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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (Dr He); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Wang, Dr Ligueros-Saylan, Dr Foley); State University at Buffalo College of Pharmacy and Pharmaceutical Sciences, Buffalo, New York (Dr Bullock); Department of Medical Physiology, Panum Institute, University of Copenhagen, Denmark (Dr Deacon, Dr Holst); and PharmaWrite LLC, Princeton, New Jersey (Dr Dunning).
Address for reprints: Address for correspondence: Yan-Ling He, PhD, DMSc, Exploratory Development, Novartis Institutes of Biomedical Research Inc, 400 Technology Square, Building 605, Rm 811, Cambridge, MA 02139-3584; e-mail: yanling.he{at}novartis.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed-meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.
Key Words: Dipeptidyl peptidase IV • GLP-1 • GIP • insulin • glucagon • glucose
Vildagliptin (previously known as LAF237) is an oral antidiabetic agent being developed for the treatment of type 2 diabetes mellitus (T2DM).5 Vildagliptin increases endogenous levels of the intact forms of GLP-1 and GIP6 by inhibiting the enzyme responsible for their degradation, dipeptidyl peptidase-4 (DPP-4).7 Although vildagliptin reduces postmeal glucose levels and improves model-assessed ß-cell function in patients with T2DM,6 several studies have failed to find an effect of vildagliptin on plasma insulin levels following ingestion of a mixed meal in patients with T2DM.5,8,9 However, vildagliptin has been shown to increase postload plasma insulin levels and to decrease glucose excursions during oral glucose tolerance tests (OGTTs) in animal models of T2DM.7,10
The aim of the present study was to assess the influence of a broad range of doses of vildagliptin (10, 25, 50, 100, 200, and 400 mg) on plasma insulin levels during a 75-g OGTT in patients with T2DM. In addition, this study examined the dose proportionality of plasma levels of parent drug, as well as the primary (plasma DPP-4 activity) and secondary (GLP-1, GIP, glucose, and glucagon) pharmacodynamic endpoints.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Men and nonfertile women with T2DM diagnosed at least 3 months previously, aged 30 to 70 years, could be enrolled provided they met the following inclusion criteria: willingness to undergo washout from prior oral antidiabetic agents, average (mean of 3 assessments) fasting plasma glucose (FPG) between 7.0 and 10.0 mmol/L during the last 2 weeks of washout, HbA1c at screening between 7.5% and 10.0%, C-peptide 0.3 nmol/L and body mass index (BMI) 
40 mg/kg2, and good health other than abnormalities associated with T2DM, as determined by past medical history, physical examination, electrocardiogram, and laboratory tests at screening. Patients were excluded if they had a history of type 1 or secondary forms of diabetes, significant diabetic complications, clinically significant cardiovascular abnormalities, liver disease, renal impairment, thyrotoxicosis, acromegaly, asthma or major skin allergies, or major gastrointestinal surgery. Patients with urinary cotinine >500 ng/mL, positive hemoccult, and positive anti-glutamic acid decarboxylase (GAD) antibody screen were excluded, as were those treated with thiazolidinediones within 4 months, Na+-channel blockers within 3 months, thiazide diuretics, beta-blockers, or any drugs considered possibly able to affect results or their interpretation. Written informed consent was obtained from all participants, and the protocol was approved by the institutional review board at the study site (SFBC International, Miami, Fla). The study was conducted in accordance with the Declaration of Helsinki and good clinical practice.
Oral Glucose Tolerance Tests
Patients checked into the clinic on the evening of day -2, and on day -1, after baseline assessments confirmed eligibility, subjects were randomized to 1 of 7 treatment sequences. Throughout the domiciled period, patients maintained a standard diabetic weight-maintaining diet (55% carbohydrate, 25% fat, 20% protein) with 25%, 35%, 35%, and 5% of calories provided at breakfast, lunch, dinner, and evening snack, respectively. During the study, patients remained alcohol and caffeine free and abstained from strenuous exercise. On each study day, following an overnight fast (10 hours), patients omitted breakfast and received study drug (placebo or vildagliptin, 10, 25, 50, 100, 200, or 400 mg) with 200 mL water between 7:00 and 8:00 AM. A 75-g oral glucose load was consumed 30 minutes after study drug. Blood samples were obtained from an indwelling cannula or by venipuncture for determination of plasma levels of parent drug (LAF237), DPP-4 activity, insulin and glucose, glucagon, intact GLP-1, and intact GIP at the following time points relative to the oral glucose load, designated as time 0:
Analytical Methods
Safety laboratory assessments, HbA1c, and glucose, insulin, and glucagon were analyzed at Medical Research Laboratories (Highland Heights, Ky) using standardized procedures. Plasma DPP-4 activity was measured with an enzymatic assay as described previously. 7 Plasma levels of intact GLP-1 were measured by enzyme-linked immunosorbent assay (ELISA) using an antibody specific for the N-terminus (Bioanalytics Department of Novartis Pharma S.A., Reueil-Malmaison, France), and GIP was measured by radioimmunoassay with an antibody (code 98171) specific for the N-terminus.11 When GLP-1 or GIP levels were below the limit of detection of the assay, values were set to 0.
