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Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

From Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (Dr He, Dr WP Dole); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Ligueros-Saylan, Dr Sunkara, Mr Sabo, Dr Zhao, Dr Wang, Dr K Dole, Dr Howard); Novartis Pharma S.A., Rueil-Malmaison, France (Dr Campestrini, Dr Pommier); and MDS Pharma Services, Lincoln, Nebraska (Dr Marion).

Address for reprints: Yan-Ling He, PhD, Exploratory Development-DMPK, Novartis Institutes for Biomedical Research, 400 Technology Square, Building 605, Cambridge, MA 02139-3584.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration–time curve from time zero to 24 hours (AUC_0-24h) and maximum plasma concentration (C_max) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC_0-24h and C_max increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Key Words: Dipeptidyl peptidase IV inhibitor • angiotensin converting enzyme inhibitor • angiotensin receptor blocker • calcium channel blocker • pharmacokinetics • type 2 diabetes • vildagliptin

A new approach to the treatment of type 2 diabetes involves the inhibition of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the hydrolysis and inactivation of the incretin hormones, glucagon-like peptide-1 and gastric inhibitory peptide.^11,12 The incretin hormones are released into the blood-stream in response to a meal, where they play a key role in maintaining circulating glucose levels via the stimulation of insulin release from pancreatic β-cells.^13,14

Vildagliptin (LAF237) is a novel, orally active, potent and selective inhibitor of DPP-4 that has been developed for the treatment of type 2 diabetes. Clinical studies have shown that vildagliptin lowers fasting and postprandial glucose levels in patients with type 2 diabetes.^15,16 The pharmacokinetics of vildagliptin have been studied in healthy subjects and in patients with type 2 diabetes. Vildagliptin is rapidly absorbed with an absolute bioavailability of 85%.¹⁷ Maximum plasma concentration (C_max) occurs 1 to 2 hours after oral administration, and the elimination half-life is around 2 hours. The effective half-life of vildagliptin (as determined by DPP-4 inhibition) is 10 hours following a 100-mg oral dose.^17-19 Vildagliptin is extensively distributed into tissues and organs with a high volume of distribution at steady state of 71 L.¹⁷ In humans, the primary elimination pathway for vildagliptin is metabolism via hydrolysis, which accounts for approximately two thirds of the elimination of an oral dose. The principal metabolic pathway involves hydrolysis at the cyano moiety leading to the generation of the inactive carboxylic acid metabolite LAY151. Oxidative metabolites represent no more than 1.6% of drug elimination; therefore, cytochrome P450 (CYP450) enzymes are not expected to contribute to the metabolism of vildagliptin. Drug interactions at the level of CYP450 isoenzymes are unlikely, because in vitro studies showed little or no inhibition of human CYP450 isoenzymes by vildagliptin and LAY151 (data on file).

This article describes the results of 3 individual drug–drug interaction studies that evaluated the pharmacokinetics of vildagliptin alone and in combination with 3 commonly prescribed antihypertensive agents: the calcium channel blocker, amlodipine; the angiotensin receptor blocker, valsartan; and the angiotensin converting enzyme (ACE) inhibitor, ramipril, in healthy subjects.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Study Design
Each study used an open-label, multiple-dose, 3-period, randomized, crossover design. Randomization was performed by Novartis Drug Supply Management using a validated system. The 100-mg daily dose of vildagliptin is the highest anticipated therapeutic dose. The doses of antihypertensive drugs were selected as the highest daily dose of valsartan (320 mg) used in clinical practice and the most commonly used doses in drug–drug interaction studies for amlodipine (5 mg) and ramipril (5 mg).

