 0 to 120 h (AUClast); the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (Cmax and AUClast) was increased by about 40% in patients with moderate hepatic impairment—the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects. Conclusion Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted.

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“…As a result, evogliptin reduced postprandial glucose by 20% to 35% compared to placebo . And another study reported the pharmacokinetic and pharmacodynamic profiles of evogliptin in renal impairment; the plasma concentration of evogliptin increased 1.98 times in severe renal impairment, but within a therapeutic window . Drug administration in patients with T2DM is usually performed over extended periods of time; therefore, an evaluation of the safety and efficacy of these drugs over a long term is extremely important.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of adding evogliptin versus sitagliptin for metformin‐treated patients with type 2 diabetes: A 24‐week randomized, controlled trial with open label extension

Hong

Park

Hwang

et al. 2017

Diabetes Obesity Metabolism

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AimsThis trial consisted of a 24‐week multicentre, randomized, double‐blind, double‐dummy, active‐controlled study and a 52‐week open label extension study to assess the efficacy and safety of evogliptin, a novel dipeptidyl peptidase‐4 inhibitor, compared to sitagliptin in patients with type 2 diabetes who have inadequate glycaemic control with metformin alone.MethodsAdult patients with type 2 diabetes mellitus (N = 222) with HbA1c 6.5% to 11% who were receiving stable doses of metformin (≥1000 mg/d) were randomized 1:1 to add‐on evogliptin 5 mg (N = 112) or sitagliptin 100 mg (N = 110) once daily for 24 weeks. The primary efficacy analysis consisted of a comparison of the change from baseline HbA1c at week 24. Non‐inferiority was concluded if the upper limit of the 2‐sided 95% confidence interval for the HbA1c difference between treatments was <0.35%.ResultsMean changes in HbA1c following addition of evogliptin or sitagliptin were −0.59% and −0.65%, respectively. The between‐group difference was 0.06% (2‐sided 95% confidence interval, −0.10 to 0.22), demonstrating non‐inferiority. After the 52‐week treatment, evogliptin caused a persistently decreased level of HbA1c (−0.44% ± 0.65%, P < .0001). In general, both treatments were well tolerated, with incidences and types of adverse events comparable between the two groups. Hypoglycaemic events, mostly mild, were reported in 0.9% of patients treated with evogliptin and in 2.8% of patients treated with sitagliptin for 24 weeks.ConclusionsEvogliptin 5 mg added to metformin therapy effectively improved glycaemic control and was non‐inferior to sitagliptin and well tolerated in patients with type 2 diabetes mellitus that was inadequately controlled by metformin alone.

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Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase‐4 inhibitor, evogliptin (DA‐1229)

Cited by 15 publications

References 18 publications

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

Pharmacokinetics and safety of evogliptin in hepatically impaired patients

Efficacy and safety of adding evogliptin versus sitagliptin for metformin‐treated patients with type 2 diabetes: A 24‐week randomized, controlled trial with open label extension

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