Plasma concentrations of vildagliptin (LAF237) were measured by a high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method. The assay consisted of a liquid-solid extraction on Oasis HLB 96-well extraction plates using an automated system followed by HPLC using an XTerra MS C18 5-µm column (Waters Corporation, Milford, Mass) with isocratic elution using 40% mobile phase A (10 mmol/L ammonium acetate [adjusted to pH 8 with ammonia solution]-methanol [95:5, v/v]) and 60% mobile phase B (acetonitrile-methanol [10:90, v/v]). Detection was performed by MS/MS with electrospray ionization (ESI) using an API 3000TM (Applied Biosystems, Foster City, Calif) mass spectrometer in positive ion mode. The masses for vildagliptin were precursor ion m/z 304 and product ion m/z 154. The lower limit of quantification for the assay was 2.0 ng/mL. The internal standard for this assay was [13C515N] vildagliptin. Within-study assay validation at nominal vildagliptin concentrations of 5.25, 400, and 900 ng/mL showed an assay precision (coefficient of variation) of 2.5% to 5.7% and a bias of -1.0% to 0.8%.
Data Analysis
The following PK parameters were determined using noncompartmental methods: tmax, Cmax, AUC0-8 h, and t
. The AUC from time 0 to the last available sample was calculated for glucose, insulin, glucagon, GLP-1, and GIP during OGTT. The percentage of DPP-4 inhibition was calculated from the measured DPP-4 activity by the following equation:
 | (1) |
where DPP-4 activity(t) is the measured DPP-4 activity at time t, and DPP-4 activity(0) is the baseline DPP-4 activity measured before the administration of vildagliptin.
The mean residence time (MRT) of DPP-4 inhibition was estimated from the DPP-4 percentage inhibition versus time profile based on the following equation:
 | (2) |
The relationship between vildagliptin concentrations and DPP-4 inhibition at 8.5 hours postdose was modeled with a simple Emax model as follows:
 | (3) |
where Emax is the maximum inhibition of DPP-4 activity by vildagliptin, C is vildagliptin concentration, and EC50 is the vildagliptin concentration that requires achieving 50% of DPP-4 inhibition.
Statistical comparisons of the PK and PD parameters were made using analysis of variance for a 7-period crossover design. For each parameter, the log-transformed data were analyzed using a linear mixed-effect model including treatment, period, and sequence as fixed factors and patient within sequence as a random factor. Each active treatment was compared to placebo.
Safety Monitoring
Safety assessments (physical examination, vital signs, electrocardiogram [ECG], hematology, chemistry, urinalysis, and hemoccult) were made at screening, baseline, and study completion. All adverse events were recorded and assessed by the investigator as to their severity and possible relationship to the study drug.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Due to limitations on the total volume of blood sampling, only 5 samples were obtained for the PK assessments. Figure 1 depicts the mean plasma drug (LAF237) concentration-time profiles for the 6 doses tested. Vildagliptin was rapidly absorbed, reaching a tmax at either the 0.5- or 1.5-hour time point. The estimated elimination half-life (t) was similar across doses, ranging from 1.6 to 2.3 hours. Both the Cmax and the AUC0-8 h increased in a dose-proportional manner. Linear regression analysis of mean values for each dose level, setting the y-intercept to zero, yielded correlation coefficients >0.99.
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As depicted in Figure 3, the relationship between vildagliptin concentrations at 8.5 hours postdose and DPP-4 inhibition (%) was fitted to a simple Emax model. The vildagliptin concentration that is required to achieve 50% of DPP-4 inhibition (EC50) was estimated to be 1.35 ± 0.14 ng/mL (= 4.5 nM), suggesting that vildagliptin is a potent DPP-4 inhibitor.
