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PHARMACOKINETICS |
From Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Sunkara, Mr Sabo, Dr Wang, Ms Campestrini, Dr Howard), Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (Dr He, Dr Dole), and Parkway Research Center Inc, North Miami Beach, Florida (Dr Rosenberg).
Address for correspondence: Gangadhar Sunkara, PhD, 435/1187, One Health Plaza, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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- and ß-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r2 = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC0-
) and maximum plasma concentration (Cmax). Dose proportionality was assessed using a statistical power model [X = ·(dose)ß]. The 90% confidence intervals of the proportionality coefficient, ß, for AUC0- (1.15-1.19) and Cmax (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC0- and Cmax but no dose-dependent changes in time to reach Cmax or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased Cmax by 19% and AUC0- by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.
Key Words: Type 2 diabetes • vildagliptin • dose proportionality • pharmacokinetics
Clinical studies have shown that once-daily administration of vildagliptin 100 mg lowers fasting, mean 24-hour, and 4-hour prandial glucose levels in patients with type 2 diabetes by improving pancreatic ß-cell function.5,6 In addition, vildagliptin improves postprandial hypertriglyceridemia in patients with type 2 diabetes.7
In healthy volunteers and patients with type 2 diabetes, vildagliptin is rapidly absorbed, with an absolute bioavailability of 
85% and a maximum plasma drug concentration (Cmax) observed 1 to 2 hours after administration.8,9 Vildagliptin has a large volume of distribution at steady state (71 L).8 The principal route of elimination is metabolism via hydrolysis of the cyano moiety, accounting for two thirds of the elimination of the drug. One third of the drug is excreted unchanged via the kidneys after intravenous administration.8 Hepatic metabolism (eg, by cytochrome P450 enzymes) does not contribute significantly to the elimination of vildagliptin.10
We describe here the results of 2 studies in healthy volunteers (1) to evaluate the dose proportionality of single oral doses of vildagliptin (25-200 mg) and (2) to determine the effect of food on the disposition of a single oral dose of vildagliptin (100 mg).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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14 hours before study drug administration, subjects were randomized to receive 1 of 4 single oral doses of the final market image (FMI) formulation of vildagliptin: 25 mg (1 x 25-mg tablet), 50 mg (2 x 25-mg tablet), 100 mg (1 x 100-mg tablet), and 200 mg (2 x 100-mg tablet). All vildagliptin doses were administered with 240 mL of water following an overnight fast of 10 to 12 hours, which was continued for a further 4 hours after the dose. Blood samples were obtained for determination of plasma drug concentrations over the 24-hour period after the dose. At 48 hours after the dose, subjects were crossed over to receive alternate doses of vildagliptin, with each subject receiving each of the 4 doses of vildagliptin during the study. At the end of the fourth dosing period, study completion evaluations were conducted.
Food Effect Study
This was an open-label, single-dose, randomized, crossover study. Following a 21-day screening period and a baseline evaluation, subjects were randomized to receive single oral doses of vildagliptin 100 mg (FMI formulation) in the fasted state or in the fed state or 100 mg of the market form (MF) of vildagliptin (used in early phase I trials) in the fasted state. In each case, vildagliptin was administered with 240 mL of water following an overnight fast of at least 10 hours. Subjects randomized to receive vildagliptin in the fed state took the study drug within 5 minutes of receiving a standard FDA high-fat breakfast (2 eggs fried in butter, 4 oz of hash brown potatoes, 2 slices of white toast with 2 pats of butter, 2 strips of bacon, 8 oz [240 mL] of whole milk; total calorific intake 1000 calories). Subjects receiving drug in the fasted state continued their fast until 4 hours after the dose, when they received a lunch. Blood samples were taken for determination of plasma drug concentrations during the 24-hour period following drug administration. At 48 hours postdosing, subjects were crossed over to receive alternate treatment, with each subject receiving each of the 2 treatments during the study. At the end of the treatment periods, study completion evaluations were conducted.
Study Population
A total of 20 healthy volunteers were enrolled into the dose proportionality study and 24 into the food effect study, all of whom completed all study treatments and procedures. Both studies enrolled healthy male and female subjects (ages 18-45 years). Subjects had a minimum body weight of 55 kg and a body mass index of 20 to 30 kg/m2. Female subjects were required to use appropriate birth control measures unless postmenopausal or surgically sterilized at least 6 months before screening. All subjects had to be able to communicate well with the investigator and comply with the requirements of the respective study. Exclusion criteria included evidence of drug or alcohol abuse; the use of any prescription drug within the previous month or the use of any over-the-counter medication within the last 14 days; clinical evidence of liver disease or injury; or any surgical or medical condition that might alter drug absorption, distribution, metabolism, or excretion.
