Absorption, metabolism and excretion of [¹⁴C]omarigliptin, a once-weekly DPP-4 inhibitor, in humans

Abstract

1. Omarigliptin (MARIZEV®) is a once-weekly DPP-4 inhibitor approved in Japan for the treatment of type 2 diabetes. The objective of this study was to investigate the absorption, metabolism and excretion of omarigliptin in humans. 2. Six healthy subjects received a single oral dose of 25 mg (2.1 μCi) [C]omarigliptin. Blood, plasma, urine and fecal samples were collected at various intervals for up to 20 days post-dose. Radioactivity levels in excreta and plasma/blood samples were determined by accelerator mass spectrometry (AMS). 3. [C]Omarigliptin was rapidly absorbed, with peak plasma concentrations observed at 0.5-2 h post-dose. The majority of the radioactivity was recovered in urine (∼74.4% of the dose), with less recovered in feces (∼3.4%), suggesting the compound was well absorbed. 4. Omarigliptin was the major component in urine (∼89% of the urinary radioactivity), indicating renal excretion of the unchanged drug as the primary clearance mechanism. Omarigliptin accounted for almost all the circulating radioactivity in plasma, with no major metabolites detected. 5. The predominantly renal elimination pathway, combined with the fact that omarigliptin is not a substrate of key drug transporters, suggest omarigliptin is unlikely to be subject to pharmacokinetic drug-drug interactions with other commonly prescribed agents.

Comparative review of dipeptidyl peptidase‐4 inhibitors and sulphonylureas

“…The DPP-4 inhibitors differ widely in their chemistry and pharmacokinetic properties [34] (Table 2). Some have intrinsically long-half-lives (alogliptin, evogliptin, gemigliptin, linagliptin, omarigliptin, sitagliptin, teneligliptin and trelagliptin) [34][35][36][37][38][39], giving sustained DPP-4 inhibition which allows once-daily or, for omarigliptin and trelagliptin, once-weekly dosing. Others have much shorter half-lives (anagliptin, saxagliptin and vildagliptin) [34,40]; however, whereas the aforementioned inhibitors interact non-covalently with the enzyme, the cyanopyrrolide moiety in anagliptin, saxagliptin and vildagliptin promotes covalent binding, resulting in these inhibitors remaining bound to the enzyme for longer than predicted from their short half-lives [41,42].…”

“…The DPP-4 inhibitors also differ in their elimination pathways (Table 2), which can influence their clinical usage. Alogliptin, linagliptin, omarigliptin, sitagliptin and trelagliptin are not appreciably metabolized, and are eliminated predominantly unchanged [34,37,39]. Gemigliptin undergoes modest hepatic metabolism to form an active metabolite which makes up ∼10% of the circulating material but which is twice as potent as the parent inhibitor [36,44].…”

“…The kidneys are important in the final elimination of most of the inhibitors, with glomerular filtration and active secretion being involved. Compounds such as alogliptin and sitagliptin rely almost exclusively on the kidneys for clearance of the active inhibitor molecules, whereas, as discussed above, metabolism is involved for several of the other compounds, although ultimately, both parent and metabolite are still predominantly cleared renally [34][35][36][37][38]40]. In contrast, the main elimination route for linagliptin is biliary excretion; at its therapeutic dose, linagliptin is mostly protein-bound, which minimizes its renal clearance (to <6%) [34].…”

Omarigliptin decreases inflammation and insulin resistance in a pleiotropic manner in patients with type 2 diabetes

“…A recent study has shown that DPP4 secreted by hepatocytes in obese mice promotes adipose inflammation and insulin resistance [14]. Omarigliptin is a DPP4 inhibitor with a half-life that enables weekly dosing and it has a wide organ distribution including the liver [1,15]. Therefore, it might decrease morning glucagon levels more effectively than daily DPP4 inhibitors [16].…”

“…Omarigliptin is a potent, selective, oral dipeptidyl peptidase 4 (DPP4) inhibitor with a half-life that allows weekly dosing [1,2]. Because they can ameliorate glycemic control in patients with type 2 diabetes without severe side effects, daily DPP-4 inhibitors have become an established part of the treatment regimens for patients over the past 10 years.…”