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Assessment of the Pharmacokinetic Interaction between the Novel DPP-4 Inhibitor Linagliptin and a Sulfonylurea, Glyburide, in Healthy Subjects
Drug Metab. Pharmacokinet. 26 (2): 123129 (2011).
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Regular Article Assessment of the Pharmacokinetic Interaction between the Novel DPP-4 Inhibitor Linagliptin and a Sulfonylurea, Glyburide, in Healthy Subjects Ulrike G RAEFE-M ODY 1, * , Peter R OSE 2, Arne R ING 2, Kerstin Z ANDER 2, Mario I OVINO 2 and Hans-Juergen W OERLE 1 1 Boehringer 2 Boehringer
Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day © 6 days) and single doses of glyburide (1.75 mg/day © 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 1855 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC ¸,ss and C max,ss were 101.7% [97.7105.8%] and 100.8% [89.0114.3%], respectively. For glyburide, there was a slight reduction in exposure of ³14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC 0¨ and C max were 85.7% [79.892.1%] and 86.2% [79.693.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable doseresponse relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments. Keywords: dipeptidyl peptidase-4 inhibitor; drug interaction; glibenclamide; glyburide; linagliptin; pharmacokinetics; type 2 diabetes
proteolysis of the incretin hormone glucagon-like peptide-1 ¤GLP-1¥.3¥ Linagliptin attains maximum plasma concentrations approximately 1.5 h after dosing at a dose of 5 mg.4¥ The non-specific protein binding of linagliptin is in the region of 70®80%.5¥ In addition, linagliptin binds tightly to DPP-4, which is, however, saturated at low linagliptin concentrations, with an EC50 of 2.82 nM.6¥ Due to this tight binding to DPP-4, protein binding is concentration dependent and, at very low concentrations, less than 1% of the total linagliptin is unbound in plasma. Linagliptin therefore shows target-mediated, nonlinear disposition kinetics.7,8¥ It has a long terminal half-life of over 130 h, which is related to the tight binding to DPP-4 and which is not sensitive to changes in absorption or elimination of unbound linagliptin caused by
Introduction Type 2 diabetes mellitus ¤T2DM¥ is a progressive disease associated with worsening hyperglycemia, increased peripheral insulin resistance, impaired insulin secretion, and reduced pancreatic Ç-cell mass.1¥ Combining two oral hypoglycemic agents generally provides greater reductions in blood glucose concentrations and/or more sustained periods of glycemic control than monotherapy.2¥ Therefore, combinations of linagliptin and sulfonylureas such as glyburide appear to be rational. Linagliptin ¤BI 1356¥ is a novel oral dipeptidyl peptidase-4 ¤DPP-4¥ inhibitor, which at a clinical dose of 5 mg reduces blood glucose concentrations by preventing the rapid
Received; September 3, 2010, Accepted; October 20, 2010 J-STAGE Advance Published Date: November 12, 2010, doi:10.2133/dmpk.DMPK-10-RG-091 *To whom correspondence should be addressed: Dr. Ulrike GRAEFE-MODY, Therapeutic Area Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, D 55216 Ingelheim, Germany. Tel. +49 (6132) 77-97480, E-mail: [email protected] This study was supported by Boehringer Ingelheim Pharma GmbH & Co. KG. 123
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extrinsic factors. The accumulation half-life, which determines the time to attain steady-state conditions, is relatively short at 11.4 h for a 5-mg dose.9¥ Thus, linagliptin steady state is reached by the third day of administration.9¥ Elimination of linagliptin primarily occurs via non-renal pathways, and metabolism was shown to play a subordinate role with all metabolites being pharmacologically inactive.10¥ In vitro, linagliptin does not inhibit any CYP enzymes other than being a weak to moderate inhibitor of CYP3A4,10¥ which did not translate into clinically relevant interactions during a sensitive CYP3A4 study in a clinical interaction study.11¥ No indications of biologically relevant changes in cytochrome P450 activity were observed in rats following repeated once-daily oral administration of 6 or 60 mg/kg linagliptin