DDDT: the big "PK" of glimepiride and epagliptin

Background: Diabetes mellitus (DM) is a common endocrine disorder
caused by insulin resistance and/or defects in insulin secretion.
Diabetes is one of the leading causes of death among adults, with 4 million people dying globally in 2017
.
Type 2 diabetes mellitus (T2 DM) accounts for about 90%
of DM.
The prevalence of T2 DM is on the rise, which is related
to aging, accelerated urbanization, obesity and other factors.
Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce blood glucose levels by increasing levels
of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin-like polypeptide (GIP).
GLP-1 and GIP increase insulin concentrations
in a glucose-dependent manner by increasing intracellular cyclic adenosine 3',5'-monophosphate (CAMP) levels and reducing glucagon concentrations.

Several clinical trials have demonstrated that the DPP-4 inhibitor epagliptin has hypoglycemic effects, leading to its approval
in South Korea in 2015.
Epagliptin is rapidly absorbed after oral administration and takes about 5 hours to reach the maximum plasma concentration (Tmax).

It is mainly eliminated
by the non-renal route of human cytochrome P450 3A (CyP3A) enzymes.
Its main metabolites 4(S)-hydroxyevogliptin (ELAGLIPTIN M7) and 4(R)-hydroxyevogliptin (ELAGLIPTIN M8) are produced
from cytochrome P3A4 and cytochrome P3A5, respectively.

In May 2000, glimepiride tablets entered China, and is the first approved third-generation sulfonylurea hypoglycemic drug that can be used simultaneously with insulin, mainly used in type 2 diabetic patients
with poor blood sugar control after diet and exercise.
The main mechanism of its hypoglycemic effect is to stimulate the secretion of insulin by the cells β pancreatic islets, which may also be related to
improving the sensitivity of surrounding tissues to insulin.
As a result, glimepiride is used as a first-line treatment
for T2 DM in many countries, including China and Japan.
Rapidly absorbed after oral administration and reaches Tmax within 3 hours, eliminated mainly by non-renal routes; This involves metabolizing CYP2C9
of glimepiride to its main metabolite, hydroxyglimepiride (glimepiride M1).
Metformin monotherapy is the recommended first-line drug therapy for T2 DM; However, in South Korea, it has a treatment failure rate of about 45%.

Many guidelines for the treatment of T2 DM recommend that combination therapy
with drugs with different mechanisms of action be recommended if glycaemic goals cannot be met with a single treatment.
Therefore, a combination of DPP-4 inhibitors and sulfonylureas for T2 DM may be an effective regimen
.
Glimepiride did not show any pharmacokinetic (PK) interactions with DPP-4 inhibitors, including vildagliptin, sitagliptin, and linagliptin
.
However, its interaction with EVO remains to be evaluated
.
Therefore, in this study, we aim to evaluate the PK and pharmacodynamic (PD) interactions
between epagliptin and glimepiride.

Objective: The dipeptidyl peptidase-4 inhibitor epagliptin, and the sulfonylurea glimepiride are used for the treatment of type 2 diabetes
.
The objective of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions
between epagliptin and glimepiride.

Materials and methods: Randomized, open-label, 3 cycles, 3 courses, 2 sequences of crossover studies
in healthy male subjects.
At each stage, subjects received multiple doses of epagliptin 5 mg alone (EVO), glimepiride 4 mg alone (GLI), or a combination of both (EVO+GLI).

Serial blood samples and urine samples were collected 168 hours and 24 hours after administration for PK and PD analysis
.

Results: 34 participants completed the study
.
The combined application of epagliptin and glimepiride did not change their plasma and urine PK profile
.
For epagliptin, the geometric mean ratio (Gmr) (Gmr) (90% confidence interval) of steady-state maximum plasma concentration (Cmax, ss) and area under the steady-state dosing interval curve (AUCτ, ss) to E (90% confidence interval) were 1.
0 2 (0.
98~1.
0 6) and 0.
97 (0.
95~1.
0 0),
respectively.
The corresponding values of EVO+GLI and GLI of glimepiride were 1.
08 (1.
01~1.
17) and 1.
08 (1.
02~1.
14),
respectively.
All values are within the normative bioequivalence standard range of 0.
8-1.
25
.
The combination of epagliptin and glimepiride lowers blood glucose
compared with epagliptin or glimepiride alone.

Fig.
1 Plasma evogliptin and glimepiride concentration-time curves
at homeostasis after epagliptin, glimepiride, or combination therapy.
Error bars indicate the standard deviation
.
(A) epagliptin, linear scale, (B) epagliptin, semi-logarithmic scale, (C) glimepiride, linear scale, and (D) glimepiride, semi-logarithmic scale
.

Table 1 Steady-state pharmacokinetic parameters of glimepiride and glimepiride M1 after glimepiride and combination therapy

Figure 2 Average Δ blood glucose (A) and Δ serum insulin (B) levels - time curve
in steady state after epagliptin, glimepride or combination therapy.
The Δ blood glucose and Δ insulin values at each time point can be obtained
by subtracting the value of 0h.
Error bars indicate the standard deviation
.

Table 2 Pharmacodynamic parameters of blood glucose and insulin levels in steady-state oral glucose tolerance test after epagliptin, glimepride or combination therapy

Conclusion: There is no PK interaction between epagliptin and glimepiride, and the combination has a stronger hypoglycemic effect
than epagliptin or glimepiride alone.

Original source:

[1] JI Lianying, CHENG Li, HONG Chengjie, ZONG Li, LI Lingjun.
Bioequivalence of glimepiride tablets in healthy subjects in China[J].
Chinese Journal of Clinical Pharmacology,2022,38(20):2464-2468.
)

[2] Hyounggyoon Yoo, Yun Kim, In-Jin Jang,et al.
Pharmacokinetic/Pharmacodynamic Interactions Between Evogliptin and Glimepiride in Healthy Male Subjects.
Drug Des Devel Ther.
2020 Nov 24; 14:5179-5187.