A Systems Model for Ursodeoxycholic Acid Metabolism in Healthy and Patients With Primary Biliary Cirrhosis.

A systems model was developed to describe the metabolism and disposition of ursodeoxycholic acid (UDCA) and its conjugates in healthy subjects based on pharmacokinetic (PK) data from published studies in order to study the distribution of oral UDCA and potential interactions influencing therapeutic effects upon interruption of its enterohepatic recirculation. The base model was empirically adapted to patients with primary biliary cirrhosis (PBC) based on current understanding of disease pathophysiology and clinical measurements. Simulations were performed for patients with PBC under two competing hypotheses: one for inhibition of ileal absorption of both UDCA and conjugates and the other only of conjugates. The simulations predicted distinctly different bile acid distribution patterns in plasma and bile. The UDCA model adapted to patients with PBC provides a platform to investigate a complex therapeutic drug interaction among UDCA, UDCA conjugates, and inhibition of ileal bile acid transport in this rare disease population.

GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p < 0.05 for both), and -1.56 (95% CI -2.95, -0.16) and -3.02 (95% CI -8.58, 2.55), respectively, in obese subjects (p < 0.05 for GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.

Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes.

The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0-≤9.5% (53-80 mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000 mg once daily or 250 mg twice daily), placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose-response relationship for change from baseline in HbA1c at week 12 (p < 0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed.

Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes.

We compared the efficacy of twice-daily doses of remogliflozin etabonate (RE) and once-daily pioglitazone with placebo for reduction in glycated haemoglobin (HbA1c) concentration. In this 12-week, double-blind, randomized, active- and placebo-controlled trial, 336 treatment-naïve subjects with type 2 diabetes and an HbA1c of 7.0-9.5% (53-80 mmol/mol) were randomized to RE (50, 100, 250, 500 or 1000 mg twice daily), matching placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c from baseline. Other endpoints included changes in body weight, lipid levels, safety and tolerability. RE produced a decreasing dose response in HbA1c at week 12 (p < 0.001), with reductions in HbA1c versus placebo ranging from 0.64 to 1.07% (p < 0.001). Statistically significant reductions in body weight for RE compared with placebo were also observed. Twice-daily RE resulted in a dose-ordered improvement in glycaemic control and was generally well tolerated.

GSK2374697, a novel albumin-binding domain antibody (AlbudAb), extends systemic exposure of exendin-4: first study in humans--PK/PD and safety.

GSK2374697 is a genetically engineered fusion protein of a human domain antibody to exendin-4. This molecule binds with a high affinity to human serum albumin, creating a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist. This study is the first evaluation of the albumin-binding domain antibody (AlbudAb) drug delivery platform in humans. The aim of this randomized clinical study was to determine the pharmacokinetics, pharmacodynamics, safety, and tolerability of GSK2374697. The pharmacokinetic profile was prolonged, with estimated half-lives ranging from 6 to 10 days. Postprandial glucose and insulin were reduced, and gastric emptying was delayed in healthy subjects, confirming anticipated GLP-1 receptor agonist pharmacology. The safety and tolerability were as expected for a potent GLP-1 agonist. Gradual titration of doses greatly improved tolerability. Rapid tolerance to nausea was observed. Study results support further investigation in type 2 diabetes and for weight loss.

Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients.

AIMS: Remogliflozin etabonate (RE) is the pro-drug of remogliflozin (R), a selective inhibitor of renal sodium-dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM). METHODS: In a double-blinded, randomized, placebo-controlled trial, subjects who were drug-naïve or had metformin discontinued received RE [100 mg BID (n = 9), 1000 mg QD (n = 9), 1000 mg BID (n = 9)], or placebo (n = 8) for 12 days. Safety parameters were assessed, including urine studies to evaluate renal function. Plasma concentrations of RE and metabolites were measured with the first dose and at steady state. RE effects on glucose levels were assessed with fasting glucose concentrations, frequently sampled 24-h glucose profiles and oral glucose tolerance tests. RESULTS: No significant laboratory abnormalities or safety events were reported; the most frequent adverse events were headache and flatulence. Plasma exposure to RE and R were proportional to administered dose with negligible accumulation. Mean 24-h UGE increased in RE treatment groups. Compared with the placebo group, 24-h mean (95% CI) changes in plasma glucose were -1.2 (-2.2 to -0.3) (100 mg BID), -0.8 (-1.7 to 0.2) (1000 mg QD) and -1.7 (-2.7 to -0.8) mmol/l (1000 mg BID). CONCLUSIONS: Administration of RE for 12 days is well-tolerated and results in clinically meaningful improvements in plasma glucose, accompanied by changes in body weight and blood pressure in subjects with T2DM.

