Helle Linnebjerg

Effect of renal impairment on the pharmacokinetics of exenatide.

What is already known about this subject Nonclinical studies have shown that exenatide is primarily cleared by the renal system. It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI). What this study adds Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide. However, exenatide is not recommended in patients with severe RI or end-stage renal disease. Aims To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). Methods Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. Results Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.). Conclusions Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.

Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes

OBJECTIVES To evaluate the effect of exenatide on gastric emptying (GE) in type 2 diabetes using scintigraphy. METHODS Seventeen subjects with type 2 diabetes participated in a randomized, single-blind, 3-period, crossover study. In each 5-day period, 5 or 10 microg exenatide or placebo was administered subcutaneously BID. Oral antidiabetic treatments were continued. The presence of cardiac autonomic neuropathy was assessed during screening. On day 5, after the morning dose, subjects consumed a 450-kcal breakfast containing (99m)Tc-labeled eggs and (111)In-labeled water, and GE was measured by scintigraphy. Plasma glucose and insulin, perceptions of appetite, and plasma exenatide were also quantified. RESULTS Exenatide slowed GE of both solid and liquid meal components [solid (T(50)(90% confidence interval [CI]); placebo, 60(50-70) min; 5 microg exenatide, 111(94-132) min; 10 microg exenatide, 169(143-201) min; both P<0.01); liquid (T(50)(90% CI), placebo, 34(25-46) min; 5 microg exenatide, 87(65-117) min; 10 microg exenatide, 114(85-154) min; both P<0.01)]. GE was not different between subjects with cardiac autonomic neuropathy (n=7), compared with those without (n=10) (P>/=0.68). Exenatide reduced postprandial glucose (area under the curve [AUC((0-6 h))]) by 69-76% and peak insulin (C(max)) by 84-86% compared with placebo. There was an inverse relationship between the postprandial rise in glucose (AUC((0-3 h))) and GE (solid T(50), r=-0.49, P<0.001). CONCLUSIONS Exenatide slows GE substantially in type 2 diabetes, which could be an important mechanism contributing to the beneficial effect of exenatide on postprandial glycemia.

Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects

OBJECTIVE Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). RESEARCH DESIGN AND METHODS This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. RESULTS Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05). CONCLUSIONS Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.

Exenatide: effect of injection time on postprandial glucose in patients with Type 2 diabetes

Aims  Exenatide is an incretin mimetic whose effect on glycaemic control in patients with Type 2 diabetes is currently under investigation. This study assessed the effect of injection time relative to a standardized meal on postprandial pharmacodynamics of exenatide in patients with Type 2 diabetes.

Effect of exenatide on the steady-state pharmacokinetics of digoxin.

This open‐label study investigated the effect of exenatide coadministration on the steady‐state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2–12, 0.25 mg once daily) and exenatide (days 8–12, 10 μg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24‐hour steady‐state digoxin exposure (AUCτ,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady‐state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Comparison of the Pharmacokinetics and Pharmacodynamics of LY2963016 Insulin Glargine and EU- and US-Approved Versions of Lantus Insulin Glargine in Healthy Subjects: Three Randomized Euglycemic Clamp Studies

OBJECTIVE LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes but with identical amino acid sequences. Three studies evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of LY IGlar and the European Union– and US-approved versions of IGlar. RESEARCH DESIGN AND METHODS These were three single-site, randomized, double-blind, two-treatment, four-period, crossover, euglycemic clamp studies. In each study, fasted healthy subjects received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, following a randomized sequence. A ≥7-day washout period separated the doses. Blood samples were collected predose and up to 24 h postdose to assess PK; PD was assessed by a euglycemic clamp lasting up to 24 h. RESULTS A total of 211 subjects participated in the three studies. The PK (area under the curve [AUC]; maximum observed concentration [Cmax]) and PD (maximum glucose infusion rate [Rmax]; total glucose infusion during the clamp [Gtot]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. Adverse events were similar between treatments. CONCLUSIONS These studies demonstrated that the PK and PD properties of LY IGlar and IGlar were similar after single 0.5 units/kg s.c. doses in healthy subjects, contributing to the totality of evidence supporting similarity of these products.

Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of Exenatide in Japanese Patients With Type 2 Diabetes Mellitus

In this single‐blind, parallel, placebo‐controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single‐dose exenatide (2.5 μg [group A] or 5 μg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 μg bid; groups C and D received 10 and 15 μg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 μg. Exenatide was well absorbed with a median tmax of 1.5 hours and mean t1/2 of 1.6 hours; exposure increased with dose. Up to 10 μg, exenatide reduced postprandial glucose concentrations in a dose‐dependent fashion compared with placebo; decreases were similar for 10 and 15 μg. An Emax model demonstrated that doses higher than 2.5 μg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 μg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men

Exenatide, a treatment for type 2 diabetes, slows gastric emptying as part of its pharmacologic action and may alter the absorption of concomitant oral drugs. This open‐label, 2‐period, fixed‐sequence study evaluated the influence of exenatide coadministration on the pharmacokinetics and pharmacodynamics of warfarin, a narrow therapeutic index drug, in healthy men (N = 16). A single, 25‐mg oral dose of warfarin, with a standardized breakfast, was administered alone in period 1 and concomitantly with 10 μg exenatide subcutaneous twice daily in period 2. Exenatide did not produce significant changes in R‐ or S‐warfarin pharmacokinetics. Although there were minor reductions in warfarin anticoagulant effect, the ratios of geometric means for the area under the international normalized ratio (INR)–time curve from dosing until the time of the last measurable INR value or maximum‐observed INR response being 0.94 (0.93‐0.96) and 0.88 (0.84‐0.92), respectively, the magnitude and direction of these changes do not suggest a safety concern from this interaction.

Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus Peripheral Action Relative to Insulin Glargine in Healthy Subjects

OBJECTIVE We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODS This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m2/min) in a fourth period, targeted to achieve 50–100% suppression of EGP. D-[3-3H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTS Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONS The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.

Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects.

Exenatide is a glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes and has been shown to lower blood glucose through multiple mechanisms, including glucose-dependent insulin secretion, suppression of postprandial glucagon release and slowing of gastric emptying. The effects of exenatide on biliary motility are unknown. This study evaluated the effect of a single dose of exenatide on cholecystokinin (CCK)-induced gallbladder emptying. Healthy subjects participated in this randomized, 2-period, double-blind crossover study. Fasting subjects received a single subcutaneous injection of exenatide (10 μg) or placebo 60 min before CCK infusion. Gallbladder volume and ejection fraction (EF) were assessed by ultrasonography before, during, and after CCK infusion (0.003 μg/kg infused over 50 min at 2 mL/min). The diameters of the main pancreatic duct and common bile duct were measured sonographically at the same time points before, during, and following CCK infusion. Administration of exenatide did not affect pre-CCK infusion gallbladder volume or EF compared to placebo. During the CCK-infusion, the mean minimum gallbladder volume was similar for exenatide (13.68 mL) and placebo (11.05 mL) (least squares mean [LSM] difference of 2.62 mL; 95% confidence interval [CI], -0.53, 5.78), but the mean maximum EF was lower for exenatide (28.79%) versus placebo (46.13%) (LSM difference of -17.34%; 95% CI, -30.54, -4.13). Exenatide had no clinically significant effects on pancreatic or bile duct diameters. In conclusion, exenatide reduced CCK-induced gallbladder emptying compared with placebo in fasting healthy subjects.