| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PHARMACOKINETICS AND PHARMACODYNAMICS |
From Eli Lilly and Company, Indianapolis, Indiana (Dr Kothare, Dr de la Peña, Dr Mace); Eli Lilly and Company, Windlesham, Surrey, United Kingdom (Dr Linnebjerg); Eli Lilly and Company, Kobe, Japan (Dr Isaka, Mr Uenaka, Mr Yamamura, Dr Shigeta); Lilly-NUS Centre for Clinical Pharmacology, Singapore (Dr Yeo, Dr Teng); Amylin Pharmaceuticals, Inc, San Diego, California (Mr Fineman); PS Clinic, Fukuoka, Japan (Dr Sakata); and Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan (Dr Irie).
Address for reprints: Prajakti Kothare, PhD, Global PK/PD and Trial Simulations, Eli Lilly and Company, Indianapolis, IN 46285; e-mail: kotharep{at}lilly.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
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.
Key Words: Exenatide • pharmacokinetics • pharmacodynamics • Japanese • type 2 diabetes
Although the number of available oral antidiabetic agents (OADs) has increased markedly over the past decade,9,10 no single agent has addressed the numerous hormonal abnormalities involved in type 2 diabetes. Many OADs and insulins also have undesirable metabolic adverse effects, including hypoglycemia, weight gain, gastrointestinal intolerance, and edema.10 Moreover, the effect of weight gain further impedes achievement of glycemic control by exacerbating insulin resistance, as obesity is a major risk factor for type 2 diabetes.11 The shortcomings of current pharmacologic agents warrant the development of alternative therapies that can address the metabolic defects of diabetes.
Exenatide (synthetic exendin 4), a 39-amino acid peptide with a molecular weight of 4186.6 Daltons,12,13 is the first member of a class of antidiabetic agents called incretin mimetics, which share metabolic effects with the naturally occurring human incretin hormone glucagon-like peptide-1 (GLP-1).14,15 Incretins are secreted by the gut in response to food intake and are known to affect several processes in the regulation of glucose homeostasis.14,15 Among the glucoregulatory activities that exenatide shares with GLP-1 include glucose-dependent enhancement of insulin secretion, suppression of inappropriately high glucagon secretion reported in type 2 diabetes, slowing of gastric emptying, and reduction of food intake with the result of body weight reduction.16-22
Exenatide pharmacokinetic and pharmacodynamic data were previously obtained from predominantly non-Asian patients. In patients with type 2 diabetes, exenatide exhibited a half-life (t) of approximately 2 hours and a time to achieve peak concentration (tmax) of 2 hours.23 Mean peak exenatide concentration (Cmax) was 211 pg/mL, and the overall mean area under the curve (AUC0-
) was 1036 pg·h/mL after subcutaneous administration of 10 µg exenatide. Based on its pharmacokinetic and pharmacodynamic properties, exenatide is administered twice daily at subcutaneous doses of 5 or 10 µg within 60 minutes prior to a meal.24 In three 30-week placebo-controlled clinical trials in patients with type 2 diabetes, exenatide therapy (10 µg bid) resulted in a clinically significant reduction in mean glycosylated hemoglobin fraction A1c (HbA1c) by 0.9% and also was associated with progressive reduction in mean body weight of 2.1 kg.25-28 The UK Prospective Diabetes Study demonstrated that a reduction in HbA1c of approximately 1.0% in patients with type 2 diabetes may reduce the risk of diabetes-related microvascular complications,29 and the Behavioral Risk Factor Surveillance System showed that for every kilogram increase in body weight, the risk for diabetes increases by approximately 9%.30
Although previous studies have included a limited number of Asian subjects, here we report the first clinical trial conducted to evaluate the pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
6.5 and 
10.0% (for patients controlled with diet/exercise alone) or HbA1c 10.0% (for patients controlled with OADs). Patients were excluded if they had a fasting plasma glucose concentration >11.0 mmol/L, insulin treatment within 3 months prior to screening, or clinically significant vascular complications. This study was approved by the Soseikai Institutional Review Board (Fukuoka, Japan), and all patients provided written informed consent. This study was conducted in accordance with the principles described in the Declaration of Helsinki, including all amendments through the 1996 South Africa revision.31
Study Design
The study design is shown in Figure 1. This was a single-blind, parallel-group, placebo-controlled inpatient study in which patients were allocated into 4 groups and randomized to receive subcutaneous administration of either exenatide (ranging from 2.5-15 µg) or placebo. During their stay at the study sites, patients were given standardized meals (25-30 kcal/kg, daily) that were consistent with dietary guidelines developed by the Japanese Diabetes Society, with approximately 60% of total energy from carbohydrates, 25% from fat, and 15% from protein. Exenatide (0.25 mg/mL; Amylin Pharmaceuticals, Inc, San Diego, California) or placebo was administered subcutaneously into the abdomen approximately 15 minutes prior to a standardized breakfast. Patients received lunch 6 hours after breakfast. Exenatide or placebo again was administered 15 minutes prior to a standardized dinner (12 hours after breakfast).