Vildagliptin/amlodipine study. Following a 21-day screening period, subjects were randomized to once-daily administration of vildagliptin 100 mg alone, amlodipine 5 mg alone, or vildagliptin 100 mg plus amlodipine 5 mg in combination, for 10 days. Each treatment period was separated by a 12-day washout period, after which subjects were crossed over to alternate treatment. Each subject received each of the 3 treatments during the course of the study. Subjects were admitted to the study center on the first and last days (days 1 and 10) of treatment; for the remainder of the treatment period, subjects returned to the study center daily to receive study treatment. An end-of-study evaluation was performed 7 to 10 days after the final dose. Test medications were administered as a single tablet with 240 mL of water between 7 AM and 9 AM, following an overnight fast of 10 to 12 hours. On the days of pharmacokinetic assessment, subjects were required to fast for an additional 4 hours after the dose. Pharmacokinetic samples were collected over the 24-hour period postdose on the last day of each treatment period.

Vildagliptin/valsartan study. Following a 21-day screening period, subjects were randomized to once-daily administration of vildagliptin 100 mg alone, valsartan 320 mg alone, or vildagliptin 100 mg plus valsartan 320 mg in combination, for 7 days. Each treatment period was separated by a 7-day washout period, after which subjects were crossed over to alternate treatment. Each subject was randomized to receive each of the 3 treatments during the course of the study. Subjects were admitted to the study center for the duration of the treatment period, and an end-of-study evaluation was performed on the last day of the treatment period. Test medications were administered as single tablets with 240 mL of water between 7 AM and 9 AM, following an overnight fast of 10 to 12 hours. On the days of pharmacokinetic assessment, subjects were required to fast for an additional 4 hours postdose. Pharmacokinetic samples were collected over the 24-hour period postdose on the last day of each treatment period.

Vildagliptin/ramipril study. Following a 21-day screening period, subjects were randomized to once-daily administration of vildagliptin 100 mg alone, ramipril 5 mg alone, or vildagliptin 100 mg plus ramipril 5 mg in combination, for 7 days. Each treatment period was separated by a 7-day washout period, after which subjects were crossed over to alternate treatment. Each subject was randomized to receive each of the 3 treatments during the course of the study. Subjects were admitted to the study center for the duration of the treatment period, and an end-of-study evaluation was performed on the last day of the treatment period. Test medications were administered as single tablets with 240 mL of water between 7 AM and 9 AM, following an overnight fast of 10 to 12 hours. On the days of pharmacokinetic assessment, subjects were required to fast for an additional 4 hours postdose. Pharmacokinetic samples were collected over the 24-hour period postdose on the last day of each treatment period.

Study Population
Each study enrolled nonsmoking male and female subjects ages 18 to 45 years (amlodipine and valsartan studies) or 18 to 65 years (ramipril study) in good health as determined by medical history, physical examination, vital signs, electrocardiogram (ECG), and routine laboratory tests. In the ramipril study, subjects had a body weight of at least 45 kg and a body mass index (BMI) of 22 to 35 kg/m². In the valsartan and amlodipine studies, subjects had a body weight of at least 50 kg and were within 15% of their ideal weight based on their height and frame. Female participants had to be sterile or post-menopausal or use an acceptable form of contraception (ie, double-barrier contraception).

All studies were conducted in compliance with the Guidelines for Good Clinical Practice and the ethical principles of the Declaration of Helsinki of the World Medical Association, and study approval was received from the Arkansas Research Human Volunteers Research Committee (Little Rock, Ark) for the ramipril study, from the Independent Investigational Review Board (Plantation, Fla) for the valsartan study, and from MDS Pharma Services Institutional Review Board (Lincoln, Neb) for the amlodipine study. Each subject provided written informed consent prior to study participation.

Significant exclusion criteria for all 3 studies included smoking (use of tobacco products in the previous 3 months); clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome; significant illness within 2 weeks of start of study; history of acute or chronic bronchospastic disease; history of clinically significant drug allergy; a known hypersensitivity to study drugs or drugs similar to study drugs; any condition that might significantly alter the absorption, distribution, metabolism or excretion of study drugs; treatment with a diuretic or a β-blocker (ramipril study).

