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PHARMACOKINETICS |
From Clinical Pharmacology (Dr Damholt), Biostatistics (Mr Pedersen), and Medical & Science-Liraglutide (Dr Ekblom, Dr Zdravkovic), Novo Nordisk A/S, Bagsværd, Denmark, and Parexel International GmbH, Berlin, Germany (Dr Golor, Dr Wierich).
Address for reprints: Milan Zdravkovic, MD, PhD, Novo Nordisk A/S, Medical & Science-Liraglutide, 2880, Bagsværd, Denmark; e-mail: mzd{at}novonordisk.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Liraglutide • NN2211 • diabetes type 2 • glucagon-like peptide-1 analogue • human subjects
, <1.5 minutes after intravenous administration) due to rapid degradation by dipeptidyl peptidase-IV, and it has become clear from human studies that 24-hour coverage with the compound is necessary to achieve satisfactory glycemic control.2
Liraglutide (NN2211) is a potent, long-acting, once-daily GLP-1 analogue obtained by derivatizing GLP-1 with a fatty acid and has kinetic properties suitable for once-daily injection.3 Clinical studies have demonstrated 24-hour glycemic control after treatment with liraglutide,4 as well as restored ß-cell response in patients with type 2 diabetes after a single-dose treatment with liraglutide.5 Furthermore, treatment with up to 0.75 mg liraglutide once daily in patients with type 2 diabetes showed improved glycemic control while body weight remained stable.6,7 Liraglutide is slowly absorbed with a time to maximal plasma concentration (tmax) of around 10 to 14 hours, and a t of around 11 to 13 hours.8 Liraglutide may thus prove efficacious for use as a therapeutic agent in patients with type 2 diabetes. As a substantial group of patients with type 2 diabetes are elderly, the current trial was conducted to assess whether there was a difference in pharmacokinetics as a function of age. Furthermore, as a secondary objective, the impact of gender on liraglutide exposure was also investigated.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Subjects were eligible for inclusion into the trial if they were in good general health, between the ages of 18 and 45 years (both inclusive) for the young subject group and equal to or older than 65 years for the elderly subject group and with a body mass index (BMI) of 18 to 30 kg/m2 (both inclusive). Key exclusion criteria were history of clinically significant systemic disorders or major diseases, pregnancy or planning to become pregnant, breast-feeding, febrile or nonfebrile illness before or during the course of the trial, or a known or suspected allergy to the trial product. Furthermore, use of prescription or nonprescription medication, substance abuse, extreme behavior in terms of diet and/or exercise, as well as recent blood donation, excluded subjects from entering the trial. Noncompliant or uncooperative subjects were excluded. Signed informed consent was obtained from each subject before the commencement of any trial-related procedure. The trial was sponsored by and performed on behalf of Novo Nordisk A/S, and liraglutide was supplied as 1.5 mL PenFill cartridges for injection using the NovoPen 1.5 (Novo Nordisk A/S, Bagsværd, Denmark).
Total duration of the trial for each subject was approximately 5 weeks, spanning 3 visits: visit 1 (screening), visit 2 (dosing; days 1-4 in-house at the clinic), and visit 3 (follow-up).
Blood Sampling and Tolerability Assessments
All subjects received a single subcutaneous injection of 1.0 mg liraglutide, corresponding to 200 µL, in the abdomen at 9:00 PM ± 15 minutes at visit 2, day 1. Blood samples were drawn in K-EDTA tubes (3 mL/time point) at 24 time points: -30 and -15 minutes before liraglutide administration and at 2, 4, 6, 8, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 24, 36, 48, and 60 hours after dosing. Plasma liraglutide concentrations were analyzed using a validated enzyme-linked immunosorbent assay (ELISA) method at Capio Diagnostik AS, Copenhagen, Denmark. Details on the validation have previously been published.8 In brief, the assay is specific for intact liraglutide, as one of the antibodies requires an intact N-terminal sequence to bind and as it includes a heat-treatment step that removes cross-reactivity to native GLP-1 in the samples. It has a repeatability of 2.4% to 6.5%, a day-to day variation of 3.7% to 10.1 %, and a lower limit of quantification of 18 pM (limit of detection, 3 pM). Dilution of samples has been documented at least up to 16-fold (corresponding to 72 nM) while maintaining linearity; further dilution is also considered acceptable, provided the dilution matrix is identical to the calibrator matrix. Interference against a number of peptides was examined and was considered irrelevant because of both the low level of interference and the low concentrations of these peptides.
