Open-label investigation of rapid initiation of extended-release buprenorphine in patients using fentanyl and fentanyl analogs.

BACKGROUND AND OBJECTIVES: Synthetic opioids, including fentanyl and fentanyl analogs, account for over 70,000 annual overdose deaths in the United States, but there is limited information examining methods of induction and maintenance outcomes for buprenorphine treatment of patients with opioid use disorder (OUD) using these opioids. METHODS: A secondary analysis of results grouped by fentanyl use status was completed for an open-label study with rapid induction of extended-release buprenorphine in the inpatient research unit. Eligible participants received a single 4 mg dose of transmucosal buprenorphine (BUP-TM) followed by an extended-release buprenorphine 300 mg injection ([BUP-XR]) after approximately 1 h. An extension study continued follow-up up to 6 months (6 monthly injections). RESULTS: Among participants with fentanyl-positive urine samples (FEN+; n = 19), all received BUP-TM, 17 received BUP-XR, 13 elected to receive a second BUP-XR injection, and 10 received all six scheduled injections. Among participants with fentanyl-negative samples (FEN-; n = 7), all received BUP-TM and BUP-XR, four elected to receive a second injection, and two participants received all six scheduled injections. Induction day clinical opioid withdrawal scale (COWS) scores were similar for FEN+ and FEN- groups. In the FEN+ group, mean COWS scores fell to below 5 within 24 h of BUP-XR injection. DISCUSSION AND CONCLUSIONS: The treatment of individuals with OUD using fentanyl with a rapid 1-day induction to BUP-XR 300 mg injection is feasible and well-tolerated. SCIENTIFIC SIGNIFICANCE: A prospective trial of participants grouped by fentanyl use status at induction demonstrates comparable patient retention and clinical response following single-day induction of BUP-XR in participants who are FEN+ and FEN-.

Open-label, rapid initiation pilot study for extended-release buprenorphine subcutaneous injection.

Background: For patients with opioid use disorder, buprenorphine extended-release injection (BUP-XR) achieves sustained therapeutic plasma concentrations, controls craving and withdrawal symptoms, and improves patient outcomes. Given retention challenges during transmucosal buprenorphine (BUP-TM) induction, assessing methods to quickly achieve sustained buprenorphine concentrations is important.Objectives: This open-label, single-group, single-center pilot study (NCT03993392) evaluated safety and tolerability of initiating BUP-XR following a single BUP-TM 4 mg dose.Methods: Eligible participants abstained from short and long-acting opioids for 6 and 24 hours, respectively. If the Clinical Opiate Withdrawal Scale (COWS) was ≥8, BUP-TM 4 mg was administered. Participants not exhibiting hypersensitivity, precipitated opioid withdrawal (POW), or sedation symptoms within 1 hour received BUP-XR 300 mg (assessed as inpatients for 48 hours and outpatients to Day 29). Endpoints were COWS score increase ≥6, independent adjudication of POW, and opioid use.Results: Twenty-six participants (14 male) received BUP-TM, 24 received BUP-XR, and 20 completed the study. After injection, COWS scores decreased from pre-BUP-TM baseline of 14.6 ± 4.1 to 6.9 ± 4.1 at 6 hours and 4.2 ± 3.2 at 24 hours. Most participants (62.5%) experienced maximum COWS scores pre-BUP-XR; 2 experienced a COWS score increase ≥6, occurring at 1 and 2 hours post-BUP-XR. By adjudication, 2/24 participants experienced POW. Irritability, anxiety, nausea, and pain were the most frequent adverse events (AEs) with no serious AEs.Conclusions: Results support increased flexibility for initiating BUP-XR. Initiating BUP-XR 300 mg following a single BUP-TM 4 mg dose was well tolerated. Although some participants initially experienced withdrawal symptoms after injection, significant symptomatic improvement was observed in all participants within 24 hours.

Modeling buprenorphine reduction of fentanyl-induced respiratory depression.

BACKGROUNDPotent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression.METHODSTo characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075-0.35 mg/70 kg (opioid naive) and 0.25-0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models.RESULTSBuprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed.CONCLUSIONOverall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine.TRIAL REGISTRATIONTrialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028)FUNDINGIndivior Inc., North Chesterfield, Virginia, USA.

Tolerance to Opioid-Induced Respiratory Depression in Chronic High-Dose Opioid Users: A Model-Based Comparison With Opioid-Naïve Individuals.

Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid-naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (Emax ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naïve and opioid-tolerant.

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study.

BACKGROUND: Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. METHODS: We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov, number NCT01899703. FINDINGS: Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were -57% (95% CI -73 to -42, p<0·0001) in the NRS, -31% (-42 to -20, p<0·0001) in the PBC-40 itch domain and -35% (-45 to -25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (-23%, 95% CI -45 to -1; p=0·037), PBC-40 itch domain, (-14%, -26 to -1; p=0·034), and 5-D itch scale (-20%, -34 to -7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI -37 to -61, p<0·0001) from 30 to 15 µM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. INTERPRETATION: In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. FUNDING: GlaxoSmithKline and National Institute for Health Research.

BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.

BACKGROUND: Pruritus (itch) is a symptom commonly experienced by patients with cholestatic liver diseases such as primary biliary cholangitis (PBC, previously referred to as primary biliary cirrhosis). Bile acids (BAs) have been proposed as potential pruritogens in PBC. The ileal bile acid transporter (IBAT) protein expressed in the distal ileum plays a key role in the enterohepatic circulation of BAs. Pharmacological inhibition of IBAT with GSK2330672 may reduce BA levels in the systemic circulation and improve pruritus. METHODS: This clinical study (BAT117213 study) is sponsored by GlaxoSmithKline (GSK) with associated exploratory studies supported by the National Institute for Health Research (NIHR). It is a phase 2a, multi-centre, randomised, double bind, placebo controlled, cross-over trial for PBC patients with pruritus. The primary objective is to investigate the safety and tolerability of repeat doses of GSK2330672, and explore whether GSK2330672 administration for 14 days improves pruritus compared with placebo. The key outcomes include improvement in pruritus scores evaluated on a numerical rating scale and other PBC symptoms in an electronic diary completed twice daily by the patients. The secondary outcomes include the evaluation of the effect of GSK2330672 on total serum bile acid (BA) concentrations, serum markers of BA synthesis and steady-state pharmacokinetics of ursodeoxycholic acid (UDCA). DISCUSSION: BAT117213 study is the first randomised controlled crossover trial of ileal bile acid transporter inhibitor, a novel class of drug to treat pruritus in PBC. The main strengths of the trial are utility of a novel, study specific, electronic symptom diary as patient reported outcome to measure the treatment response objectively and the crossover design that allows estimating the treatment effect in a smaller number of patients. The outcome of this trial will inform the trial design of future development phase of the IBAT inhibitor drug. The trial will also provide opportunity to conduct metabonomic and gut microbiome studies as explorative and mechanistic research in patients with cholestatic pruritus. TRIAL REGISTRATION: EudraCT number: 2012-005531-84, ClinicalTrials.gov Identifier: NCT01899703 , registered on 3(rd) July 2013.

Pharmacokinetics and Pharmacodynamics of the SGLT2 Inhibitor Remogliflozin Etabonate in Subjects with Mild and Moderate Renal Impairment.

Remogliflozin etabonate (RE), the prodrug of remogliflozin, is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), enabling urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. Renal function declines more rapidly in patients with type 2 diabetes, making it difficult or unsafe to continue on some antidiabetic therapeutics. In an initial effort to understand the potential utility of RE in patients with renal impairment, the pharmacodynamics and pharmacokinetics of RE were evaluated in a single oral dose (250 mg) in patients with renal impairment as compared with control subjects. As shown by pharmacodynamic measurements of urinary glucose excretion, there was no clinically significant reduction in the ability of remogliflozin to inhibit SGLT2. In addition, there were no significant changes in area under the curve (from 0 to infinity) or half-life of remogliflozin, suggesting renal impairment does not alter the pharmacokinetics of remogliflozin. In contrast to other SGLT2 inhibitors which accumulate in patients with renal impairment, adjustment of the dosage of RE in subjects with mild or moderate renal impairment is not indicated based on the observations in this study.

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release.