Subjects followed a standard weight-maintaining diet. No prescription or over-the-counter medications (with the exception of acetaminophen) were permitted in the 14 days before the commencement of study treatment until completion of the study. Subjects were not permitted to take part in any strenuous physical exercise for 7 days before dosing until after the study completion or to take alcohol for 72 hours before dosing until after the study completion evaluation. Intake of xanthine-containing food or beverages was discontinued 48 hours before dosing and was not permitted at any time during the study.

Pharmacokinetic Measurements
Blood samples (2-4 mL in heparinized tubes) were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein at 0 hours (pre-dose) and at regular intervals during the 24 hours following dosing on the days of pharmacokinetic profiling. An additional sample was taken immediately before dosing on days 5 and 6 in both the ramipril and valsartan studies and on day 9 in the amlodipine study to determine whether steady-state plasma drug concentrations had been reached by the day of pharmacokinetic profiling (days 7 and 10, respectively). Trough plasma concentrations in all 3 studies showed that plasma drug concentrations had reached steady state by the days of pharmacokinetic profiling (data not shown).

In the amlodipine study, blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, and 24 hours after dosing. In the valsartan study, blood samples were collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing. In the ramipril study, blood samples were collected at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing. Blood samples were frozen at 18°C (for amlodipine and valsartan determination) or 70°C (for vildagliptin and ramipril determination) until analyses were performed.

Plasma concentrations of vildagliptin, amlodipine, valsartan, ramipril, and ramiprilat were determined using liquid chromatography/tandem mass spectrometry. Samples were extracted on Oasis HLB (vildagliptin and ramipril; Waters Corp, Milford, Mass), Oasis MCX (amlodipine; Waters Corp), or Empore (valsartan; 3M, St. Paul, Minn) 96-well solid-phase extraction plates using an automated liquid-handling system.

Extracted vildagliptin samples were fractionated using an XTerra MS C18 high-performance liquid chromatography (HPLC) column (150 x 2.1 mm; Waters Corp) and eluted with a mobile phase comprising 40% solvent A (10 mmol/L ammonium acetate [pH 8]/methanol [95:5, vol/vol]) and 60% solvent B (acetonitrile/methanol [10:90, vol/vol]) at a flow rate of 0.20 mL/min. Detection was performed using an API3000 electrospray ionization mass spectrometer (Applied Biosystems, Foster City, Calif). The internal standard for this assay was [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 160. The lower limit of quantification (LLOQ) for vildagliptin using this assay was 2 ng/mL. Across the 3 studies, within-study assay validation at nominal vildagliptin concentrations of 5.25, 400, and 900 ng/mL showed an assay precision of 2.8% to 12.2% and a bias of –6.7% to 8.5%.

Extracted amlodipine samples were fractionated using a Symmetry C18 HPLC column (50 x 2.1 mm; Waters Corp) and eluted with a mobile phase comprising 0.01 mol/L ammonium acetate containing 0.08% acetic acid-methanol (40:60, vol/vol) at a flow rate of 0.20 mL/min. Detection was performed using an API3000 electrospray ionization mass spectrometer (Applied Biosystems). The internal standard for this assay was amlodipine-D₄. The masses for amlodipine were precursor ion m/z 409.1 and product ion m/z 238.0 and for amlodipine-D₄, precursor ion m/z 413.2 and product ion m/z 238.0. The LLOQ for amlodipine using this assay was 50 pg/mL. Within-study assay validation at nominal amlodipine concentrations of 100, 800, and 1600 pg/mL showed an assay precision of 5.8% to 8.2% and a bias of –2.9% to –2.5%.

Extracted valsartan samples were fractionated using a Symmetry C18 HPLC column (30 x 2.1 mm; Waters Corp) and eluted with a mobile phase comprising methanol-acetic acid–0.1% trifluoroacetic acid (35:20:45, vol/vol/vol) at a flow rate of 0.20 mL/min. Detection was performed using an API3000 electrospray ionization mass spectrometer (Applied Biosystems). The internal standard for this assay was D₉-valsartan. The masses for valsartan were precursor ion m/z 436 and product ion m/z 291 and for D₉-valsartan, precursor ion m/z 445 and product ion m/z 300. The LLOQ for valsartan using this assay was 0.02 µg/mL. Within-study assay validation at nominal valsartan concentrations of 0.05, 4, and 8 µg/mL showed an assay precision of 4.5% to 5.0% and a bias of –0.8% to 2.6%.

