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Impact of Voglibose on the Pharmacokinetics of Dapagliflozin

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Impact of Voglibose on the Pharmacokinetics of Dapagliflozin Diabetes Ther (2013) 4:41–49 DOI 10.1007/s13300-012-0016-5 ORIGINAL RESEARCH Impact of Voglibose on the Pharmacokinetics of Dapagliflozin in Japanese Patients with Type 2 Diabetes Akira Imamura • Masahito Kusunoki • Shinya Ueda • Nobuya Hayashi • Yasuhiko Imai To view enhanced content go to www.diabetestherapy-open.com Received: September 24, 2012 / Published online: January 10, 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com ABSTRACT glucose reabsorption. This study was performed to assess the effect of the oral antidiabetic agent Introduction: Dapagliflozin is an orally voglibose [0.2 mg thrice daily (t.i.d.)] at steady- administered selective sodium-glucose state, on the pharmacokinetics, safety and cotransporter 2 (SGLT2) inhibitor under tolerability of dapagliflozin administered as a development for the treatment of type 2 single oral dose (10 mg) to Japanese patients diabetes mellitus (T2DM). Dapagliflozin lowers with T2DM. blood glucose through a reduction in renal Methods: This was an open-label, multi-center, ClinicalTrials.gov: #NCT01055652. drug–drug interaction study. A single oral dose of dapagliflozin (10 mg) was administered to 22 A. Imamura (&) Japanese patients with T2DM in the presence Moriya Keiyu Hospital, 980-1, Tatuzawa, and absence of voglibose (0.2 mg t.i.d.). Serial Moriya City, Ibaraki 302-0118, Japan e-mail: [email protected] blood samples were collected before and at regular prespecified intervals after each M. Kusunoki The Institute for Rehabilitation Studies, Kobe dapagliflozin dose to determine dapagliflozin International University, 9-1-6 Koyocho-naka, plasma concentrations and to evaluate Higashinada-ku, Kobe-city, Hyogo 658-0032, Japan pharmacokinetic parameters. Based on a S. Ueda Á N. Hayashi mixed effect analysis of variance model, AstraZeneca K.K, 1-88 Ohyoda-naka 1-chome, Kita-ku, Osaka 531-0076, Japan including the dosing condition as a fixed effect and patients as a random effect, the Y. Imai Bristol-Myers K.K., Shinjuku Island Tower, ratios of geometric means of area under curve 6-5-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo from time 0 to infinity (AUC ) and maximum 163-1328, Japan 0-inf observed plasma concentration (Cmax) with and without voglibose were estimated along with two-sided 90% confidence intervals (CIs). Results: In Japanese patients with T2DM, the Enhanced content for this article is available on the journal web site: exposure to dapagliflozin following a single oral www.diabetestherapy-open.com 123 42 Diabetes Ther (2013) 4:41–49 dose of dapagliflozin 10 mg was not influenced within the gastrointestinal tract to decrease by the concomitant administration of voglibose and delay the intestinal absorption of (0.2 mg t.i.d.). The geometric ratio (90% CI) for carbohydrate [5–7]. dapagliflozin AUC0-inf with/without voglibose Dapagliflozin is a first-in-class selective was 1.009 (0.954, 1.067), and for Cmax 1.040 sodium-glucose cotransporter 2 (SGLT2) (0.899, 1.204). The median time to Cmax (tmax) inhibitor under development for the treatment and plasma clearance of dapagliflozin were also of T2DM that improves glycemic control by similar between treatments. The mean half-life reducing the reabsorption of glucose in the (t) for dapagliflozin was slightly higher when kidney and enhancing the urinary excretion of administered in combination with voglibose. excess glucose [8, 9]. As with voglibose, the Dapagliflozin 10 mg was well tolerated when mechanism of action of dapagliflozin is administered alone and in combination with independent of insulin secretion or action and voglibose in Japanese patients with T2DM. efficacy, and its safety has been evaluated in a Conclusion: The results presented here support broad range of patients with T2DM as a the co-administration of dapagliflozin and monotherapy [10, 11] and as an add-on voglibose without dose adjustment of either to metformin, glimepiride, pioglitazone, agent. sitagliptin, and insulin [11–17]. Both dapagliflozin and voglibose effectively control Keywords: Dapagliflozin; Drug-drug interaction; postprandial blood glucose excursions in Pharmacokinetics; Sodium-glucose cotransporter patients with T2DM [18, 19]. Thus, the co- 2 inhibitor; Type 2 diabetes; Voglibose administration of dapagliflozin with voglibose could potentially provide a complementary approach to glycemic control. INTRODUCTION Predictable dose-proportional pharmacokinetic and pharmacodynamic parameters with The number of people diagnosed with dapagliflozin have been demonstrated in diabetes worldwide has more than doubled both Japanese and non-Japanese subjects since 1980 to nearly 350 million [1]. The rise [20–22]. Dapagliflozin is metabolized via the in prevalence of diabetes has been uridine diphosphate-glucuronosyltransferase 1A9 particularly rapid in Japan and is likely to pathway to an inactive metabolite, dapagliflozin have been fueled by changes in lifestyle [2]. 