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Table III reports the AUC0-5 h of intact GLP-1 and the AUC0-4 h of intact GIP during OGTTs performed after oral administration of placebo or vildagliptin. The oral glucose load increased plasma levels of GLP-1 and GIP after administration of placebo, and each dose level of vildagliptin significantly and similarly increased the postload AUCs for GLP-1 (by 24%-41%) and GIP (by 30%-50%) relative to placebo. There was no significant difference in the GLP-1 AUC0-5 h or the GIP AUC0-4 h among vildagliptin dose levels.
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Each dose level of vildagliptin also increased the insulin response to oral glucose and decreased postload glucose and glucagon levels. For the sake of clarity, Figure 4 depicts plasma insulin (panel A), glucose (panel B), and glucagon (panel C) levels during OGTTs performed after placebo and only 1 dose level (100 mg) of vildagliptin, representing an anticipated clinical dose. Vildagliptin increased the insulin AUC by approximately 35% and decreased the glucose and glucagon AUCs by approximately 11%. Table IV summarizes the insulin, glucose, and glucagon data obtained during OGTTs following each dose level of vildagliptin. With the exception of the effect of 25 mg vildagliptin on the glucose AUC0-5 h, which did not achieve statistical significance due to higher variability, each dose of vildagliptin similarly and significantly increased the insulin AUC0-5 h, decreased the glucose AUC0-5 h, and decreased the glucagon AUC0-4 h. There was no significant difference in these parameters among vildagliptin dose levels.
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In general, vildagliptin appeared to be well tolerated. A total of 8 of the 16 patients reported a total of 16 adverse events (AEs). The only AEs suspected to be related to study medication were 2 instances of mild headache (in 1 patient after 100 mg vildagliptin and in another patient after 400 mg vildagliptin) and 1 instance of mild nausea in 1 patient following 400 mg vildagliptin. One serious AE not suspected to be drug related (moderate chest pain) led to discontinuation of a patient after the period 7 dose (400 mg), and 1 AE (moderate abdominal pain) not suspected to be drug related led to discontinuation of a patient after the period 6 dose (400 mg). No clinically relevant changes in clinical laboratory tests, vital signs, or ECG findings were reported.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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An explanation for the apparent discrepancies among various studies of vildagliptin and postload insulin levels may be found by considering (1) the absolute glucose loads (representing the main stimulus for incretin hormone release from the gut) and (2) the increases in peripheral glucose levels (postload glucose excursions, representing the primary stimulus for insulin secretion) that occur during OGTT versus a mixed meal. It should also be recognized that (1) the insulin response to nutrient intake reflects the synergistic actions of (circulating) glucose and the incretin hormones, (2) the insulinotropic effects of GLP-1 and GIP are glucose dependent, and (3) the incretin effect is intact and fully functional in healthy subjects but markedly impaired in patients with T2DM13 due to impaired release of GLP-114 and impaired insulinotropic potency of GIP.15
The total glucose load in a standardized mixed meal may be less than, similar to, or even greater than the 75-g load used for an OGTT, depending on the size and composition of the meal. However, the postload glucose excursion following a 75-g OGTT is approximately 4 times that following a mixed meal containing 75 g of carbohydrate.16 Nonetheless, in healthy subjects, even a 75-g oral glucose load produces only a moderate glucose excursion (
4.0 mmol/L, limited by a normally functioning pancreas), but the stimulus for incretin hormone release is robust. Because both the secretion and action of incretin hormones are intact in healthy subjects, further enhancement of incretin hormone levels through inhibition of DPP-4 may not lead to any augmentation of postload insulin levels. In contrast, as in the present study in patients with T2DM, a 75-g oral glucose load elicits a much greater glucose excursion (11.0 mmol/L, allowed by impaired islet function), representing an increased stimulus for insulin secretion. But in part due to impaired GLP-1 release and impaired GIP action, the insulin response is inadequate in diabetic subjects. Accordingly, increasing plasma levels of the intact form of the incretin hormones, by inhibiting DPP-4 with vildagliptin, increases postload insulin levels during OGTT in patients with T2DM.