All subjects provided written informed consent, and both studies were performed in accordance with the Guidelines for Good Clinical Practice and adhered to the principles of the Declaration of Helsinki of the World Medical Association. Both studies were conducted at a single center (Parkway Research Center Inc, North Miami Beach, Fla). Approval for both studies was received from the Western International Review Board (Olympia, Wash).
In both studies, all subjects were admitted to the study center at least 12 hours before administration of the first dose of study drug and remained domiciled until the end-of-study evaluations were completed. Enrolled subjects were prohibited from undertaking strenuous physical exercise for 7 days before dosing until the end of the study, and alcohol was not allowed for 72 hours before dosing until after study completion. Intake of xanthine-containing food or beverages was discontinued 48 hours before dosing for the duration of the study.
Pharmacokinetic Measurements
In both studies, blood samples were taken predose (0 hours) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15, and 24 hours following administration of vildagliptin. All blood samples (2 mL) were collected into heparinized tubes either by direct venipuncture or by an indwelling cannula inserted in a forearm vein, centrifuged at 4°C, and stored at -70°C until analyses were performed. Plasma concentrations of vildagliptin were determined by a central laboratory (Novartis Pharma SAS, Rueil-Malmaison, France) using a liquid chromatography/positive electrospray ionization tandem mass spectrometry (LC-MS/MS) assay. Sample extraction was performed on Oasis HLB 96-well extraction plates (Waters Corp, Milford, Mass) using an automated liquid handling system. Samples were washed with successive washes with 300 µL of methanol/2% ammonium hydroxide (5:95, v/v), 300 µL of methanol/2% ammonium hydroxide (20:80, v/v), and 300 µL of water. The analytes were eluted twice with 75 µL of methanol/0.1% trifluoroacetic acid (80:20, v/v), evaporated at ambient temperature under nitrogen to a final volume of approximately 50 µL, and diluted with 50 µL of methanol/0.5% ammonium hydroxide (15:85, v/v).
Extracted vildagliptin samples were analyzed by high-performance liquid chromatography (HPLC)-MS/MS using an XTerra MS C18 HPLC column (150 x 2.1 mm; Waters Corp, Milford, Mass) and eluted with a mobile phase comprising 40% solvent A (10 mmol/L ammonium acetate [pH 8]/methanol [95:5, v/v]) and 60% solvent B (acetonitrile/methanol [10:90, v/v]) at a flow rate of 0.20 mL/min. Detection was performed in MS/MS using an API3000 electrospray ionization mass spectrometer (Applied Biosystems, Foster City, Calif) in positive ion mode. The internal standard for this assay was [13C 155N]vildagliptin. The retention time on HPLC was 2.5 minutes for vildagliptin and 2.8 minutes for [13C 155N]vildagliptin. The masses for vildagliptin were precursor ion m/z 304 and product ion m/z 154 and for [13C 155N]vildagliptin precursor ion m/z 310 and product ion m/z 150. The lower limit of quantification for the assay was 2.0 ng/mL. Across the 2 studies, within-study assay validation at nominal vildagliptin concentrations of 5.25, 400, and 900 ng/mL showed an assay precision (coefficient of variation, CV) of 3.2% to 10.0% and a bias of -5.9% to 2.8%.
The following pharmacokinetic parameters were determined for vildagliptin using noncompartmental methods with WinNonlin Pro (version 4.1; Pharsight, Mountain View, Calif): Cmax, time to reach Cmax (tmax), area under the plasma concentration-time curve from time zero to time t (AUC0-t), area under the plasma concentration-time curve from time zero to infinity (AUC0-), and terminal elimination half-life (t
).
Safety and Tolerability Assessments
Safety and tolerability assessments included the monitoring and recording of all adverse events and any concomitant medications and significant non-drug therapies. Evaluations of routine blood chemistry, hematology, urine analysis, electrocardiograph (ECG) recordings, and physical examinations were performed at scheduled intervals during the studies.