Laboratory assessments were performed throughout the trial and included routine blood hematology, biochemistry, and urinalysis (performed by W & T GmBH, Berlin, Germany), physical examination, vital signs, electrocardiogram, adverse events, and hypoglycemic episodes. Plasma glucose levels were assessed using a glucose meter (One-Touch Ultra, LifeScan, Milpitas, Calif) at predose, before each meal on days 2 and 3, and on day 4. Hypoglycemic episodes were categorized as major if the subject was unable to treat him- or herself (irrespective of glucose level). For subjects with symptoms but able to treat him- or herself, it was categorized as minor if plasma glucose was less than 3.1 mmol/L and categorized as symptoms only if either plasma glucose was 
3.1 mM or if no glucose value was available. Any adverse events occurring were recorded at each visit. All blood samples were drawn through a catheter, and the total blood volume drawn as part of the study was approximately 150 mL/subject.
Pharmacokinetic Parameters
The following pharmacokinetic parameters were calculated based on the liraglutide plasma concentrations: area under the liraglutide plasma concentration curve (AUC) from time 0 to last quantifiable concentration (AUC0-t), from time 0 to infinity (AUC0-
), apparent clearance (CL/F), apparent volume of distribution (Vz/F), and terminal plasma elimination t, whereas maximal plasma concentration (Cmax) and tmax were obtained directly from the concentration-time profile of liraglutide. The parameters were estimated using WinNonlin version 3.3 (Pharsight Corp, Mountain View, Calif).
Statistical Analysis
The sample size calculation was based on the power of a comparison between the 2 age groups (primary end point) using an equivalence test for the primary end point, AUC0-t. The equivalence criterion was defined as the 90% confidence interval (CI) for the ratio of AUC0-t between the 2 age groups being completely contained in the equivalence interval (0.80:1.25). With a sample size of 32 subjects, the power was estimated to 82.8%. The power of comparison for gender (secondary end point) was assumed to be the same as for the comparison between the 2 age groups.
Comparisons between age and sex groups of base-line values of age, weight, and BMI were performed using a normal linear model including effects of age group and sex. The model also included an interaction between age group and sex, but this interaction term was in no case statistically significant (P > .13) and was therefore removed from the model.
The comparisons for all pharmacokinetic parameters (except tmax) between young versus elderly subjects and male versus female subjects were performed using an analysis of covariance (ANCOVA) model for log-transformed values, with age group and sex as fixed effects and log (body weight) as a covariate. For tmax, nonparametric estimates and 90% CIs according to Hodges-Lehmann9 were calculated for the differences between age groups and between sexes. For the parametric analysis, the data are presented as mean ± SD, and a significance level of .05 was used.
Comparisons between age and sex groups of frequencies of subjects with any adverse events and frequencies of subjects with treatment-emergent gastrointestinal adverse events were performed using the Fischer exact test. The comparisons between age groups were stratified by sex, and the comparisons between sex groups were stratified by age group. The hypothesis of a common odds ratio for the 2 strata was tested and accepted (P = 1).
