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Safety, Pharmacokinetics and Pharmacodynamics of Remogliflozin

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Safety, Pharmacokinetics and Pharmacodynamics of Remogliflozin Hussey et al. BMC Pharmacology and Toxicology 2013, 14:25 http://www.biomedcentral.com/2050-6511/14/25 RESEARCH ARTICLE Open Access Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus Elizabeth K Hussey1, Anita Kapur1*, Robin O’Connor-Semmes1, Wenli Tao1, Bryan Rafferty1ˆ, Joseph W Polli1, Charles D James Jr2 and Robert L Dobbins1 Abstract Background: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the renal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widely used for the treatment of T2DM. Methods: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin alone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable duration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for the duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma glucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid) assessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling occurred on Day 3 of each treatment period. Results: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin did not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly lower for remogliflozin and its metabolite after co-administration with metformin compared with administration of RE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in lactic acid. Conclusions: Coadministration of metformin and RE was well tolerated in this study. The results support continued development of RE as a treatment for T2DM. Trial registration: ClinicalTrials.gov, NCT00376038 Keywords: Remogliflozin etabonate, SGLT2 inhibitor, Metformin, Pharmacokinetics, Type 2 diabetes mellitus * Correspondence: [email protected] ˆDeceased 1GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA Full list of author information is available at the end of the article © 2013 Hussey et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hussey et al. BMC Pharmacology and Toxicology 2013, 14:25 Page 2 of 11 http://www.biomedcentral.com/2050-6511/14/25 Background inhibitor of SGLT2 [28] but circulates at approximately Type 2 diabetes mellitus (T2DM) is a chronic disease char- 20% of the plasma concentrations of remogliflozin; thus acterized by deteriorating glycemic control and an associ- GSK279682 is expected to contribute to some of the ob- ated risk of complications. Evidence from controlled served SGLT-2 inhibitor pharmacology. Single oral doses of clinical trials suggests that improving glycemic control can remogliflozin etabonate up to 1000 mg in healthy subjects substantially reduce the long-term microvascular complica- and repeated dosing in subjects with T2DM (up to 1000 tions of diabetes [1-5]. Current guidelines recommend that mg BID for 2 weeks) have been safe and well tolerated T2DM patients should be initially managed with diet and [29,30]. Remogliflozin etabonate is intended for use in the exercise followed by pharmacological treatment with met- treatment of T2DM as monotherapy. Given its mechanism formin as the preferred step 1 agent, unless there are con- of action, it would be a candidate for combination with met- traindications to metformin use. When glycemic goals are formin and other antidiabetic therapies as well. The os- not achieved, the dose of metformin is increased or a sec- motic diuresis associated with increased urine glucose ond agent is added [6,7]. In this treatment algorithm, suit- excretion provides a potential mechanism for pharmacoki- ability for combination with metformin becomes a critical netic drug–drug interactions due to the extensive renal concern in developing new antidiabetic agents. clearance of metformin, although treatment with the diur- Metformin is a dimethylbiguanide that reduces elevated etic hydrochlorothiazide for 2 weeks had no significant blood glucose levels primarily through its effects on redu- effect on the clearance of metformin in subjects with cing hepatic glucose production and improving peripheral T2DM [31]. tissue sensitivity to insulin. Metformin is typically adminis- This study was designed to evaluate the effect of tered with meals and has an oral bioavailability of approxi- remogliflozin etabonate on metformin exposure in T2DM mately 40 to 60% [8]. It undergoes extensive renal excretion subjects. Secondarily, the effect of metformin on steady 3 times the glomerular filtration rate [9] and has a mean state plasma concentrations of remogliflozin etabonate, plasma elimination half-life between 4.0 and 8.7 hours. remogliflozin (active entity) and the active metabolite, There are no clinically relevant metabolic interactions GSK279782 was evaluated. Three days of dosing (total of 5 reported with metformin, and it is neither metabolized nor doses) was considered adequate to achieve steady-state inhibits the metabolism of other drugs [10]. However, there conditions for both metformin and remogliflozin. Safety are several transporter related drug interactions, in particu- problems that might be related to a pharmacokinetic drug– lar with cationic drugs that have been reported [9]; these drug interaction were also monitored. typically don’t require a dose adjustment. The main adverse event of clinical concern with metformin is lactic acidosis, a Methods potentially life-threatening side effect that may be associ- This single-center, Phase 1 study was conducted at ated with high plasma concentrations of metformin and Medica Sur Hospital and Clinical Foundation Pharma renal insufficiency [11-13]. Unit (CIF-BIOTEC), Mexico. This study was approved The low-affinity, high-capacity sodium-dependent glu- by the investigational center ethics committee (Hospital cose co-transporter-2 (SGLT2), which is expressed specific- Medical Sur Ethics Committee) and was conducted in ally in the renal proximal tubule [14,15], plays a major role accordance with Good Clinical Practice and the princi- in the reabsorption of glucose by the kidney. SGLT2 has re- ples of the Declaration of Helsinki. All subjects provided cently gained recognition as a potential therapeutic target their written informed consent before study participa- for reducing hyperglycemia in T2DM, and several selective tion. The study was registered at http://clinicaltrials.gov SGLT2 inhibitors are being evaluated in the clinic [16-22]. with the identifier NCT00376038. In diabetic animal models, pharmacological inhibition of SGLT2 leads to glucosuria followed by normalization of Subjects plasma glucose levels and consequent improvement in in- Male and female subjects (post-menopausal women or pre- sulin resistance [23-25]. This mechanism may provide im- menopausal women with documented hysterectomy or provements in both fasting and postprandial hyperglycemia tubal ligation) with documented T2DM (≥3months),ran- without causing weight gain or other dose-limiting side ef- ging in age from 30 to 64 years and with a body mass index fects observed with other oral antidiabetic approaches [26]. of 22 to 35 kg/m2,wereeligibleforthestudy.Enoughsub- Remogliflozin etabonate is the prodrug of the highly se- jects were to be enrolled to ensure completion of at least lective and potent SGLT2 inhibitor, remogliflozin. Adminis- 12 evaluable subjects. Pre-study screening included a med- tration of remogliflozin etabonate has been shown to ical history, physical examination, medical and laboratory increase urinary glucose excretion in a dose-dependent evaluations, including 12-lead ECG, and a urinary drug manner in mice and rats and to exhibit antidiabetic efficacy screen. Subjects were required to be free of clinically signifi- in several diabetic rodent models [27]. Remogliflozin is fur- cant medical and laboratory abnormalities, to have ther metabolized to GSK279782, which is an equally potent glycosylated hemoglobin (HbA1c) <10%, and fasting plasma Hussey et al. BMC Pharmacology and Toxicology 2013, 14:25 Page 3 of 11 http://www.biomedcentral.com/2050-6511/14/25 glucose (FPG) <280 mg/dL, and to be controlled by diet Subjects were asked to refrain from drinking grapefruit alone or metformin. Standard exclusion criteria concerning juice or eating grapefruit for at least 3 days before the first blood donation, alcohol and drug
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