Safety and Tolerability Assessments
Safety was evaluated based on reports of treatment-emergent adverse events, physical examinations, vital signs (blood pressure and pulse rate), 12-lead electrocardiograms (ECGs), clinical laboratory evaluations, and blood glucose measurements. Vital signs were evaluated before the morning dose and at 2 and 8 hours after the morning dose on days 1, 2, 6, and 10 and at poststudy follow-up. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed on days 1, 3, and 9, and time-averaged daily means were calculated for each. Hypoglycemia was defined as blood glucose <50 mg/dL, with symptoms of hypoglycemia including dizziness, faintness, or sweating. Fasting blood glucose was assessed every day prior to the morning dose. In addition, blood glucose was measured if the subject experienced symptoms of hypoglycemia or at the investigator's discretion.
|
Pharmacokinetic, Pharmacodynamic, and Exposure-Response Assessments
All pharmacokinetic, pharmacodynamic, and exposure-response analyses were conducted using WinNonlin Professional (Version 4.1, Pharsight Corporation, Mountain View, California). Exenatide single-dose (day 2) and multiple-dose (day 10) pharmacokinetic parameters were computed by standard noncompartmental methods. The maximum observed plasma exenatide concentration (Cmax), time to achieve peak concentration (tmax), area under the concentration-time curve (with extrapolation to infinity after a single dose [AUC0-] or over the dosing interval after multiple dosing [AUC
,ss]), apparent clearance (after single dose [CL/F] or at steady state [CLp,ss/F]), apparent volume of distribution (Vz/F or Vz,ss/F), and terminal half-life (t) were calculated. Changes in exenatide steady-state exposure (AUC,ss and Cmax,ss on day 10) as a function of dose were assessed with the use of the following equation: Log(pharmacokinetic parameter) = intercept + slope * Log(dose).33,34
Absolute plasma glucose concentrations (observed) were used to analyze the following: area under the postprandial plasma glucose curve (AUC0-3 h and AUC0-6 h), maximum postprandial plasma glucose concentration (Cmax), and time to maximum observed concentration (tmax). For each patient, baseline was defined as absolute AUC0-6 h on day 1 (predose), which was compared to those on days 2 and 10. Similar analyses were conducted for insulin and glucagon data.
Pharmacodynamic parameters taken at day 10 were analyzed statistically. Each parameter was log-transformed prior to analysis and modeled with treatment as factor and day 1 (baseline) value as covariate. The mean difference between each dose group and placebo, along with the 90% confidence interval (CI), was calculated and back-transformed to yield the estimate and confidence interval for the ratio of geometric means, with placebo as reference.
Twenty-four-hour mean changes from baseline for blood pressure and heart rate were calculated. The baseline was defined as the 24-hour mean on day 1 for each variable. These were analyzed by fitting a linear mixed effects model with subject as a random effect and day and dose as fixed effects. The baseline (day 1) values were included in the model as a covariate. Least squares mean and the 95% CI were calculated for each day and dose combination.
