Impact of Voglibose on the Pharmacokinetics of Dapagliflozin in Japanese Patients with Type 2 Diabetes

Abstract

IntroductionDapagliflozin is an orally administered selective sodium-glucose cotransporter 2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin lowers blood glucose through a reduction in renal glucose reabsorption. This study was performed to assess the effect of the oral antidiabetic agent voglibose [0.2 mg thrice daily (t.i.d.)] at steady-state, on the pharmacokinetics, safety and tolerability of dapagliflozin administered as a single oral dose (10 mg) to Japanese patients with T2DM.MethodsThis was an open-label, multi-center, drug–drug interaction study. A single oral dose of dapagliflozin (10 mg) was administered to 22 Japanese patients with T2DM in the presence and absence of voglibose (0.2 mg t.i.d.). Serial blood samples were collected before and at regular prespecified intervals after each dapagliflozin dose to determine dapagliflozin plasma concentrations and to evaluate pharmacokinetic parameters. Based on a mixed effect analysis of variance model, including the dosing condition as a fixed effect and patients as a random effect, the ratios of geometric means of area under curve from time 0 to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) with and without voglibose were estimated along with two-sided 90% confidence intervals (CIs).ResultsIn Japanese patients with T2DM, the exposure to dapagliflozin following a single oral dose of dapagliflozin 10 mg was not influenced by the concomitant administration of voglibose (0.2 mg t.i.d.). The geometric ratio (90% CI) for dapagliflozin AUC0-inf with/without voglibose was 1.009 (0.954, 1.067), and for Cmax 1.040 (0.899, 1.204). The median time to Cmax (tmax) and plasma clearance of dapagliflozin were also similar between treatments. The mean half-life (t½) for dapagliflozin was slightly higher when administered in combination with voglibose. Dapagliflozin 10 mg was well tolerated when administered alone and in combination with voglibose in Japanese patients with T2DM.ConclusionThe results presented here support the co-administration of dapagliflozin and voglibose without dose adjustment of either agent.

Comparison of the pharmacokinetics and pharmacodynamics of dapagliflozin in patients with type 1 versus type 2 diabetes mellitus

“…cytochrome P450) or transporters . No clinically meaningful drug–drug interactions have been observed between dapagliflozin and commonly co‐administered oral antihyperglycaemic medications, such as metformin, pioglitazone, glimepiride, sitagliptin and voglibose , or with other agents often prescribed in patients with T2DM (warfarin, simvastatin, valsartan and digoxin) .…”

“…cytochrome P450) or transporters [12,13]. No clinically meaningful drug-drug interactions have been observed between dapagliflozin and commonly co-administered oral antihyperglycaemic medications, such as metformin, pioglitazone, glimepiride, sitagliptin and voglibose [14,15], or with other agents often prescribed in patients with T2DM (warfarin, simvastatin, valsartan and digoxin) [16]. In a first exploratory study of dapagliflozin as add-on therapy to insulin in patients with T1DM, dapagliflozin was found to have acceptable short-term tolerability and predictable pharmacokinetic and pharmacodynamic profiles [17], as previously observed for patients with T2DM [10,18].…”

Drug–Drug Interactions with Sodium-Glucose Cotransporters Type 2 (SGLT2) Inhibitors, New Oral Glucose-Lowering Agents for the Management of Type 2 Diabetes Mellitus

“…The addition of dapagliflozin in patients insufficiently controlled with glimepiride resulted in significant reduction in HbA 1c with only a slightly increased risk of hypoglycaemia [29] . A Japanese study demonstrated that voglibose, an alpha-glucosidase inhibitor, does not modify the PK of dapagliflozin [30] . Several clinical studies have confirmed that dapagliflozin is effective and safe when combined with other glucose-lowering agents for the management of T2DM [20] .…”

Pharmacokinetic drug interactions are unlikely when sodium–glucose cotransporters type 2 inhibitors are used to treat type 2 diabetes mellitus

“…[3]. Although some slight alterations in SGLT2 inhibitor exposure have been documented during coadministration of some glucose-lowering agents (Table 1), these are not considered to be clinically relevant [12][13][14][15][16][17][18].…”

“…Selected pharmacokinetic parameters and drug interactions associated with sodium-glucose cotransporters type 2 inhibitors, as reviewed by Scheen[3] Effect of co-administration on exposure to SGLT2 inhibitor/other glucose-lowering agent[12][13][14][15][16][17][18] CYP cytochrome P450, NR not reported, OAT3 organic anion transporters type 3, SGLT2 sodium-glucose cotransporters type 2, UGT uridine diphosphate-glucuronosyltransferase, $ indicates no change, : indicates slight non-clinically relevant increase, :: indicates clinically relevant increase, ; indicates slight non-clinically relevant decrease, ;; indicates clinically relevant decrease Use safely with other glucose-lowering agents Dapagliflozin, canagliflozin and empagliflozin do not appear to significantly influence the pharmacokinetics of other glucose-lowering agents(Table 1)…”