The statistical analysis was performed in SAS version 8.2 or later (SAS Institute Inc, Cary, NC).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Liraglutide Pharmacokinetics
Mean liraglutide plasma concentrations are presented by age group (Figure 1) and by gender (Figure 2), and summary pharmacokinetic parameters for male, female, young, and elderly are presented in Table II. Furthermore, CL/F and Vz/F by age are presented in Figure 3. AUC0-t adjusted for body weight (significant covariate; P = .001) was found to be equivalent in young and elderly subjects (primary end point), with an estimated ratio of 0.94 (90% CI, 0.84-1.06; P = .39). There was no significant effect of gender (secondary end point) on the AUC0-t adjusted for body weight (significant covariate; P = .001) of liraglutide (P = .38; estimated ratio, 1.08; 90% CI, 0.93-1.26) (Table III). Furthermore, there was no significant effect of gender (P = .64) and age (P = .37) on Cmax adjusted for weight (significant covariate; P < .001) (90% CI are presented in Table III). There was no gender by age interaction in the statistical analysis.
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Median tmax ranged from 11 to 13 hours in the 2 age groups (Figure 1 and Table II). Likewise, the mean t ranged from 12 to 14 hours in the 2 age groups, with an overall mean of 13.5 hours. Comparable results were obtained for male and female subjects (Figure 2 and Table II).
Tolerability Assessments
All subjects completed the trial. Adverse events were of mild or moderate severity, and significantly more young subjects compared to elderly subjects reporting an adverse event (P = .02), with 7 subjects reporting 14 events and 1 subject reporting 2 events, respectively, but with no significant difference for gastrointestinal side effects (P = .32). In addition, there were significantly more female subjects reporting adverse events compared with male subjects (7 of 16 vs 1 of 16; P = .02). There was no significant difference in the number of female subjects compared to male subjects reporting a gastrointestinal adverse event (P = .32). The most frequent adverse events were headache (4 events), vomiting (4 events), and nausea (3 events). The gastrointestinal adverse events tended to occur at the time of Cmax. No adverse events were serious or severe in nature. No clinically relevant changes were found for any of the laboratory parameters investigated, and no episodes of hypoglycemia were reported. Plasma glucose concentrations using the glucose meters are shown in Figure 4. The lowest plasma glucose level measured was 3.8 mM.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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With respect to the tolerability assessments, there were no serious adverse events reported. As expected, based on the glucose-dependent stimulation of insulin secretion5 observed with liraglutide, no hypoglycemic episodes were reported. Five subjects experienced gastrointestinal symptoms; 4 of whom were female (3 young and 1 elderly). Because both the young versus the elderly and female versus male subjects had a significantly higher fraction of subjects reporting an adverse event, the higher frequency in female subjects cannot directly be explained by the apparent higher plasma concentrations observed for female subjects, as this result was not observed for young versus elderly subjects (Figure 1). The frequency of gastrointestinal adverse events suggests that subjects should not start directly at 1 mg liraglutide but that a stepwise titration should be applied.
When adjusted for body weight, no effect of gender or age was found on the pharmacokinetics of liraglutide. A stepwise dose titration approach is recommended to minimize the risk of gastrointestinal adverse events.
These data were presented in part as an abstract and poster at the annual conference of the American Diabetic Association, San Diego, June 2005. The authors thank Dr Julie Edmed, who provided medical writing services, in accordance with the EMWA guidelines for medical writing, on behalf of Novo Nordisk A/S. The trial was performed in accordance with local laws and regulations and after obtaining ethical approval.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1. Holst JJ. Enteroglucagon. Annu Rev Physiol. 1997;59: 257-271.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Larsen J, Hylleberg B, Ng K, Damsbo P. Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Diabetes Care. 2001;24: 1416-1421.
3. Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000;43: 1664-1669.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Degn KB, Juhl CB, Sturis J, et al. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004;53: 1187-1194.
5. Chang AM, Jakobsen G, Sturis J, et al. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes. 2003;52: 1786-1791.
6. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27: 1335-1342.
7. Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med. 2005;22: 1016-1023.[CrossRef][Medline] [Order article via Infotrieve]
8. Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002;45: 195-202.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Lachin JM. Group sequential monitoring of distribution-free analyses of repeated measures. Stat Med. 1997;16: 653-668.[CrossRef][Medline]
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