Extracted ramipril samples were fractionated using a Zorbax SB-phenyl HPLC column (4.6 x 150 mm; Agilent Technologies, Santa Clara, Calif) and eluted with a mobile phase comprising methanol (75% vol/vol) and 0.025% formic acid at a flow rate of 0.5 mL/min. Detection of ramipril and ramiprilat was performed using a Quattro Ultima mass spectrometer (Waters Corp). The internal standards for this assay were [²H₃]ramipril and [²H₃]ramiprilat. The masses were precursor ion m/z 417.3 and product ion m/z 234.0 (ramipril) and precursor ion m/z 389.3 and product ion m/z 206.0 (ramiprilat) and for the internal standards, precursor ion m/z 420.3 and product ion m/z 237.0 ([²H₃]ramipril) and precursor ion m/z 392.3 and product ion m/z 209.0 ([²H₃]ramiprilat). The LLOQ of the assay was 0.1 ng/mL for both ramipril and ramiprilat. Within-study assay validation at nominal ramipril and ramiprilat concentrations of 0.2, 25.0, and 40.0 ng/mL showed an assay precision of 5.7% to 8.7% for ramipril and 5.9% to 12.0% for ramiprilat. The observed assay bias was 1.0% to 5.8% for ramipril and –10.5% to –6.0% for ramiprilat.

The following pharmacokinetic parameters for vildagliptin, amlodipine, valsartan, ramipril, and ramiprilat were estimated with noncompartmental methods using WinNonlin Pro (version 4.1, Pharsight Corp, Mountain View, Calif): C_max (maximum plasma concentration), t_max (time to reach C_max), AUC_0-24h (area under the plasma concentration–time curve from time zero to 24 hours), t_1/2 (terminal elimination half-life), and CL/F (apparent total clearance of drug from plasma, corrected for bioavailability). The t_1/2 of amlodipine was not estimated because the 24-hour sampling period was not long enough to allow its calculation.

Safety and Tolerability Assessments
Safety and tolerability assessments included routine laboratory tests (blood chemistries, hematological profile, and urinalysis), physical examination, ECG, and vital signs. Any undesirable sign, symptom, or medical condition occurring during the study was recorded as an adverse event (AE) regardless of suspected relation to the study medications.

Statistical Analyses
For the vildagliptin/amlodipine study, a sample size of 18 subjects ensured at least 80% power to establish bioequivalence between the 2 treatments if the intrasubject coefficients of variation (CV) were not greater than 0.20 for C_max and AUC. For the vildagliptin/valsartan study, a sample size of 30 subjects ensured at least 80% power to establish bioequivalence if intrasubject CV was not greater than 0.35 for C_max and AUC or 99% power if the intrasubject CV for C_max and AUC was not greater than 0.20. For the vildagliptin/ramipril study, a sample size of 18 subjects ensured at least 90% power to detect a 22% change in ramipril bioavailability if intrasubject CV for C_max and AUC was not greater than 0.20.

Log-transformed AUC_0-24h and C_max values for vildagliptin and each antihypertensive agent were analyzed by a linear mixed-effects model using the PROC MIXED SAS procedure. The sources of variation included in the analysis of variance model were sequence, subject (sequence), period, and treatment, with subject (sequence) as random effect. The resulting 90% confidence intervals (CIs) for the ratio of means (coadministration vs administration alone) were used to evaluate potential drug–drug interactions. Lack of interaction was demonstrated if the 90% CIs of the geometric mean ratios for AUC_0-24h and C_max were contained within the range 0.80 to 1.25.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Subject Characteristics
The demographic and baseline characteristics of subjects enrolled in the 3 studies are summarized in Table 1. Most subjects were male, and mean age, height, weight, and BMI were similar across the 3 studies. The valsartan study mainly enrolled subjects who were Hispanic (30/34 subjects), whereas non-Hispanic subjects were enrolled in the other 2 studies. Most patients were Caucasian in the amlodipine (18/21 subjects) study; in the ramipril study, most subjects were Caucasian (13/22 subjects), and the others were black.