Effect of ranitidine on the pharmacokinetics of triazolam and alpha-hydroxytriazolam in both young (19-60 years) and older (61-78 years) people.

OBJECTIVE: This study evaluated the effect of oral ranitidine (75 mg and 150 mg) on the pharmacokinetics of triazolam (0.25 mg) and its major metabolite, alpha-hydroxytriazolam, in both young and older people. Metabolite data were used to distinguish the mechanism of this interaction. METHOD: This was a randomized, open-label, 3-way crossover study. Eighteen young (19-60 years) and 12 older (61-78 years) men and women were randomly assigned to receive evening doses of triazolam 0.25 mg (1) alone, (2) on the third day of dosing ranitidine 75 mg twice daily for 4 days, and (3) on the third day of dosing ranitidine 150 mg twice daily for 4 days. RESULTS: In the young group, mean triazolam area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was 10% and 28% higher after treatment with 75 mg and 150 mg ranitidine, respectively. In the older group, mean triazolam AUC(0-infinity) was 31% and 28% higher after treatment with 75 mg and 150 mg ranitidine, respectively. There was no change in the alpha-hydroxytriazolam/triazolam AUC(0-infinity) ratio in either age group, indicating that neither formation nor elimination of alpha-hydroxytriazolam was affected by ranitidine. There were no changes in the half-life of triazolam or alpha-hydroxytriazolam. CONCLUSION: Ranitidine increases oral absorption of triazolam in both young and older people. This effect is likely caused by elevation of gastrointestinal pH, allowing for greater absorption of acid-labile triazolam. The difference in this effect between age groups at the lower 75-mg dose of ranitidine suggests that older people may be more sensitive to the antisecretory effect of ranitidine.

Stereoselective pharmacokinetics of chlorpheniramine and the effect of ranitidine.

This single-dose, randomized, crossover study was carried out to investigate the potential effect of ranitidine on the pharmacokinetics of chlorpheniramine. The study also afforded an opportunity to add to the limited data currently available on the stereoselective pharmacokinetics of chlorpheniramine. Healthy subjects received a single oral 4 mg dose of racemic chlorpheniramine on two separate occasions: alone, and on day 6 of dosing with ranitidine 75 mg b.i.d. for 8 days. Serum concentrations and urinary recovery of (S)-(+)- and (R)-(-)-chlorpheniramine were unaffected by administration of ranitidine, indicating no pharmacokinetic drug-drug interaction. The observed chlorpheniramine pharmacokinetic data were consistent with previous data and indicated approximately 2.5-fold higher serum concentrations of the (S)-(+) enantiomer. Previously reported high variability in chlorpheniramine pharmacokinetics was greatly reduced by well-controlled food and fluid intake.

Use of the InteliSite capsule to study ranitidine absorption from various sites within the human intestinal tract.

PURPOSE: The purpose of this study was to evaluate the extent of ranitidine absorption from an externally activated drug-delivery system in two distinct regions of the intestine (jejunum and ileum) in healthy human volunteers. This investigation also was designed to evaluate the utility of the InteliSite capsule for studying regional intestinal drug absorption in humans. METHODS: The intestinal absorption of ranitidine from the jejunum and ileum was compared in eight, healthy volunteers in this open-label, two-way crossover study. In two of the eight volunteers, absorption from the colon also was studied. Subjects swallowed the capsule containing ranitidine solution (121 mg) and 100 microCi of 99mTc-DTPA. The endcap of the capsule contained 20 microCi of (111)In-DTPA. At the desired intestinal site, the capsule was activated by the application of an external RF magnetic signal (6.78 MHz operating frequency) and the ranitidine solution was released. Blood samples were collected from a forearm vein for 12 hours after capsule activation. RESULTS: The capsule released the ranitidine solution when activated in the jejunum, ileum and colon (visualized by the gamma camera). There was no difference in the extent of ranitidine absorption or ranitidine pharmacokinetics when the capsule was activated in the jejunum or ileum. CONCLUSIONS: This study demonstrates the utility of a novel, externally activated drug-delivery system to assess site-specific intestinal drug absorption in humans. Results indicate that use of the InteliSite capsule method to evaluate site-specific intestinal ranitidine absorption in humans yields data similar to that obtained previously by means of oral intubation studies.