An exposure-response analysis was conducted across dose groups to quantify changes in postprandial glucose response from predose (day 1) to day 10 as a function of exenatide exposure with the use of an Emax model. The Emax model is described as follows: Effect = (Emax x AUC0-3 h)/(AUC50 + AUC0-3 h), where Effect is the change from baseline in postprandial glucose lowering, Emax is the maximum change in postprandial glucose concentrations in the presence of exenatide, AUC0-3 h is the exenatide exposure over the first 3 hours postdose, and AUC50 is the exenatide AUC0-3 h postdose associated with 50% of maximal glucose reduction. Because the most prominent changes in plasma glucose profiles were apparent approximately 3 hours postprandial, exenatide AUC0-3 h and postprandial glucose AUC0-3 h were analyzed as the exposure and response variables, respectively.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Baseline and demographic characteristics were well balanced across treatment groups with a mean ± standard deviation (SD) age of 53.0 ± 8.9 years, body mass index of 26.1 ± 4.0 kg/m2, HbA1c of 7.6% ± 0.9%, and fasting plasma glucose of 157 ± 24 mg/dL. Thirty-seven of the 40 patients completed the study.
Safety and Tolerability of Exenatide
There were no serious adverse events reported during the study. Twenty-three of the 40 patients who received study drug reported a total of 143 adverse events, increasing in incidence with increasing doses of exenatide. Patients who experienced at least 1 adverse event after the administration of placebo or 2.5, 5, 10, or 15 µg exenatide (n = 8 for each group) were as follows: 62.5% (5 patients), 37.5% (3 patients), 25% (2 patients), 87.5% (7 patients), and 75% (6 patients), respectively. The most common adverse events were gastrointestinal in nature (nausea [31% of adverse events], abdominal distention [28%], stomach discomfort [9%], and vomiting [8%]). No nausea or vomiting was reported by patients who received placebo or 2.5 µg exenatide. There was an overall trend for the incidence of nausea to decrease with continued exposure to exenatide at the 5- and 10-µg doses. Three patients treated with 15 µg exenatide discontinued the study due to moderate nausea or vomiting on days 6, 7, and 8, respectively.
No significant changes were observed in mean diastolic or systolic blood pressures at day 9, apart from an increase (3.22 mm Hg [95% CI, 0.23-6.20 mm Hg]) in diastolic blood pressure in patients who received 10 µg exenatide, with no apparent clinical significance.
Patients who received 2.5 and 5 µg exenatide experienced increases (3.60 bpm [CI, 0.57-6.64 bpm] and 7.27 bpm [CI, 5.52-9.03 bpm], respectively) in baseline for mean 24-hour heart rates on day 3, which returned to baseline by day 9. Patients who received 10 and 15 µg experienced increases (9.67 bpm [CI, 7.02-12.31 bpm] and 9.66 bpm [CI, 6.41-12.91 bpm], respectively) on day 9.
No clinically relevant ECG abnormalities or changes in laboratory parameters related to the study drug were observed. There were no reported episodes of hypoglycemia.
Exenatide Pharmacokinetics
The mean plasma concentration-time profiles of exenatide after single and multiple doses are presented in Figures 2A, B. Following single- and multiple-dose administration, exenatide was well absorbed, with a median tmax of approximately 1.5 hours, and rapidly eliminated, with a monoexponential decline (Tables I and II). Mean t was 1.38 hours after a single dose and 1.55 hours after multiple doses. Although the study was not powered for a dose proportionality analysis, a graphical inspection of exenatide exposure following multiple doses showed an approximate dose-proportional increase over the dose range from 2.5 to 15 µg (Figure 3). Slope and intercept estimates derived from a power model analysis33,34 were 1.24 (CI, 1.10-1.38) and 4.00 (CI, 3.73-4.27) for AUC,ss and 1.18 (CI, 1.02-1.34) and 2.91 (CI, 2.60-3.21) for Cmax, respectively, generally indicating dose-dependent increases in exposure (Figure 3). In general, mean exenatide clearance was not substantively different after single and multiple doses, indicating a lack of time dependence in exenatide pharmacokinetics (Tables I and II). In keeping with the linear pharmacokinetic properties of exenatide, CLp,ss/F, Vz,ss/F, and t values were independent of dose. Estimates for the accumulation ratio were 0.99 (CI, 0.82-1.20) and 1.28 (CI, 1.07-1.54) for 2.5 and 5 µg, respectively, indicating that exenatide exposure after single and repeated bid dosing was comparable.