A total of 21 subjects were randomized and received treatment in the amlodipine study. Of these, 19 subjects completed the study: 1 subject discontinued because of an AE suspected to be related to study medication, and 1 subject discontinued because of a protocol deviation. In the valsartan study, 34 subjects were randomized and 28 completed the study: 4 subjects discontinued because of AEs (2 of which were suspected to be related to study medication) and 2 subjects withdrew consent. Of the 22 subjects enrolled in the ramipril study, 18 completed the study: 2 withdrew consent and 2 were lost to follow-up. All randomized subjects were included in the safety analyses of each study.

Pharmacokinetic Analyses
Vildagliptin/amlodipine study. Coadministration of vildagliptin 100 mg once daily with amlodipine 5 mg once daily had no notable effect on the steady-state plasma concentration–time profile of vildagliptin (Figure 1a). There were no significant changes in vildagliptin AUC_0-24h, C_max, t_max, or t_1/2 (Table 2). The point estimate and 90% CIs of the geometric mean ratios for vildagliptin C_max (geometric mean ratio 1.08 [90% CI 1.00, 1.17]) and AUC_0-24h (geometric mean ratio 1.03 [90% CI 0.99, 1.07]) were within the accepted equivalence range of 0.80 to 1.25.

View larger version (17K): [in this window] [in a new window]   Figure 1. Plasma concentration–time profiles for vildagliptin following once-daily administration of vildagliptin alone and in combination with (a) amlodipine, (b) valsartan, or (c) ramipril in healthy subjects. Data are presented as mean ± SD.

Similarly, coadministration of vildagliptin and amlodipine had no major effect on the steady-state plasma concentration–time profile (Figure 2a) or pharmacokinetic parameters of amlodipine (Table 3). The point estimates and 90% CIs of the geometric mean ratios for amlodipine C_max (geometric mean ratio 0.94 [90% CI 0.91, 0.97]) and AUC_0-24h (geometric mean ratio 0.95 [90% CI 0.93, 0.98]) were within the equivalence limits of 0.80 to 1.25. Coadministration of vildagliptin and amlodipine had no notable effect on the t_max, t_1/2, or CL/F of either drug (Tables 2 and 3).

View larger version (17K): [in this window] [in a new window]   Figure 2. Plasma concentration–time profiles for (a) amlodipine, (b) valsartan, and (c) ramipril and ramiprilat following once-daily administration alone or in combination with vildagliptin in healthy subjects. Data are presented as mean ± SD.

Vildagliptin/valsartan study. Coadministration of vildagliptin 100 mg once daily with valsartan 320 mg once daily had no notable effect on the steady-state plasma concentration–time profile of vildagliptin (Figure 1b) or AUC_0-24h and C_max (Table 2). The point estimates and 90% CIs of the geometric mean ratios for vildagliptin C_max (geometric mean ratio 0.89 [90% CI 0.81, 0.98]) and AUC_0-24h (geometric mean ratio 0.99 [90% CI 0.95, 1.04]) were within the equivalence range of 0.80 to 1.25. Other vildagliptin pharmacokinetic parameters (t_max, t_1/2, and CL/F) were similar whether vildagliptin was administered alone or coadministered with valsartan (Table 2).

Coadministration of vildagliptin and valsartan increased valsartan C_max by 14% (geometric mean ratio 1.14 [90% CI 0.98, 1.34]) and AUC_0-24h by 24% (geometric mean ratio 1.24 [90% CI 1.09, 1.41]) (Figure 2b). However, this difference was largely driven by 1 subject who showed a difference in geometric mean ratios from the other subjects of greater than 3 SD. Other valsartan pharmacokinetic parameters (t_max, t_1/2, and CL/F) were similar whether valsartan was administered alone or coadministered with vildagliptin (Table 3).