Statistical Analyses
Dose proportionality study. Pharmacokinetic parameters were assessed using the power model, Y = ·(dose)ß, where Y is the response variable (pharmacokinetic parameter), is the expected value of Y at a reference dose, and ß is the exponent used for examining the proportionality. The relationship between dose and pharmacokinetic parameter is considered to be dose proportional if the 90% confidence interval (CI) for ß is within the dose-proportional limits (L, U), such that dose-normalized pharmacokinetic parameters are equivalent between any 2 dose levels. Following Smith et al,11 the dose proportionality limits can be derived according to the expression L = 1 + Ln(
)/Ln(R) and U = 1 - Ln()/Ln(R), where is the lower limit of bioequivalence range and R is the ratio between the highest and the lowest doses. With = 0.8 and R = 200/25 = 8, the dose proportionality limits are L = 0.89 and U = 1.11. A sample size of 20 subjects was estimated based on Student t distribution for the exponent estimates using 80% statistical power and 5% significance level. The intrasubject CV for vildagliptin pharmacokinetic parameters is needed to derive the standard error of the exponent estimates for the t statistic; the intrasubject CV was set at 0.24 in sample size calculation to be conservative because the CV value is around 0.20 for vildagliptin AUC and Cmax in previous studies.
Food effect study. The effect of food on vildagliptin pharmacokinetic parameters (AUC and Cmax) was assessed by an analysis of variance (ANOVA) of log-transformed data using the PROC MIXED SAS procedure (SAS Institute, Cary, NC). The sources of variation in the analysis model were sequence, subject (sequence), period and treatment as fixed effects, and subject (sequence) as a random effect. Using the ESTIMATE statement, we constructed the contrast between vildagliptin (fed, test) and vildagliptin (fasted, reference), and between formulations FMI (fasted, test) and MF (fasted, reference). Bioequivalence was established if the 90% CIs of the geometric mean ratios were within the range of 0.80 to 1.25. A sample size of 20 subjects was determined to be sufficient to ensure at least 80% power to establish bioequivalence, assuming an intrasubject CV of no more than 0.20 for vildagliptin pharmacokinetic parameters. Because we used a Williams design with 3 treatments (vildagliptin FMI tablet in fasted and fed state and vildagliptin MF formulation in fasted state), 6 treatment sequences were incorporated into the design, and so 24 subjects were enrolled in the study to ensure an equal number of subjects (n = 4) in each treatment sequence.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Dose Proportionality Study
Mean plasma concentration versus time curves following the administration of a single oral dose of vildagliptin 25 to 200 mg showed a dose-dependent increase in plasma drug concentration (Figure 1). There was a linear increase in Cmax and exposure (AUC0-) with vildagliptin dose (Table II). Linear regression of dose versus mean Cmax and AUC0- yielded correlation coefficients (r2) of 0.999 for both pharmacokinetic parameters (Figure 2), indicating a linear relationship between vildagliptin dose and Cmax and AUC0-. Both tmax (median range, 1.25-1.75 hours) and t (mean range, 1.7-3.1 hours) were comparable across the dose range. The proportionality coefficients (ß) for AUC0-, AUC0-t, and Cmax were 1.16 (90% CI, 1.15-1.18), 1.17 (90% CI, 1.15-1.19), and 1.09 (90% CI, 1.04-1.14), respectively. Because the 90% CI values for these parameters fell outside the acceptance range of 0.89 to 1.11, dose proportionality was not demonstrated based on the predefined criteria. However, deviation of the observed AUC and Cmax from values predicted by the dose proportionality model was estimated to be less than 7.7% for all doses, and there was a 2.1- to 2.3-fold increase in mean AUC and Cmax with each doubling of the vildagliptin dose.
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Food Effect Study
Bioequivalence was established for MF and FMI formulations of vildagliptin; the 90% CIs of geometric mean ratios for Cmax, AUC0-t, and AUC0- following administration of a 100-mg dose in the fasted state were all within the predefined 0.80 to 1.25 acceptance range for bioequivalence (data not shown). Mean Cmax of vildagliptin decreased by 19% when the FMI tablet was administered with food (Table III; Figure 3). ANOVA analysis showed that although the 90% CIs for AUC0-t (geometric mean ratio: 0.89 [0.85-0.94]) and AUC0- (geometric mean ratio: 0.90 [0.86-0.94]) fell within the range for bioequivalence, the lower limit of the 90% CI for Cmax (geometric mean ratio: 0.81 [0.75-0.87]) was just outside the acceptance range. Median tmax values were 1.75 hours in the fasted state and 2.5 hours when vildagliptin was administered with food (Table III).