for 4 days. In addition, no evidence of enzyme induction ¤CYP1A2, 2B6, or 3A4¥ was found in human hepatocytes ¤unpublished data¥. Therefore, linagliptin is not an inducer of hepatic cytochrome P450. Glyburide and other sulfonylureas produce their hypoglycemic effects by stimulating the secretion of insulin from pancreatic Ç-cells.12¥ By closing ATP-sensitive K-channels in the Ç-cell plasma membrane, a messenger cascade is triggered, which promotes insulin release. Glyburide reduces KATP activity by targeting the sulfonylurea receptor SUR1.13¥ The usual starting dose of glyburide is 2.5 to 5 mg daily, while those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily.14¥ The major metabolite of glyburide is a 4-trans-hydroxy derivative; a second metabolite, a 3-cis-hydroxy derivative, has also been characterized. These metabolites contribute no significant hypoglycemic action, since they are only weakly active. Glyburide is excreted as metabolites in the bile and urine ¤approximately 50% via each route¥. The major hepatic isozymes responsible for the formation of the metabolites of glyburide are CYP3A4, CYP2C9, CYP2C8, and CYP2C19.15¥ A recent study has demonstrated that CYP3A4 is the most important of these enzymes in the metabolism of glyburide in vitro.16¥ This randomized, open-label, three-period, two-way crossover study was designed to investigate the effect of linagliptin on the pharmacokinetics of glyburide and vice versa. Methods Study participants: This study ¤internal reference number 1218.30¥ was carried out on 10 male and 10 female subjects, aged 18 to 55 years, who were healthy based on a complete medical history, vital signs, 12-lead electrocardiogram ¤ECG¥, and clinical laboratory tests. Subjects were not enrolled if they had any relevant history of renal, hepatic, cardiovascular, gastrointestinal, neurologic, metabolic, or hormonal disorders; if they had donated blood, participated in another clinical trial, or had taken any prescription or non-prescription drugs with a long ¤h24 h¥ half-life within at least 1 month ¤or ten half-lives of the respective drug, whichever was longer¥ prior to administration or during the
study; if they had an alcohol or drug abuse problem; if they smoked more than 10 cigarettes, 3 cigars, or 3 pipes per day, or if they could not refrain from smoking for the duration of the trial. Subjects were also not permitted to take any herbal remedies within 10 days of the start of dosing and throughout the study. In the case of adverse events ¤AEs¥ in need of treatment, concomitant therapy was permitted. In the case of clinical signs of hypoglycemia or a blood glucose level below 55 mg/dL ¤g3.1 mmol/L¥, glucose was to be administered stepwise as appropriate. For minor pain, paracetamol was allowed. Female subjects of child-bearing age ¤and their male partners¥ were excluded unless willing and able to use appropriate barrier contraception. A number of restrictions were imposed on the subjects, including avoidance of excessive physical activity during the course of the study and abstention from alcoholic beverages, caffeine, juices of certain fruits ¤e.g., apples, oranges, and grapefruits¥, methylxanthine-containing drinks or foods ¤coffee, tea, cola, energy drinks, chocolate, etc.¥, vegetables from the mustard green family ¤e.g., kale, broccoli, and watercress¥, and charbroiled meats for 24 h preceding the first administration of study medication and on the main study days. Citrus fruits, in particular grapefruits and Seville oranges and their juices, were not permitted for 5 days before the first administration of study medication and until after the last sample from each period was collected. The subjects were not allowed to eat any foods other than those provided by the study center while admitted to the study center. The subjects had to fast for 10 h prior to medical laboratory blood sampling and drug administration. All subjects gave written informed consent. The protocol was approved by the Ethikkommittee der Landesärztekammer Baden-Württemberg, and the study was conducted in compliance with the guidelines on good clinical practice and with ethical standards for human