GSK-1614235 and KGA-2727 are potent, selective inhibitors of the SGLT1 sodium-dependent glucose transporter. Nonclinical (KGA-2727) and clinical (GSK-1614235) trials assessed translation of SGLT1 inhibitor effects from rats to normal human physiology. In rats, KGA-2727 (0.1 mg/kg) or vehicle was given before oral administration of 3-O-methyl-α-d-glucopyranose (3-O-methylglucose, 3-OMG) containing 3-[3H]OMG tracer. Tracer absorption and distribution were assessed from plasma, urine, and fecal samples. SGLT1 inhibition reduced urine 3-OMG recovery and increased fecal excretion. SGLT1 inhibitor effects on plasma glucose, insulin, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were also measured during a standard meal. Incremental glucose, insulin, and GIP concentrations were decreased, indicating downregulation of ß-cell and K cell secretion. Minimal effects were observed in the secretion of the L cell product, GLP-1. With the use of a three-way, crossover design, 12 healthy human subjects received placebo or 20 mg GSK-1614235 immediately before or after a meal. Five minutes into the meal, 3-OMG was ingested. Postmeal dosing had little impact, yet premeal dosing delayed and reduced 3-OMG absorption, with an AUC0-10 of 231±31 vs. 446±31 µg·h(-1)·ml(-1), for placebo. Recovery of tracer in urine was 1.2±0.7 g for premeal dosing and 2.2±0.1 g for placebo. Incremental concentrations of insulin, C-peptide, and GIP were reduced for 2 h with premeal GSK-1614235. Total GLP-1 concentrations were significantly increased, and a trend for increased peptide YY (PYY) was noted. SGLT1 inhibitors block intestinal glucose absorption and reduce GIP secretion in rats and humans, suggesting SGLT1 glucose transport is critical for GIP release. Conversely, GLP-1 and PYY secretion are enhanced by SGLT1 inhibition in humans.

Exploring glycosuria as a mechanism for weight and fat mass reduction. A pilot study with remogliflozin etabonate and sergliflozin etabonate in healthy obese subjects.

Inhibitors of sodium-dependent glucose co-transporter 2 (SGLT2) increase glucose excretion in the urine and improve blood glucose in Type 2 diabetes mellitus. Glycosuria provides an energy and osmotic drain that could alter body composition. We therefore conducted a pilot study comparing the effects on body composition of two SGLT2 inhibitors, remogliflozin etabonate (RE) 250 mg TID (n = 9) and sergliflozin etabonate (SE) (1000 mg TID) (n = 9), with placebo (n = 12) in obese non-diabetic subjects. Both drugs were well tolerated during 8 weeks of dosing, and the most common adverse event was headache. No urinary tract infections were observed, but there was one case of vaginal candidiasis in the RE group. As expected, RE and SE increased urine glucose excretion, with no change in the placebo group. All the subjects lost weight over 8 weeks, irrespective of treatment assignment. There was a reduction in TBW measured by D2O dilution in the RE group that was significantly greater than placebo (1.4 kg, p = 0.029). This was corroborated by calculation of fat-free mass using a quantitative magnetic resonance technique. All but one subject had a measurable decrease in fat mass. There was significant between-subject variability of weight and fat loss, and no statistically significant differences were observed between groups. Despite a lack of a difference in weight and fat mass loss, the leptin/adiponectin ratio, a measure of insulin resistance, was significantly decreased in the RE group when compared to placebo and SE, suggesting that this SGTL-2 inhibitor may improve metabolic health independent of a change in fat mass.

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus.

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.

First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus.

BACKGROUND: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. METHODS: This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661. RESULTS: RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes. CONCLUSIONS: The results support progression of RE as a potential treatment for T2DM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571661.

Reduced T2* values in soleus muscle of patients with type 2 diabetes mellitus.

Tissue water transverse relaxation times (T2) are highly sensitive to fluid and lipid accumulations in skeletal muscles whereas the related T2* is sensitive to changes in tissue oxygenation in addition to factors affecting T2. Diabetes mellitus (DM) affects muscles of lower extremities progressively by impairing blood flow at the macrovascular and microvascular levels. This study is to investigate whether T2 and T2* are sensitive enough to detect abnormalities in skeletal muscles of diabetic patients in the resting state. T2 and T2* values in calf muscle of 18 patients with type 2 DM (T2DM), 22 young healthy controls (YHC), and 7 age-matched older healthy controls (OHC) were measured at 3T using multi-TE spin echo and gradient echo sequences. Regional lipid levels of the soleus muscle were also measured using the Dixon method in a subset of the subjects. Correlations between T2, T2*, lipid levels, glycated hemoglobin (HbA1c) and presence of diabetes were evaluated. We found that T2 values were significantly higher in calf muscles of T2DM subjects, as were T2* values in anterior tibialis, and gastrocnemius muscles of T2DM participants. However, soleus T2* values of the T2DM subjects were significantly lower than those of the older, age-matched HC cohort (22.9±0.5 vs 26.7±0.4 ms, p<0.01). The soleus T2* values in the T2DM cohort were inversely correlated with the presence of diabetes (t = -3.46, p<0.001) and with an increase in HbA1c, but not with body mass index or regional lipid levels. Although multiple factors may contribute to changes in T2* values, the lowered T2* value observed in the T2DM soleus muscle is most consistent with a combination of high oxygen consumption and poor regional perfusion. This finding is consistent with results of previous perfusion studies and suggests that the soleus in individuals with T2DM is likely under tissue oxygenation stress.

Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2, improves serum glucose profiles in type 1 diabetes.

OBJECTIVE: Remogliflozin etabonate (RE), an inhibitor of the sodium-glucose transporter 2, improves glucose profiles in type 2 diabetes. This study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of RE in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: Ten subjects managed with continuous subcutaneous insulin infusion were enrolled. In addition to basal insulin, subjects received five randomized treatments: placebo, prandial insulin, 50 mg RE, 150 mg RE, and mg RE 500. RESULTS: Adverse events and incidence of hypoglycemia with RE did not differ from placebo and prandial insulin groups. RE significantly increased urine glucose excretion and reduced the rise in plasma glucose concentration after oral glucose. RE reduced incremental adjusted weighted mean glucose (0-4 h) values by 42-49 mg/dL and mean glucose (0-10 h) by 52-69 mg/dL. CONCLUSIONS: RE can be safely administered with insulin in type 1 diabetes and reduces plasma glucose concentrations compared with placebo.

Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies.

Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose cotransporter-2 inhibitor. This work investigated the absorption, metabolism, and excretion of [(14)C]remogliflozin etabonate in humans, as well as the influence of P-glycoprotein (Pgp) and cytochrome P450 (P450) enzymes on the disposition of remogliflozin etabonate and its metabolites to understand the risks for drug interactions. After a single oral 402 ± 1.0 mg (106 ± 0.3 µCi) dose, [(14)C]remogliflozin etabonate is rapidly absorbed and extensively metabolized. The area under the concentration-time curve from 0 to infinity [AUC((0-∞))] of plasma radioactivity was approximately 14-fold higher than the sum of the AUC((0-∞)) of remogliflozin etabonate, remogliflozin, and 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-ß-d-glucopyranoside (GSK279782), a pharmacologically active N-dealkylated metabolite. Elimination half-lives of total radioactivity, remogliflozin etabonate, and remogliflozin were 6.57, 0.39, and 1.57 h, respectively. Products of remogliflozin etabonate metabolism are eliminated primarily via renal excretion, with 92.8% of the dose recovered in the urine. Three glucuronide metabolites made up the majority of the radioactivity in plasma and represent 67.1% of the dose in urine, with 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-ß-d-glucopyranosiduronic acid (GSK1997711) representing 47.8% of the dose. In vitro studies demonstrated that remogliflozin etabonate and remogliflozin are Pgp substrates, and that CYP3A4 can form GSK279782 directly from remogliflozin. A ketoconazole clinical drug interaction study, along with the human mass balance findings, confirmed that CYP3A4 contributes less than 50% to remogliflozin metabolism, demonstrating that other enzyme pathways (e.g., P450s, UDP-glucuronosyltransferases, and glucosidases) make significant contributions to the drug's clearance. Overall, these studies support a low clinical drug interaction risk for remogliflozin etabonate due to the availability of multiple biotransformation pathways.

Multiple-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: a randomized double-blind study.

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium-dependent glucose cotransporter-2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose-proportional pharmacokinetic characteristics. Mean half-life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose-related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose-related reduction in body weight (mean changes of -0.09, -1.55, and -1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N-acetyl-beta-D-glucosaminidase, and beta(2)-microglobulin levels tended to increase.

Single-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus.

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of approximately 0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes.