Comparing a mixed meal to an OGTT in patients with T2DM, the differential effect of vildagliptin on postload insulin levels may again be explained by the stronger stimulus for insulin secretion (postload glucose excursion) provided by the OGTT versus a mixed meal. In previous studies of vildagliptin during standard meal tests in patients with T2DM, the postmeal glucose excursions (during placebo treatment) were approximately 2.2 to 4.4 mmol/L.5,6,8 Thus, it appears that vildagliptin elicits an absolute increase in postload insulin when large glucose excursions provide a strong, independent stimulatory effect on insulin secretion, but vildagliptin produces only a relative increase when moderate, more physiologic glucose excursions act as the primary stimulus for insulin secretion. This interpretation is consistent with animal studies of other DPP-4 inhibitors that have found more substantial effects to increase postload insulin levels in Zucker fatty rats compared to lean littermates.17,18
It should be recognized that in the earlier findings, vildagliptin had a minimal net effect on plasma insulin levels after mixed meals discussed above, derived from studies of 4-weeks' or greater duration. Accordingly, repeated administration of vildagliptin is associated with reductions in FPG5,6,8 and improved insulin sensitivity.19 These effects of vildagliptin tend to offset its insulinotropic actions and are in part responsible for the reduced glucose load.
Several other findings in the present study merit additional comment. In agreement with (unpublished) findings in healthy subjects, after single oral doses of vildagliptin (10-400 mg) in patients with T2DM, the increases in Cmax and AUC0-8 h for parent drug were dose proportional, and the elimination half-life of vildagliptin in plasma was approximately 2 hours. Even 8.5 hours after administration of 10 mg vildagliptin (time 8 hours relative to glucose load), plasma drug levels averaged 2.2 ng/mL (= 7.3 nM). Because the IC50 for vildagliptin to inhibit DPP-4 in vitro is 2.7 nM,7 the finding that plasma DPP-4 activity remained inhibited by >50% at this time point (cf Table II) is entirely consistent with the known potency of vildagliptin. Furthermore, because it has been established that in rats, this degree of inhibition of DPP-4 results in significant enhancement of plasma levels of intact GLP-1,10 it is not surprising that all doses of vildagliptin tested produced significant and similar increases of circulating incretin hormone levels. Each dose level of vildagliptin also elicited significant and similar increases of insulin and decreases in glucose and glucagon during OGTT in patients with T2DM, consistent with mediation of these effects by the incretin hormones.
In view of the pharmacokinetic and pharmacodynamic characteristics determined by the present study, the observed dose dependency of the duration of DPP-4 inhibition would be predicted. The sustained effect of vildagliptin to inhibit plasma DPP-4 activity (eg, 35% inhibition observed 24 hours after the 100-mg dose) can be readily explained by the drug concentration remaining 24 hours after dosing in relation to the potency of vildagliptin. The predicted level 24 hours after the 100-mg dose is 0.6 ng/mL (2.0 nM, based on the peak level [605 ng/mL] at 1 hour and the plasma half-life of 2.3 hours for this dose). Because the IC50 of vildagliptin estimated in this study was 1.5 ng/mL (4.5 nM), it appears that there are adequate vildagliptin levels remaining (within the limits of estimating both the IC50 and the drug levels at 24 hours) to explain the sustained effect of vildagliptin, irrespective of its short half-life, and that this is explained by its high potency.
The high potency of vildagliptin is due to its unique binding characteristics at the enzyme level. Vildagliptin is itself a substrate of DPP-4, and it is cleaved into an inactive metabolite partially by DPP-4 as well. Vildagliptin displays tight binding and slow dissociation from the enzyme, which is reflected by a relatively long dissociation half-life of 1 hour.20 This contrasts with other DPP-4 inhibitors (such as sitagliptin, with an IC50 of 18 nM21 and EC50 of 25 nM22) that only inhibit the DPP-4 enzyme competitively. This enables vildagliptin to achieve the same inhibition of DPP-4 at lower concentrations than would be required for DPP-4 inhibitors that are simple competitive inhibitors.
As a result, a therapeutic objective of maintaining a biologically relevant degree of inhibition of DPP-4 activity throughout the day would be attainable with a 50- or 100-mg dose, once or twice a day. In clinical studies to date, significant improvements in glycemic control in patients with T2DM have been reported using 25-mg bid,9 50-mg qd,5 and 100-mg qd8 dose regimens.
In summary, this study (1) established the dose proportionality of vildagliptin pharmacokinetics; (2) confirmed that inhibition of DPP-4 with vildagliptin significantly increases circulating postload levels of intact GLP-1 and GIP, reduces postload glucose excursions, and suppresses inappropriate glucagon secretion; and (3) ascertained that vildagliptin increases plasma insulin levels during 75-g oral glucose tolerance tests in patients with T2DM. We conclude that vildagliptin is a potent and orally effective DPP-4 inhibitor that improves glucose tolerance in patients with type 2 diabetes by incretin hormone-mediated improvements in pancreatic islet function.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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15. Nauck MA, Heimesaat MM, Orskov C, et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91: 301-307.[Web of Science][Medline] [Order article via Infotrieve]
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