experimentation established by the Declaration of Helsinki ¤1996 version¥ and in accordance with applicable regulatory requirements. Study design: This was a randomized, open-label, two-way crossover, multiple-dose study in healthy subjects of linagliptin ¤1H-purine-2,6-dione,8-ª¤3R¥-3-amino-1piperidinyl«-7-¤2-butynyl¥-3,7-dihydro-3-methyl-1-ª¤4-methyl-2-quinazolinyl¥methyl«¥;14¥ Boehringer Ingelheim Pharma GmbH & Co. KG; 5 mg/day¥ and glyburide ¤Aventis Pharma Deutschland; 1.75 mg/day¥. Oral doses of linagliptin were administered alone for 5 days ¤Days 1®5 of treatment period A¥, linagliptin plus glyburide were administered for 1 day ¤Day 6 of treatment period B¥, and glyburide alone was administered for 1 day ¤Day 1 of treatment period C¥ ¤Fig. 1¥. Due to the long elimination half-life of linagliptin,4,7,8¥ treatment A was immediately followed by treatment B without a washout period. Healthy subjects were randomized ¤1:1¥ to receive one of two treatment sequences: treatment A then B followed by a drug elimination period of at least 35 days before
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
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Absence of PK Interaction between Linagliptin and Glyburide Treatment sequence AB_C Treatment A 5 mg linagliptin q.d. for 5 days
Treatment B 1.75 mg glyburide single dose + 5 mg linagliptin q.d. on Day 6
Washout period of ≥35 days
Treatment C 1.75 mg glyburide single dose
Treatment C 1.75 mg glyburide single dose
Washout period of ≥7 days
Treatment A 5 mg linagliptin q.d. for 5 days
Treatment B 1.75 mg glyburide single dose + 5 mg linagliptin q.d. on Day 6
Randomization
Treatment sequence C_AB
q.d., once daily
Fig. 1. Schematic diagram of trial design and dosing schedule
treatment C ¤ABðC¥, or treatment C followed by washout of at least 7 days before treatment A then B ¤CðAB¥. Following an overnight fast, study medication was administered with approximately 240 mL of water to subjects in the standing position. Medications were administered at 0800 and all doses of study medication were witnessed. Subjects were kept under close medical surveillance onsite on all days of pharmacokinetic profiling until 25 h after drug administration ¤from the morning of Day 5 to the morning of Day 8 within treatment period AB and from the morning of Day 1 until the morning of Day 2 within treatment period C¥. Medical examination was performed at screening ¤within 21 days before administration of any study medication¥ and at the follow-up visit ¤at least 7 days after the conclusion of treatment¥. Water was allowed ad libitum except for 1 h before and after drug administration. Standardized meals were served at 1 h, 4 h, 9 h, and 13 h following drug administration on inhouse days. The observation time after the final drug administration was at least 8 days. The subjects were not allowed to lie down for 2 h following drug administration, except for medical examination, carrying out an ECG, or assessing vital signs. Pharmacokinetic assessments: For quantification of the plasma concentrations of the analyte linagliptin, blood was taken from a forearm vein into an ethylenediaminetetraacetic acid ¤EDTA¥-anticoagulant blood-drawing tube. For quantification of the plasma concentrations of glyburide, blood samples were taken from a forearm vein into Sarstedt S-Monovette plasma lithium-heparin tubes. Blood samples were taken at the following time points during treatment AB for pharmacokinetic profiling: at 15, 30, and 45 min and at 1, 1.5, 2, 3, 4, 6, 8, and 12 h following administration on Day 5 ¤linagliptin alone¥ and Day 6 ¤linagliptin and glyburide¥, and at predose or in the morning on Days 1, 3, 4, 5, 6, and 7. For treatment C, blood samples were taken for pharmacokinetic profiling at 15 min predose, at 15, 30, and 45 min, and at 1, 1.5, 2, 3, 4, 6, 8, and 12 h after administration of glyburide on Day 1, and in the morning on Days 2 and 3. The EDTA or lithium-heparin anticoagulated blood samples were centrifuged immediately at 2000®4000 ' g for 10 min at 4®8ôC. Plasma was collected in two aliquots ¤each containing at least 0.6 mL plasma¥ and frozen immediately at or below %20ôC.
