Exenatide - pharmacokinetics, pharmacodynamics, safety and tolerability in patients ≥ 75 years of age with Type 2 diabetes.

OBJECTIVE: This study evaluated pharmacokinetics, pharmacodynamics,safety, and tolerability of single doses of exenatide in elderly Type 2 diabetes (T2D)patients. METHODS: This placebo-controlled,patient-blind, crossover study compared elderly patients (≥ 75 y, n = 15) to controls( ≥ 45 to ≤ 65y, n = 15) with T2D. Patients were randomized to single subcutaneous doses of exenatide 5µg, placebo or exenatide 10 µg (Sequence 1) or placebo, exenatide 5 µg or exenatide 10 µg (Sequence 2) before a standardized breakfast over three consecutive days. Serial blood samples were collected for plasma exenatide and serum glucose concentrations.Pharmacokinetic data from this study were also integrated with those from six other clinical pharmacology studies to further evaluate the impact of age on plasma exenatide apparent clearance (CL/F) (139 controls ( ≤ 65 y); 28 elderly patients (> 65 y)). RESULTS: Mean ± SD ages for control and elderly patients were 57 ± 6 y and 78 ± 3 y, respectively.All elderly patients had renal impairment at baseline, as compared with one third of controls. Dose-normalized plasma exenatide maximum concentration and exposure were greater in elderly patients, but between-age group differences were neither statistically significant nor considered clinically relevant. The integrated pharmacokinetic analysis showed a significant linear relationship between plasma exenatide CL/F and renal clearance (test of slope = 0, p < 0.001),with no additional effect from age. Exenatide dose-dependently blunted postprandial serum glucose excursions in both age groups. No hypoglycemia or serious adverse events were reported, and exenatide was generally well tolerated in both age groups. CONCLUSIONS: Exenatide dose adjustments should be determined by renal function rather than age in elderly T2D patients.

A thorough QT study to evaluate the effects of singledose exenatide 10 µg on cardiac repolarization in healthy subjects.

OBJECTIVE: This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. METHODS: Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 µg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 µg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia's correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. RESULTS: Based on ΔQTcF and ΔQTcI assessments, exenatide 10 µg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide's glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. CONCLUSION: This study demonstrated that single-dose exenatide 10 µg was not associated with clinically meaningful prolongation of the QTc interval.

Patterns of switching phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction: results from the Erectile Dysfunction Observational Study.

AIMS: This report describes patterns of treatment changes with the phosphodiesterase type 5 (PDE5) inhibitors tadalafil, sildenafil and vardenafil, and variables associated with those treatment changes, during the 6-month, prospective, pan-European Erectile Dysfunction Observational Study (EDOS). METHODS: EDOS observed 8047 men > or = 18 years old with erectile dysfunction (ED), who began or changed ED therapy as part of their routine healthcare. Patients could change ED treatment at any time during EDOS. Data were collected at baseline and at 3 (+/- 1) and 6 (+/- 1) months. Analyses included ED treatment-naïve patients with complete follow-up who were prescribed a PDE5 inhibitor at baseline (n = 4026). RESULTS: Most patients, regardless of what PDE5 inhibitor they were prescribed at baseline, continued on that same PDE5 inhibitor throughout the study. Continuation rates were approximately 89% in the tadalafil cohort, vs. 63-64% in the sildenafil and vardenafil cohorts. The variables most strongly associated with increased risk of switching were prescription of sildenafil or vardenafil, vs. tadalafil, at baseline (odds ratios 4.43 and 4.14 respectively; p < 0.0001). Of patients who switched from tadalafil to another treatment, nearly 25% had switched back to tadalafil by study end. In contrast, of patients who switched from sildenafil or vardenafil, < 10% from each cohort had switched back to their original treatment by study end. CONCLUSION: The data suggest that tadalafil treatment in treatment-naïve ED patients may increase their likelihood of treatment continuation. These findings should be interpreted conservatively due to the observational nature of the study.