3-O-glucuronide [23]. No clinically significant In Japanese medical practice there is an drug–drug interaction has been observed in increasing use of combination therapy with patients when dapagliflozin was administered in multiple antidiabetic drugs in the treatment combination with some commonly employed of type 2 diabetes mellitus (T2DM) [3]. antihyperglycemic agents (metformin, Frequently an alpha-glucosidase inhibitor is pioglitazone, glimepride, or sitagliptin) [24]or a part of this treatment regimen. Voglibose other agents that are commonly used in patients is an oral antihyperglycemic agent of the with T2DM (warfarin, simvastatin, valsartan, and alpha-glucosidase inhibitor class that is digoxin) [25]. widely used in the management of T2DM Due to the differing pharmacokinetics of in Japan [4]. Voglibose undergoes minimal each treatment no drug–drug interaction systemic absorption and primarily functions was anticipated between dapagliflozin and 123 Diabetes Ther (2013) 4:41–49 43 voglibose. However, due to the possible future Key exclusion criteria included a diagnosis co-administration of dapagliflozin with of type 1 diabetes mellitus, a history of voglibose in Japan, the aim of the study diabetic ketoacidosis, a calculated creatinine reported here was to assess the potential for clearance \50 mL/min (calculated by Cockroft- drug–drug interaction between dapagliflozin Gault formula), urine albumin:creatinine and voglibose in Japanese patients with T2DM. ratio [1,800 mg/g ([203.4 mg/mmol), severe As voglibose is not orally absorbed, only hepatic insufficiency and/or significant the effect of voglibose on the plasma abnormal liver function defined as aspartate pharmacokinetics of dapagliflozin was studied. aminotransferase (AST) more than three-times the upper limit of normal (ULN) and/or alanine aminotransferase (ALT) more than three- MATERIALS AND METHODS times the ULN, total bilirubin [2.0 mg/dL ([34.2 lmol/L), congestive heart failure defined Subjects as New York Heart Association (NYHA) class III and IV, unstable or acute congestive heart failure, An open-label, multi-center, drug–drug significant cardiovascular history within the past interaction study was conducted to assess the 6 months prior to the screening visit (defined as: effect of voglibose [0.2 mg thrice daily (t.i.d.)] on myocardial infarction, unstable angina pectoris, the pharmacokinetics, safety and tolerability of transient ischemic attack, unstable, or previously dapagliflozin administered as a single oral dose undiagnosed arrhythmia), cardiac surgery, (10 mg) to Japanese patients with T2DM. The or revascularization (coronary angioplasty study was performed in accordance with the or bypass grafts), or cerebrovascular accident, Declaration of Helsinki and is consistent with systolic blood pressure (BP) C170 mmHg and/or ICH/Good Clinical Practice, applicable regulatory diastolic BP C100 mmHg as an average value or requirements, and the AstraZeneca policy on creatine kinase more than three-times the ULN. Bioethics and Human Biological Samples. All subjects provided written informed consent. Study Design Male or female subjects C20 years of age were eligible for entry into the trial if they had a The study consisted of two pharmacokinetic clinical diagnosis of T2DM, were already on sampling periods (Fig. 1). In period 1, each voglibose treatment with a steady dosage for at patient (already on a stable dose of 0.2 mg least 8 weeks (one change in voglibose dose to t.i.d. voglibose) took a single oral dose of 10 mg 0.2 mg t.i.d. was permitted up to 4 weeks before dapagliflozin on Day 1 together with voglibose study commencement), had a fasting C-peptide (0.2 mg t.i.d.) and plasma samples (3 mL) were [1.0 ng/mL (0.33 nmol/L), fasting plasma collected serially at predetermined time glucose levels B180 mg/dL, and glycated points for up to 72 h after the dose for hemoglobin (HbA1c) levels B8.5%. Women of pharmacokinetic assessment. Voglibose was child-bearing potential were required to have administered just before each meal. This was had a negative urine pregnancy test and to be followed by a dapagliflozin and voglibose using an adequate method of contraception washout period of 7 days. In period 2, a throughout the study and for up to 4 weeks single oral dose of 10 mg dapagliflozin after the study. was administered without voglibose and no 123 44 Diabetes Ther (2013) 4:41–49 Dapagliflozin concentration in plasma was analyzed within the known period of stability by high-performance liquid chromatography tandem mass spectrometry (HPLC–MS) methodology after solid phase extraction (Atlanbio). The lower limit of quantification
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