|
|
Following multiple doses, decreases in postprandial glucose concentrations were dose dependent up to 10 µg, with similar lowering after 10 and 15 µg exenatide (Table III and Figure 4A). The mean reductions in glucose AUC0-6 h after multiple-dose administration were 29.7% (21.8%-36.8%), 33.4% (25.9%-40.1%), 42.1% (35.1%-48.3%), and 45.6% (37.8%-52.4%) at 2.5, 5, 10, and 15 µg exenatide, respectively.
|
Effects of multiple bid doses of exenatide on plasma glucagon are shown in Table III and Figure 4C. For evaluated doses, higher exenatide doses were associated with lower plasma glucagon concentrations. Compared with placebo, the differences in glucagon concentrations were more obvious in the first 2 to 3 hours postprandial, and the absolute glucagon AUC0-6 h was reduced across all dose groups.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between absolute glucose AUC0-3 h from baseline and exenatide AUC0-3 h is shown in Figure 5. The Emax and AUC50 of the relationship were 557 mg·h/dL and 158 pg·h/mL, respectively, suggesting that exenatide AUC0-3 h of 158 pg·h/mL is required to provide 50% of maximal glucose-lowering response. The mean exenatide AUC0-3 h at doses of 2.5, 5, 10, and 15 µg were 122 pg·h/mL, 285 pg·h/mL, 647 pg·h/mL, and 933 pg·h/mL, respectively. Hence, mean exenatide AUC0-3 h at doses of 5 µg and higher exceeded the AUC50.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Exenatide was expected to exhibit similar pharmacokinetic/pharmacodynamic properties in Japanese subjects as in non-Japanese people. According to International Conference on Harmonisation (ICH) guidelines, various pharmacokinetic/pharmacodynamic properties are associated with a low potential for ethnic sensitivity.35 Specifically, exenatide is a peptide that is subcutaneously administered and therefore would not be subjected to polymorphic differences in gut or liver enzyme expression or dietary variations. Following administration, exenatide is excreted by glomerular filtration with catabolic degradation of the peptide in renal tubules and reabsorption of the resulting amino acids.36,37 Each of these processes is passive and does not involve saturable enzyme systems. The pharmacokinetics and pharmacodynamics of exenatide have been studied extensively in non-Japanese populations,13,15,17-28,32,37-40 and these data, in view of the ICH guidelines, are consistent with a low potential for ethnic sensitivity for exenatide.
The study design offered an opportunity for robust characterization of exenatide pharmacokinetics and pharmacodynamics in Japanese patients, given a wide dose range under single- and multiple-dose conditions. Exenatide was rapidly absorbed, suggesting dose-proportional increases in exposure that were consistent with previous studies.23 Due to its short half-life, exenatide did not demonstrate systemic accumulation after multiple bid dosing. The results of this study are consistent with the theoretical expectations for a lack of ethnic sensitivity in pharmacokinetic properties. Although some have reported that ethnic differences may exist in the underlying defects of type 2 diabetes,3-8 the parameters observed in this study were similar to those from a meta-analysis of studies in non-Asian patients with type 2 diabetes.23
Consistent with data from phase III clinical trials in non-Asian patients with type 2 diabetes,38 exenatide was generally well tolerated in the present study, with mild to moderate nausea as the most frequently reported adverse event, and the incidence of nausea tended to decrease during the study. Due to the short duration of this trial, it is not possible to evaluate the effects of exenatide on HbA1c or body weight. However, in previous trials, loss in body weight following exenatide treatment was not due to gastrointestinal side effects, as there was a lack of correlation between incidence of nausea and reduction in body weight, and glucose lowering is unlikely the result of such effects.22,39,40
|
|
|
The present study also supports glucose-dependent insulinotropism.17,19-20 Postprandial glucose and concomitant insulin levels were relatively increased after the 2.5-µg dose. In contrast, when prevailing glucose concentrations remained at euglycemic levels after 5 µg or higher of exenatide, postprandial insulin concentrations were reduced compared with the levels observed following placebo.
