Pharmacokinetics of the Long-Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function.

The pharmacokinetics of LY2605541 (basal insulin peglispro), a novel long-acting basal insulin analogue, was evaluated in 5 groups of subjects with varying degrees of renal function based on creatinine clearance: normal renal function (>80 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (30-50 mL/min), severe renal impairment (<30 mL/min), or end-stage renal disease (ESRD) requiring hemodialysis. Serial blood samples for pharmacokinetic analyses were collected up to 12 days following a single 0.33 U/kg subcutaneous dose of LY2605541. The apparent clearance (CL/F) and half-life across groups were not affected by renal function. Cmax values were lower in subjects with increasing severity of renal impairment; however, the small decrease in Cmax did not affect the overall exposure. Regression analysis showed that LY2605541 clearance is independent of renal function (slope = 0.000863; P = .885). The mean fraction of LY2605541 eliminated by a single hemodialysis session was 13% in subjects with ESRD. LY2605541 was generally well tolerated in healthy subjects and those with renal impairment following a single 0.33 U/kg subcutaneous dose. Given these data, no dose adjustment of LY2605541 based on pharmacokinetics is recommended in renal impairment or in patients undergoing hemodialysis.

Single-dose pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 in healthy subjects.

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.

Pharmacokinetics, safety, and tolerability of single- and multiple-dose exenatide once weekly in Chinese patients with type 2 diabetes mellitus.

BACKGROUND: This open-label, single-period study assessed the pharmacokinetics, safety, tolerability, and pharmacodynamics of exenatide once weekly (q.w.), following single and multiple weekly subcutaneous (s.c.) injections in native Chinese patients with type 2 diabetes (T2D). METHODS: Patients (n = 25; mean [±SD] age 51.3 ± 8.2 years; body mass index 25.6 ± 2.4 kg/m(2) ; HbA1c 7.4 ± 1.2%; duration of diabetes 3.1 ± 3.1 years) previously treated with diet modification and exercise alone or incombination with stable metformin doses were enrolled in the study. Twenty-five patients received weekly doses of 2 mg, s.c., exenatide q.w. for 10 weeks, followed by 10 weeks observation. Pharmacokinetic parameters of exenatide, fasting plasma glucose (FPG), HbA1c, and body weight were summarized using descriptive statistics. RESULTS: Steady state plasma exenatide concentrations (299 pg/mL) were attained within 8 weeks. Exenatide q.w. was generally well tolerated, and the majority of adverse events reported were mild in severity. The most frequent study drug-related adverse events were diarrhea and vomiting. Decreases were observed from baseline to 10 weeks in FPG (~3.0 mmol/L), HbA1c (~1.0%), and body weight (~3.8 kg). CONCLUSIONS: This is the first clinical trial of exenatide q.w. in native Chinese patients with T2D. The results suggest that exenatide q.w. has a pharmacokinetic profile in this patient population similar to that observed in other ethnic and racial populations, and appears to be safe and generally well tolerated, with the potential to improve glycemic control and decrease body weight without increasing the risk of hypoglycemia.

Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1.

INTRODUCTION: The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic ß-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss. AREAS COVERED: This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials. EXPERT OPINION: GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.

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.

Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial.

BACKGROUND: Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use. METHODS: This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 µg, levonorgestrel [LV] 150 µg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 µg BID from Days 1 through 4 and at 10 µg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period. RESULTS: Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial. CONCLUSIONS: The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00254800.

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 [AUC(0-)(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 tR(max50), tR(last)) 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.

Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing.