Bioanalytical methods: Plasma concentration of linagliptin was analyzed using a validated high-performance liquid chromatography/tandem mass spectrometry ¤HPLCMS/MS¥ assay as described previously.17¥ The calibration curves of undiluted plasma samples were linear over the range of concentrations from 0.10 to 20.0 nmol/L for linagliptin. In-study assay validation at nominal concentrations of 0.25, 1.0, and 15.0 nmol/L yielded an assay imprecision and inaccuracy of 2.4 to 7.8% and 5.3 to 9.2%, respectively. Plasma concentrations of glyburide were analyzed by a fully validated HPLC-MS/MS method by Covance Laboratories Ltd ¤Harrogate, UK¥, using glimepiride as the internal standard. The assay included sample clean-up by protein precipitation. No interference of endogenous compounds was seen. The calibration curves of undiluted plasma samples were linear over the range of concentrations from 1.00 to 400 ng/mL using a plasma volume of 25 µL. Imprecision and inaccuracy results for glyburide at nominal concentrations of 3.0, 160.0, and 320.0 ng/mL were 5.1 to 10.4% and 0.6 to 5.0%, respectively. Plasma concentrations of linagliptin are given in nM in order to be comparable with previously published data on linagliptin4,7®9¥ ¤1 ng/mL is 2.12 nM¥, whereas plasma concentrations of glyburide are given in ng/mL for easier comparison with historical data. Pharmacokinetic methods: Pharmacokinetic analyses were carried out by non-compartmental analysis of the plasma concentration®time data using WinNonlin software ¤Pharsight Corporation, Mountain View, California¥. The maximum concentration ¤Cmax or Cmax,ss¥ and the time to maximum concentration ¤tmax or tmax,ss¥ values were obtained by inspection of the plasma concentration data. Actual sampling times were used for the pharmacokinetic analysis. The apparent terminal rate constant ¤Ð¥ was estimated by regression of the terminal log-linear portion ¤determined by inspection¥ of the plasma concentration®time profile using the last three available data points; the half-life ¤t1/2¥ was calculated as the quotient of ln¤2¥ and Ð. The area under the plasma concentration®time curve ¤AUC¥ was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The steady-state area under the plasma drug concentration®time curve over dosing interval Ø ¤AUCØ,ss¥
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
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of linagliptin was calculated using the extrapolated or interpolated concentration at time point Ø. AUC0®W of glyburide was estimated as the sum of the AUC to the last measured concentration and the extrapolated area given by the quotient of the last predicted concentration and Ð. Statistical analysis: Statistical analysis was carried out on the treated set for safety analysis and evaluation of demographics and baseline characteristics, and on the pharmacokinetic analysis set. All 20 subjects were included in the treated set. One subject withdrew after taking glyburide alone ¤treatment C¥; this subject was excluded from the pharmacokinetic analysis, resulting in 19 subjects in the pharmacokinetic set. The relative bioavailability of a single dose of glyburide with and without concurrent linagliptin and the relative bioavailability of linagliptin at steady state with and without concurrent glyburide were determined. AUC0®W, Cmax, AUCØ,ss, and Cmax,ss were natural log transformed before fitting the ANOVA model, which included effects accounting for úsequence,û úsubjects within sequences,û úperiod,û and útreatment.û úSubjects within sequencesû were considered random, with the other effects considered fixed. For tests on subject, period, and treatment effects, the denominator sum of squares was the sum of squares for error. For tests on sequence effects, the denominator was the sum of squares for the subjects. All other parameters were analyzed descriptively. The difference between the expected log means was estimated by the difference in the corresponding least square means ¤point estimate¥. Two-sided 90% confidence intervals ¤CIs¥ based on the t distribution were computed. These quantities underwent back-transformation to the original scale to give the point estimator ¤geometric mean¥ and interval estimates for the median intra-subject ratio between the test and reference. The study sample size was not based on a power calculation, but was considered to be adequate to characterize a potential interaction with sufficient accuracy based on previous experience gained in similar studies.11,18¥ Results Demographics: Twenty healthy Caucasian subjects, aged 19®48 years, were enrolled and 19 of these completed all of the treatment and study procedures as outlined in the study protocol. Five male and five female subjects were randomized to each sequence ¤ABðC or CðAB¥. One subject randomized to sequence CðAB discontinued the trial prematurely ¤Day 5 of treatment period A¥ because placing of the venous cannula was not possible. The participantsö mean ¤standard deviation¥ age was 35.9 ¤+10.3¥ years, mean weight was 72.7 ¤+10.8¥ kg, and mean body mass index was 23.8 ¤+2.6¥ kg/m2. Pharmacokinetic results: The geometric mean glyburide plasma concentration®time profiles with and without linagliptin are shown in Figure 2 and the geometric mean pharmacokinetic parameters are given in Table 1.