Patients with type 2 diabetes may exhibit paradoxical increases in postprandial glucagon concentrations, resulting in excessive hepatic glucose production.16 In keeping with its known mechanistic properties, exenatide reduces plasma glucagon concentrations in the postprandial state, thus potentially reestablishing a more favorable insulin-to-glucagon ratio in the physiological environment.20,21 Likewise, in the present trial, exenatide resulted in a dose-related reduction in plasma glucagon concentrations. However, these actions may not fully explain the observed glucoregulatory effect of exenatide. Data from previous trials with non-Asian patients confirm that exenatide reduces gastric emptying, substantively contributing to improved glycemic control in the postprandial state.21,24 The present analysis does not include an assessment of the rate of gastric emptying, and thus the contribution of gastric emptying cannot be determined here, a limitation to the current study.
Overall, the similarity in pharmacokinetic and pharmacodynamic properties between Japanese and non-Japanese subjects lends credence to applying the existing body of clinical pharmacology information of exenatide to the Japanese population.
The exposure-response relationship of exenatide previously has been quantified in non-Japanese subjects.42 The model related exenatide exposure and postprandial glucose concentrations over the first 3 hours postdose because the pharmacodynamic-time profile changes fairly dynamically over this time period. The model demonstrates that at low exposure, postprandial glucose reduction occurs in a linear pattern. As exposure increases, an asymptotic region on the curve is reached at which further glucose reductions are not observed. Thus, the analysis confirms that doses of 5 and 10 µg are in the asymptotic portion of the exposure-response curve. Similarly, the present study suggests an exposure-response relationship of exenatide in Japanese subjects such that doses of 5 µg or more may be necessary to provide clinically relevant glucose-lowering responses, with 10 µg bid exhibiting a near maximal glucose reduction. Given that mean exposures for doses of 5 and 10 µg are in the asymptotic portion of the exposure-response curve, minor changes in exposure at therapeutic doses are unlikely to yield pharmacodynamic differences.
|
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Financial disclosure: Financial support for this study was provided by Eli Lilly and Company, Indianapolis, Indiana, and Amylin Pharmaceuticals, Inc, San Diego, California. Prajakti Kothare, Helle Linnebjerg, Yoshitaka Isaka, Kazunori Uenaka, Ayuko Yamamura, Kwee Poo Yeo, Amparo de la Peña, Choo Hua Teng, Kenneth Mace, and Hirofumi Shigeta are employed by and are shareholders of Eli Lilly and Company. Mark Fineman is employed by and is a shareholder of Amylin Pharmaceuticals, Inc.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Hirose T, Kawamori R. Diabetes in Japan. Curr Diabetes Rep. 2005;5: 226-229.[CrossRef]
2. Kawamori R. Diabetes trends in Japan. Diabetes/Metab Res Rev. 2002;18(suppl 3): S9-S13.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Chiu KCM, Cohan PM, Lee NPP, Chuang L-MMP. Insulin sensitivity differs among ethnic groups with a compensatory response in [beta]-cell function. Diabetes Care. 2000;23: 1353-1358.
4. Torrens JIM, Skurnick JP, Davidow ALP, et al. Ethnic differences in insulin sensitivity and [beta]-cell function in premenopausal or early perimenopausal women without diabetes: the Study of Women's Health Across the Nation (SWAN). Diabetes Care. 2004;27: 354-361.