Vildagliptin/ramipril study. Coadministration of vildagliptin 100 mg once daily with ramipril 5 mg once daily had no major effect on the steady-state plasma concentration–time profile (Figure 1c) or pharmacokinetic parameters of vildagliptin (Table 2). The point estimates and 90% CIs for steady-state vildagliptin C_max (geometric mean ratio 1.14 [90% CI 1.05, 1.24]) and AUC_0-24h (geometric mean ratio 0.99 [90% CI 0.93, 1.04]) were within the equivalence limits of 0.80 to 1.25.

Coadministration of vildagliptin and ramipril had no major effect on the steady-state plasma concentration–time profile (Figure 2c) or pharmacokinetic parameters of ramipril or its active metabolite, ramiprilat (Table 3). The point estimates and 90% CIs for ramipril C_max (geometric mean ratio 0.94 [90% CI 0.91, 0.97]) and AUC_0-24h (geometric mean ratio 0.91 [90% CI 0.85, 1.09]) and for ramiprilat C_max (geometric mean ratio 1.00 [90% CI 0.94, 1.06]) and AUC_0-24h (geometric mean ratio 1.00 [90% CI 0.96, 1.04]) were within the acceptance limits for equivalence.

Safety and Tolerability
Vildagliptin 100 mg was generally well tolerated when administered alone or in combination with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg once daily in healthy subjects. Overall, there were no notable differences in either the incidence or type of AEs observed during coadministration of vildagliptin with amlodipine, valsartan, or ramipril compared with administration of these drugs alone (Table 4).

Vildagliptin/amlodipine study. Eleven of the 21 subjects randomized in the study reported a total of 32 AEs (28 mild, 3 moderate, and 1 severe), of which 20 were suspected to be related to study treatment. No serious adverse events were reported during the study. One subject experienced a severe AE (dizziness) during combined treatment with vildagliptin and amlodipine, which was suspected to be related to study treatment. One subject receiving vildagliptin plus amlodipine discontinued treatment after reporting mild visual disturbances 4 days after initiation of the combination treatment. Ophthalmological examination revealed no abnormalities in either eye, and the AE was not suspected as being related to the study treatment.

Vildagliptin/valsartan study. Of the 34 randomized subjects, 23 reported a total of 90 AEs (84 mild and 6 moderate), of which 14 were suspected to be related to study treatment. One serious AE (erosive gastritis), which resulted in discontinuation, was recorded during vildagliptin treatment, but this was considered to be the result of a previous underlying condition and not related to the study treatment. Three other subjects discontinued because of adverse events; 2 of these (facial edema in a subject receiving vildagliptin plus valsartan treatment, and elevated -glutamyltransferase level in a subject receiving vildagliptin alone followed by valsartan alone) were suspected to be related to study treatment.

Vildagliptin/ramipril study. Eighteen of the 22 randomized subjects experienced a total of 45 AEs (44 mild and 1 moderate). The highest incidence of AEs (19/45) was observed with vildagliptin plus ramipril treatment. The incidence of AEs was lower in patients receiving vildagliptin alone (13/45) or ramipril alone (13/45). All AEs (100%) were suspected to be related to study treatment.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Approximately 80% of patients with diabetes have hypertension and should be treated with antihypertensive drugs concomitantly with their antidiabetic medications.^1,10 A recent retrospective cohort study of almost 10 000 patients with diabetes and hypertension showed that 62% of patients received either an ACE inhibitor or an angiotensin receptor blocker, whereas approximately one third of patients received calcium channel blockers.¹⁰ The 3 studies reported here were designed to investigate the potential pharmacokinetic interactions between the DPP-4 inhibitor, vildagliptin, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the ACE inhibitor, ramipril. The results of these studies demonstrate that there are no clinically relevant pharmacokinetic interactions between vildagliptin and these antihypertensive agents when coadministered in healthy subjects.