Glyburide plasma conc. [ng/mL]
Ulrike GRAEFE-MODY, et al. 180
Linagliptin + Glyburide (n = 19) Glyburide (n = 19)
150 120 90 60 30 0 0
4
8
12
Time [hours]
Fig. 2. Geometric mean glyburide plasma concentrations after administration of a single dose of 1.75 mg glyburide given alone or in combination with 5 mg linagliptin Table 1. Geometric mean (% geometric coefficient of variation) non-compartmental pharmacokinetic parameters of glyburide after oral administration of a single dose of 1.75 mg glyburide alone and in combination with 5 mg linagliptin
Parameter
Glyburide ¦ Linagliptin Test ¤n © 19¥
Glyburide
Adjusted GMR ¤90% CI¥
Reference ¤n © 19¥ Test/Reference, %
Glyburide AUC0®W ªng&h/mL«
299 ¤34.0¥
348 ¤32.7¥
85.7 ¤79.8®92.1¥
Cmax ªng/mL«
113 ¤28.2¥
131 ¤32.2¥
86.2 ¤79.6®93.3¥
tmax ªh«a
1.50 ¤1.00®2.02¥
1.50 ¤1.00®2.02¥
t1/2 ªh«
2.09 ¤53.8¥
2.28 ¤42.7¥
a
For tmax, the median and range ¤min®max¥ is given. GMR, geometric mean ratio; CI, confidence interval.
The adjusted glyburide Cmax GMR ¤glyburide ¦ linagliptin/ glyburide¥ was 86.2% ¤90% CI: 79.6®93.3%¥. The adjusted glyburide AUC0®W GMR was 85.7% ¤90% CI: 79.8® 92.1%¥. Although the lower limit of the CIs for the mean ratios fell just below the usual acceptance range of 80® 125%, the slight reduction in glyburide exposure observed ¤approximately 14%¥ when coadministered with linagliptin was not judged to be clinically relevant, and the median tmax ¤1.5 h¥ was identical for the single and combined regimens. For linagliptin, the geometric mean steady-state plasma concentration®time profiles ¤Fig. 3¥ and pharmacokinetic parameters were similar when administered alone or with glyburide ¤Table 2¥. Median tmax,ss was 1.52 h when linagliptin was given alone and 2.00 h when coadministered with glyburide, but with a similar range of 0.50 to 3.00 h for both treatments. The linagliptin AUCØ,ss and Cmax,ss GMRs ¤linagliptin ¦ glyburide/linagliptin¥ were 101.7% ¤90% CI: 97.7®105.8%¥ and 100.8% ¤90% CI: 89.0® 114.3%¥, respectively. Safety and tolerability: Linagliptin and glyburide were generally well tolerated, whether administered alone or coadministered. Only one AE was of severe intensity ¤headache at the screening visit in one subject¥. This AE occurred prior to any study medication and did not require
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Linagliptin plasma conc. [nmol/L]
Absence of PK Interaction between Linagliptin and Glyburide 18
Linagliptin + Glyburide (n = 19) Linagliptin (n = 19)
15 12 9 6 3 0 0
4
8
12
16
20
24
Time [hours]
Fig. 3. Geometric mean linagliptin steady-state plasma concentrations after administration of 5 mg linagliptin monotherapy for 5 days or in combination with 1.75 mg glyburide on Day 6
Table 2. Geometric mean (% geometric coefficient of variation) non-compartmental pharmacokinetic parameters of linagliptin at steady state following multiple oral administration of 5 mg/day linagliptin alone and in combination with a single dose of 1.75 mg glyburide
Parameter
Linagliptin ¦ Glyburide Test ¤n © 19¥
Linagliptin
Adjusted GMR ¤90% CI¥
Reference ¤n © 19¥ Test/Reference, %
Linagliptin AUCØ,ss ªnmol&h/L«
168 ¤22.8¥
166 ¤22.3¥
101.7 ¤97.7®105.8¥
Cmax,ss ªnmol/L«
12.9 ¤36.0¥
12.7 ¤31.9¥
100.8 ¤89.0®114.3¥
tmax,ss ªh«a
2.00 ¤0.500®3.00¥ 1.52 ¤0.500®3.00¥
a
For tmax,ss, the median and range ¤min®max¥ is given. GMR, geometric mean ratio; CI, confidence interval.