BACKGROUND AND OBJECTIVES: Exenatide is a glucagon-like peptide-1 receptor agonist, available in an immediate-release (IR), twice-daily formulation, which improves glycaemic control through enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated postprandial glucagon secretion, slowing of gastric emptying and reduction of food intake. The objectives of these studies were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an extended-release (ER) exenatide formulation in patients with type 2 diabetes mellitus. PATIENTS AND METHODS: Patients with type 2 diabetes participated in either a single-dose trial (n = 62) or a repeated-administration trial (n = 45). The pharmacokinetic and safety effects of single-dose subcutaneous administration of exenatide ER (2.5 mg, 5 mg, 7 mg or 10 mg) versus placebo were studied over a period of 12 weeks in patients with type 2 diabetes. These results were used to predict the dose regimen of exenatide ER required to achieve steady-state therapeutic plasma exenatide concentrations. A second clinical study investigated the pharmacokinetics, pharmacodynamics and safety of weekly exenatide ER subcutaneous injections (0.8 mg or 2 mg) versus placebo in patients with type 2 diabetes over a period of 15 weeks. Furthermore, population-based analyses of these studies were performed to further define the exposure-response relationships associated with exenatide ER. RESULTS: Exenatide exposure increased with dose (2.5 mg, 5 mg, 7 mg or 10 mg) and exhibited a multiple-peak profile over approximately 10 weeks. Multiple-dosing pharmacokinetics were predicted from superpositioning of single-dose data; weekly administration of exenatide ER 0.8 mg and 2 mg for 15 weeks confirmed the predictions. Weekly dosing resulted in steady-state plasma exenatide concentrations after 6-7 weeks. Fasting plasma glucose levels were reduced similarly with both doses after 15 weeks (-42.7 ± 15.7 mg/dL with the 0.8 mg dose and -39.0 ± 9.3 mg/dL with the 2 mg dose; both p < 0.001 vs placebo), and the integrated exposure-response analysis demonstrated that the drug concentration producing 50% of the maximum effect (EC(50)) on fasting plasma glucose was 56.8 pg/mL (a concentration achieved with both the 0.8 mg and 2 mg doses of exenatide ER). The 2 mg dose reduced bodyweight (-3.8 ± 1.4 kg; p < 0.05 vs placebo) and postprandial glucose excursions. Glycosylated haemoglobin (HbA(1c)) levels were reduced with the 0.8 mg dose (-1.4 ± 0.3%; baseline 8.6%) and with the 2 mg dose (-1.7 ± 0.3%; baseline 8.3%) [both p < 0.001 vs placebo]. Adverse events were generally transient and mild to moderate in intensity. CONCLUSION: These studies demonstrated that (i) a single subcutaneous dose of exenatide ER resulted in dose-related increases in plasma exenatide concentrations; (ii) single-dose exposure successfully predicted the weekly-dosing exposure, with 0.8 mg and 2 mg weekly subcutaneous doses of exenatide ER eliciting therapeutic concentrations of exenatide; and (iii) weekly dosing with either 0.8 or 2 mg of exenatide ER improved fasting plasma glucose control, whereas only the 2 mg dose was associated with improved postprandial glucose control and weight loss. [Clinicaltrials.gov Identifier: NCT00103935].

Safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly in Japanese patients with type 2 diabetes.

This randomized, placebo-controlled, double-blind, parallel study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly (QW) in 30 Japanese patients with type 2 diabetes (T2D) suboptimally controlled by diet and exercise alone or combined with biguanide, sulfonylurea, thiazolidinedione, or combinations of these agents (58.6% male; 58+/-9 years; body mass index 26.3+/-2.9 kg/m(2); hemoglobin A(1c) [HbA(1c)] 7.4+/-0.8%; fasting plasma glucose [FPG] 156.1+/-29.1 mg/dL; duration of T2D 6+/-5 years; means +/- SD). Patients were randomized in a 1:1:1 ratio to subcutaneous placebo QW, exenatide QW 0.8 mg, or exenatide QW 2.0 mg for 10 weeks. All evaluable patients were analyzed (placebo QW, n=10; exenatide QW 0.8 mg, n=10; exenatide QW 2.0 mg, n=9), unless otherwise stated. Steady-state plasma exenatide concentrations were observed by Week 8 of the study. For the evaluable pharmacokinetic population, geometric mean (90% confidence interval) steady-state plasma concentrations (pg/mL) were 81.2 (68.3-96.4) and 344.5 (256.5-462.7) with exenatide QW 0.8 mg (n=8) and exenatide QW 2.0 mg (n=5), respectively. Baseline-to-Week 10 glycemic improvements with placebo QW, exenatide QW 0.8 mg, and exenatide QW 2.0 mg, respectively, were: HbA(1c) (%): -0.4+/-0.3, -1.0+/-0.7, and -1.5+/-0.7; FPG (mg/dL): -20.5+/-20.4, -25.2+/-10.9, and -50.8+/-27.8; and 2-hour postprandial plasma glucose excursions (mg/dL): -8.8+/-26.9, -50.0+/-41.1, and -59.7+/-26.8 (means +/- SD). No serious adverse events (AEs) were reported and no AEs led to study discontinuation in any group. The most frequent AE observed was mild-to-moderate injection site induration. No serious hypoglycemia was reported. Exenatide QW for 10 weeks was well tolerated and improved short-term glycemic control in Japanese patients with suboptimally controlled T2D.

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 microg [group A] or 5 microg [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 microg bid; groups C and D received 10 and 15 microg 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 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

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.

Effect of renal impairment on the pharmacokinetics of exenatide.

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 microg) 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 microg 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 microg) unsuitable in severe RI or ESRD.

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 microg 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.

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 microg 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 (AUCtau,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.