Amlodipine is metabolized through the CYP450 system, principally via the CYP3A4 isoenzyme. The lack of pharmacokinetic interaction between vildagliptin and amlodipine demonstrated in the present study is not surprising given that previous in vitro studies have shown that CYP450 metabolism does not play a role in the elimination of vildagliptin or its inactive metabolite LAY151 (data on file). Amlodipine also inhibits P-glycoprotein (P-gp)-mediated transport,^20-22 but vildagliptin is only a weak substrate for P-gp (K_m >500 µM), and in vitro studies have shown that vildagliptin (up to 100 µmol/L) does not inhibit P-gp-mediated efflux of rhodamine-123 in a carcinoma cell line overexpressing P-gp (data on file). Interactions between vildagliptin and amlodipine at the level of P-gp are therefore unlikely.

The majority of an orally administered dose of valsartan is excreted unchanged (81%), with the remainder being metabolized via oxidative biotransformation to valeryl 4-hydroxy valsartan (9%) and other unidentified metabolites (6%).²³ The enzyme responsible for the 4-hydroxylation of valsartan was recently identified as CYP2C9.²⁴ The potential for clinically significant drug–drug interactions via CYP2C9 is thought to be low. Given the lack of interaction of vildagliptin or LAY151 with the CYP450 system, effects of vildagliptin on the elimination of valsartan are unlikely. In the present study, coadministration of vildagliptin and valsartan did not alter the steady-state pharmacokinetics of vildagliptin but did result in nonsignificant increases in valsartan AUC_0-24h and C_max of 24% and 14%, respectively. Although these increases were not statistically significant, the 90% confidence intervals of the geometric means for valsartan AUC_0-24h and C_max fell outside the acceptance range for equivalence. Other pharmacokinetic parameters (t_max, t_1/2, and CL/F) were unchanged following coadministration. A less than 30% increase in exposure is unlikely to have any notable effect on the efficacy or tolerability of valsartan, and so the observed changes are unlikely to be of clinical significance.

There was no notable pharmacokinetic interaction between vildagliptin and the ACE inhibitor, ramipril. Ramipril is a prodrug that is rapidly absorbed from the gastrointestinal tract and hydrolyzed—primarily in the liver—to the active metabolite, ramiprilat, which has about 6 times the ACE inhibitory activity of its parent compound.²⁵ Therefore, changes in the pharmacokinetics of ramiprilat are also of clinical relevance. The results of this study demonstrate that coadministration of vildagliptin and ramipril had no effect on systemic exposure (AUC_0-24h and C_max) to ramiprilat, as demonstrated by the observation that the 90% confidence intervals of the geometric mean ratios for ramiprilat AUC_0-24h and C_max were within the limits for equivalence.

Vildagliptin was generally well tolerated in healthy subjects when administered alone or in combination with amlodipine, valsartan, or ramipril. Overall, there were no notable differences in either the incidence or type of AEs observed following coadministration of vildagliptin with amlodipine, valsartan, or ramipril compared with each agent administered alone. The good safety and tolerability observed with vildagliptin in these studies are in agreement with data from previous multiple-dosing studies. In a recent clinical trial in patients with type 2 diabetes, multiple-dose administration of vildagliptin 25 to 100 mg over a 12-week treatment period was associated with a tolerability profile comparable to that of placebo.²⁶

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
Coadministration of the novel DPP-4 inhibitor, vildagliptin, with the commonly prescribed antihypertensive drugs amlodipine, valsartan, or ramipril in healthy subjects does not result in clinically meaningful pharmacokinetic changes in any of these drugs. Consequently, no adjustment in dosage based on pharmacokinetic considerations is expected to be required should these drugs need to be coadministered in patients with type 2 diabetes and hypertension.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 
We thank Jerry Herron for his valuable contribution to the study. Financial disclosure: This study was supported by Novartis Pharmaceuticals Corporation. All authors (with the exception of Dr Marion) are employees of Novartis Pharmaceuticals Corporation and are eligible for Novartis stock and stock options.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

 

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