treatment intervention; all other AEs were of mild or moderate intensity. All subjects recovered and study medication intake was completed in all cases. One subject discontinued the trial prematurely as the investigational staff could not place the venous cannula. Six subjects ¤30.0%¥ reported AEs that were considered to be drug related. For linagliptin, three subjects ¤15.0%¥ reported three related AEs ¤headache in two subjects, sensation of heaviness in one subject¥. For linagliptin ¦ glyburide, four subjects ¤21.1%¥ reported five related AEs ¤hypoglycemia in two subjects, dizziness in two subjects, and somnolence in one subject¥. For glyburide, four subjects ¤20.0%¥ reported four related AEs ¤hypoglycemia in one subject and headache in three subjects¥. Two cases of hypoglycemia ¤one during glyburide monotherapy and one during combination treatment¥ required treatment with a single dose of glucose. Physical examinations, vital signs, 12lead resting ECGs, and laboratory analyses revealed no clinically relevant changes. Discussion The progressive nature of T2DM means that most patients eventually require multiple therapies to obtain adequate glycemic control.2¥ Indeed, around half of T2DM patients require more than one hypoglycemic agent within 3 years of
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diagnosis. Moreover, despite an expanding armamentarium, around half of T2DM patients still show HbA1c levels in excess of 7%.19¥ Against this background, there is a pressing need for novel hypoglycemic drugs with distinct mechanisms of action. Glyburide and linagliptin, for example, both increase insulin secretion, but influence pancreatic Ç-cell function through distinct mechanisms. Linagliptin is safe, well tolerated, and effective as monotherapy or in combination with metformin.4,9,11,20¥ Sulfonylureas remain one of the most commonly prescribed drugs used to manage T2DM;21¥ however, as sulfonylureas can cause severe hypoglycemia, appropriate dosing is essential in clinical practice. Therefore, this study assessed the pharmacokinetics of the combination of glyburide and linagliptin in healthy volunteers. This multiple-dose study used the expected therapeutic dose of linagliptin to detect an effect on glyburide pharmacokinetics. Glyburide has a wide therapeutic window ¤clinical maintenance doses range from 1.25 to 20 mg daily¥,14¥ and in this study, the 1.75-mg dose was chosen to lower the risk of hypoglycemia. With this dose, mean maximum concentrations of 131 ng/mL were obtained, which is even higher than the 109 ng/mL observed after single-dose administration of 5 mg glyburide in a comparable study.22¥ This indicates that the exposure reached with a dose of 1.75 mg was adequate to detect a possible interaction with linagliptin. Despite comparable maximum concentrations, glyburide plasma concentrations declined more rapidly in this study than in the study by Karim et al.,22¥ resulting in concentrations falling below the lower limit of quantification of 1 ng/mL beyond 12 h. The determined apparent terminal half-lives of 2.1 and 2.3 h indicated that even increasing the assay sensitivity by a factor of 10 would not have yielded detectable concentrations beyond 24 h, and therefore would not have added significant information. However, when interpreting the concentration®time profiles, assay sensitivity was not considered to affect the overall study results and interpretation. Administration of a single oral dose of glyburide had no clinically meaningful effect on the steady-state pharmacokinetics of linagliptin in this study. Glyburide was not expected to significantly alter the pharmacokinetic profile of linagliptin or vice versa. Nevertheless, concomitant administration of glyburide and linagliptin reduced the glyburide GMRs for Cmax and AUC0®W by approximately 14%. Glyburide median tmax was comparable for both treatments. In view of the absence of a predictable plasma concentration®response relationship for sulfonylureas in general, and for glyburide in particular,23¥ a 14% reduction in glyburide exposure is considered to have no clinical relevance for the glycemic efficacy or safety of patients receiving linagliptin and glyburide concomitantly. Although CIs in the range 80®125% indicate no interaction between drugs, the clinical relevance must be judged on an individual drug basis. The FDA Draft Guidance on Drug Interactions ¤2006¥ states that úwhen the 90% CIs for systemic exposure
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Ulrike GRAEFE-MODY, et al.