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Safety and Tolerability
No adverse events were reported by any of the subjects in either study following oral administration of vildagliptin. In addition, no clinically significant abnormalities in vital signs or ECG measurements were observed in either study. No clinically relevant changes in laboratory parameters were observed in the dose proportionality study. However, 2 patients in the food effect study had elevated creatine kinase levels (551 IU/L and 401 IU/L, respectively) at the end of the study, which returned toward normal by the next study visit and were not considered to be clinically relevant.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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In the dose proportionality study, linear regression analysis of the relationship between vildagliptin dose and AUC0- and Cmax yielded correlation coefficients (r2) of 0.999 for both parameters, demonstrating a strong linear relationship over the 25- to 200-mg dose range. The limits of the 90% CIs of AUC0- (1.15-1.19) and Cmax (1.04-1.14) fell outside the predefined range for dose proportionality (0.89-1.11). Therefore, the relationship between dose and AUC0- and Cmax was not strictly dose proportional. Nevertheless, the deviation of observed values from those predicted by the power model for dose proportionality was small (<7.7%), and ratios of AUC and Cmax between neighboring doses of vildagliptin (eg, 25 vs 50 mg, 50 vs 100 mg, 100 vs 200 mg) were comparable. For true dose proportionality, doubling the vildagliptin dose should result in a doubling of the pharmacokinetic measure. In this study, there was a 2.1- to 2.3-fold increase in AUC0- and Cmax with each doubling of dose across the 25- to 200-mg dose range. Therefore, vildagliptin can be considered to display near dose-proportional pharmacokinetics, and the small deviations from dose proportionality reported here are not considered to be clinically significant. The t and tmax for vildagliptin in this study were consistent with those reported in previous pharmacokinetic studies in healthy volunteers and patients with type 2 diabetes using similar doses.9,12
There were no clinically relevant changes in the pharmacokinetics of vildagliptin when a single oral dose was administered following a standard high-fat meal compared with administration in the fasted state. Although the 90% CIs of the geometric mean ratios for AUC0-t and AUC0- were within the acceptance range for bioequivalence (0.80-1.25), Cmax was reduced by 19% when administered with a high-fat meal. The observed Cmax in the fed state was 431 ng/mL, which is approximately 30-fold higher than the reported IC90 of vildagliptin for DPP-4 inhibition (15 ng/mL) (data on file). Consequently, the 19% reduction in Cmax observed in the fed state is unlikely to have any impact on the ability of vildagliptin to inhibit DPP-4. Therefore, the changes in vildagliptin Cmax reported in the present study are not considered to be clinically relevant, and consequently vildagliptin tablets can be administered without regard to meals. The vildagliptin single-dose pharmacokinetics reported here are comparable to multiple-dose pharmacokinetics observed in other studies.9,12,13 In the present study, plasma concentrations of vildagliptin following an oral dose of 25 to 200 mg returned to predosing levels within 24 hours. This is in agreement with previous pharmacokinetic data that demonstrated no evidence of dose accumulation of vildagliptin at doses of up to 400 mg (data on file). Therefore, no differences are expected to be seen with multiple-dose administration of vildagliptin in a clinical setting.
No adverse events were reported by any randomized subject in either study. In addition, assessments of vital signs, ECG, blood biochemistry, hematology, and urine analysis did not reveal any clinically significant changes in any subject. The apparent excellent safety and tolerability of vildagliptin in these 2 studies are in agreement with the safety profile of single-dose administrations of vildagliptin up to 200 mg/d in other studies. However, the lack of adverse events in both studies suggests that a factor of underreporting may have played a role. The safety and tolerability of vildagliptin following single-dose administration to healthy volunteers mirror those following multiple-dose administration. In a recent clinical study in patients with type 2 diabetes, multiple-dose administration of vildagliptin 25 to 100 mg was associated with a placebo-like safety profile over a 12-week treatment period.14 The predominant ethnicity of subjects enrolled in both studies was Hispanic. Although differences in the disposition of vildagliptin among ethnic subgroups have not been identified, caution should nevertheless be exercised in extrapolating the results to specific ethnic subpopulations.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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