CONTEXT: Native glucagon-like peptide-1 increases insulin secretion, decreases glucagon secretion, and reduces appetite but is rapidly inactivated by dipeptidyl peptidase-4. Albiglutide is a novel dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin designed to have sustained efficacy in vivo. OBJECTIVES: The objectives were to investigate pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide in type 2 diabetes subjects. METHODS: In a single-blind dose-escalation study, 54 subjects were randomized to receive placebo or 9-, 16-, or 32-mg albiglutide on d 1 and 8. In a complementary study, 46 subjects were randomized to a single dose (16 or 64 mg) of albiglutide to the arm, leg, or abdomen. RESULTS: Significant dose-dependent reductions in 24-h mean weighted glucose [area under the curve((0-24 h))] were observed, with placebo-adjusted least squares means difference values in the 32-mg cohort of -34.8 and -56.4 mg/dl [95% confidence interval (-54.1, -15.5) and (-82.2, -30.5)] for d 2 and 9, respectively. Placebo-adjusted fasting plasma glucose decreased by -26.7 and -50.7 mg/dl [95% confidence interval (-46.3, -7.06) and (-75.4, -26.0)] on d 2 and 9, respectively. Postprandial glucose was also reduced. No hypoglycemic episodes were detected in the albiglutide cohorts. The frequency and severity of the most common adverse events, headache and nausea, were comparable with placebo controls. Albiglutide half-life ranged between 6 and 7 d. The pharmacokinetics or pharmacodynamic of albiglutide was unaffected by injection site. CONCLUSIONS: Albiglutide improved fasting plasma glucose and postprandial glucose with a favorable safety profile in subjects with type 2 diabetes. Albiglutide's long half-life may allow for once-weekly or less frequent dosing.

MRI assessment of drug-induced fluid accumulation in humans: validation of the technology.

PURPOSE: The purpose of this study was to evaluate the feasibility of using proton and sodium magnetic resonance imaging (MRI) to detect fluid accumulation produced by fludrocortisone and nifedipine - two drugs known to cause salt/water retention by different mechanisms. MATERIALS AND METHODS: Twelve young healthy male subjects were randomly assigned to one of two groups and treated with either fludrocortisone or nifedipine for 14 or 25 days, respectively. The change in sodium MRI, as well as in proton T(2) value and T(1)-weighted signal intensity in the calf following postural change [referred to here as 'postural delta signal'(PDS)], was evaluated before, during and after drug administration. The changes in MRI PDS were compared to conventional physiological parameters, including body weight, calf volume and pitting edema. RESULTS: When compared to the baseline pretreatment values, the subjects treated with fludrocortisone showed a 5.5% increase in sodium MRI PDS (P=.01), a 2-ms increase in proton T(2) PDS of the gastrocnemius muscle (P=.06) and a body weight gain of 2.3% (P=.001) within 1 week. In the nifedipine-treated subjects, the sodium MRI PDS increased by 6% versus baseline (P=.03), while the proton T(2) PDS of the gastrocnemius muscle increased by 3.7 ms (P=.01), associated with a 0.5% weight gain (P=.55), within 3 weeks. No significant changes were noted in the T(1)-weighed images following postural change. Measurements of calf circumference, volume and pitting edema did not show consistent changes associated with the drug administration. CONCLUSION: The postural change in sodium MRI and proton T(2) signals provides a sensitive method for detecting the fluid accumulation produced by fludrocortisone and nifedipine. The MRI results are consistent with treatment-induced increases in extracellular fluid volume and correlate well with the observed weight gain. These findings support the potential utility of MRI for the evaluation of medication-induced fluid retention.

Proton and sodium MRI assessment of fluid level in calf tissue.

PURPOSE: To investigate the feasibility of using (1)H and (23)Na MRI to detect fluid levels in the lower leg muscle. MATERIALS AND METHODS: Proton and sodium MRI was applied to detect body fluid levels in the lower leg muscles of 18 healthy young male subjects at 3T and 4T. The paradigms under investigation were a postural change from sitting upright to lying supine, and saline infusion. RESULTS: We found that the average proton MR signal in gastrocnemius and soleus muscles were reduced following the postural change by 3.5% +/- 1.4% (P < 0.05) and rose following saline infusion by 3.7% +/- 0.9% (P < 0.01). More dramatically, the sodium MR signal decreased by 7.1% +/- 1.2% (P < 0.01) following the postural change and increased following saline infusion by 12% +/- 3.8% (P < 0.05). The ratio of intra- to extracellular fluid levels was 1.6 +/- 0.5 for the subjects based on the acquired proton and sodium data. CONCLUSION: Our results indicate that proton and sodium MRI can be used to assess fluid levels in the lower extremities, and this technique may be applied to evaluate fluid retention.