5. Fukushima M, Usami M, Ikeda M, et al. Insulin secretion and insulin sensitivity at different stages of glucose tolerance: a cross-sectional study of Japanese type 2 diabetes. Metabolism. 2004;53: 831-835.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Izuka M, Fukushima M, Taniguchi A, et al. Factors responsible for glucose intolerance in Japanese subjects with impaired fasting glucose. Hormone Metab Res. 2007;39: 41-45.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Mitsui R, Fukushima M, Nishi Y, et al. Factors responsible for deteriorating glucose tolerance in newly diagnosed type 2 diabetes in Japanese men. Metabolism. 2006;55: 53-58.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Suzuki HM, Fukushima MM, Usami MM, et al. Factors responsible for development from normal glucose tolerance to isolated postchallenge hyperglycemia. Diabetes Care. 2003;26: 1211-1215.
9. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 2002;287: 360-372.
10. Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin North Am. 2005;34: 77-98.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Anderson JW, Kendall CW, Jenkins DJ. Importance of weight management in type 2 diabetes: review with meta-analysis of clinical studies. J Am Coll Nutr. 2003;22: 331-339.
12. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992;267: 7402-7405.
13. BYETTA [prescribing information]. 2007. Available at: http://pi.lilly.com/us/byetta-pi.pdf. Accessed June 24, 2008.
14. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: 2929-2940.
15. Triplitt CL. New technologies and therapies in the management of diabetes. Am J Managed Care. 2007;13(suppl): S47-S54.[Web of Science][Medline] [Order article via Infotrieve]
16. Basu A, Shah P, Nielsen M, Basu R, Rizza RA. Effects of type 2 diabetes on the regulation of hepatic glucose metabolism. J Invest Med. 2004;52: 366-374.[Web of Science][Medline] [Order article via Infotrieve]
17. Degn KB, Brock B, Juhl CB, et al. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004;53: 2397-2403.
18. Edwards CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol. 2001;281: E155-E161.[Web of Science]
19. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002;87: 1282-1290.
20. Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88: 3082-3089.
21. Kolterman OG, Kim DD, Shen L, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health-System Pharm. 2005;62: 173-181.
22. Poon T, Nelson P, Shen L, et al. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study. Diabetes Technol Ther. 2005;7: 467-477.[CrossRef][Medline] [Order article via Infotrieve]
23. Reddy S, Park S, Fineman M, et al. Clinical pharmacokinetics of exenatide in patients with type 2 diabetes. AAPS J. 2005;7(suppl 2). Abstract M1285.
24. Linnebjerg H, Kothare PA, Skrivanek Z, et al. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabetic Med. 2006;23: 240-245.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: 2628-2635.
26. Buse JB, Klonoff DC, Nielsen LL, et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007;29: 139-153.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
27. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28: 1092-1100.
28. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28: 1083-1091.
29. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: 837-853.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
30. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care. 2000;23: 1278-1283.
31. World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA. 1997;277: 925-926.
32. Fineman MSB, Bicsak TAP, Shen LZP, et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003;26: 2370-2377.
33. Gough K, Hutchison M, Keene O, et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Inf J. 1995;29: 1039-1048.
34. Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17: 1278-1283.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
35. International Conference on Harmonisation. ICH topic E5(R1): ethnic factors in the acceptability of foreign clinical data. 1998. Available at: http://www.emea.europa.eu/htms/human/ich/ichefficacy.htm. Accessed June 24, 2008.
36. Copley K, McCowen K, Hiles R, Nielsen LL, Young A, Parkes DG. Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr Drug Metab. 2006;7: 367-374.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
37. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. 2007;64: 317-327.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
38. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24: 275-286.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
39. Riddle MC, Henry RR, Poon TH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes/Metab Res Rev. 2006;22: 483-491.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
40. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8: 419-482.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
41. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49: 1751-1760.[Abstract]
42. Fineman M, Phillips L, Jaworowicz DJ, et al. Model-based evaluations to select and confirm doses in the clinical development of exenatide. Clin Pharm Ther. 2007;81(suppl 111). Abstract PIII-82.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