ratios fall entirely within the equivalence range of 80®125%, standard Agency practice is to conclude that no clinically significant differences are present. This is, however, a very conservative standard and a substantial sample would need to be studied to meet it.û24¥ In this study with glyburide, there is no safety issue in terms of toxicity, as the exposure to the drug was reduced when coadministered with linagliptin. In terms of efficacy, a 14% reduction in exposure was considered not clinically relevant as there is a high interindividual variability with this drug.16,23¥ Any inhibitory effects of linagliptin on metabolizing enzymes ¤such as cytochromes¥ or efflux transporters ¤e.g., P-gp¥ that are involved in the absorption, disposition, or elimination of glyburide would be expected to result in an increase of glyburide exposure. Because a minor reduction in glyburide exposure was observed resulting from linagliptin co-medication, any relevant inhibitory effects on these enzymes or transporters can be excluded. The data from this study demonstrate that linagliptin had no relevant effect on the CYP2C9-metabolized drug glyburide, and therefore it appears that linagliptin would be unlikely to affect the pharmacokinetics of other drugs primarily metabolized by this pathway. CYP2C9 contributes to the metabolism of several widely used agents, including non-steroidal anti-inflammatory drugs, oral anticoagulants, and oral hypoglycemics.23,25¥ As linagliptin did not alter the pharmacokinetics of glyburide, pharmacokinetic interactions with other sulfonylureas ¤such as glipizide¥ and other drugs primarily metabolized by CYP2C9 are not expected. A recent study on the contribution of human cytochrome P450 enzymes to glyburide metabolism found that the primary enzyme involved in the metabolism of glyburide in vitro was CYP3A4.16¥ When linagliptin was incubated with recombinant human P450 enzymes, the only enzyme that was active in metabolizing linagliptin was CYP3A4.10¥ In the present study, if linagliptin were competitively inhibiting the metabolism of glyburide by CYP3A4 in vivo, an increase in glyburide levels would have been expected, in contrast to the 14% decrease in exposure reported here. A drug®drug interaction study between linagliptin and simvastatin ¤a CYP3A4 substrate¥ reported no clinically relevant effect on the pharmacokinetics of simvastatin and concluded that linagliptin coadministration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates. This study involved healthy volunteers, and the hypoglycemic effects of linagliptin were not investigated. Nevertheless, no hypoglycemia emerged in this cohort of healthy subjects with normoglycemia during treatment with linagliptin alone. The two cases of hypoglycemia occurred with glyburide monotherapy and combination treatment. This suggests that glyburide was responsible for the hypoglycemia. Multiple doses of linagliptin as monotherapy and with a single dose of glyburide were well tolerated. This is in agreement with the excellent tolerability of linagliptin
seen in previous clinical studies involving healthy subjects and patients with T2DM.4,9®11,18,26¥ In a recently reported phase III study of linagliptin as add-on therapy to a sulfonylurea in patients with inadequately controlled T2DM, linagliptin produced a statistically significant and clinically relevant reduction in HbA1c from baseline compared with sulfonylurea plus placebo after 24 weeks of treatment.27¥ The study patientsö sulfonylurea drug was administered during the entire trial duration ¤including washout and placebo run-in periods¥ in an unchanged dosage and linagliptin was added to this background therapy at a once-daily dose of 5 mg. The incidence of hypoglycemia was low and occurred at a similar rate in the two treatment arms ¤5.6 vs. 4.8% for the combination of sulfonylurea and linagliptin or placebo, respectively¥. Therefore, adding linagliptin to sulfonylurea treatment did not increase the risk of hypoglycemia, and the results of this 24-week trial indicate that linagliptin can be used safely as an add-on therapy in patients with insufficient glycemic control receiving treatment with a sulfonylurea.27¥ In summary, steady-state concentrations of linagliptin have no relevant impact on the pharmacokinetics of glyburide. The minor changes in glyburide pharmacokinetics observed in the present study are not expected to meaningfully alter the glycemic efficacy or safety of glyburide. Linagliptin was well tolerated as monotherapy and in combination with glyburide, with no drug®drug interaction potential with medications metabolized predominately by CYP2C9 or CYP3A4. Acknowledgments: Boehringer Ingelheim would like to thank the subjects and staff who participated in this study. This work was supported by Boehringer Ingelheim. Writing and editorial assistance was provided by Stephanie Milsom of PHASE II International, which was contracted by Boehringer Ingelheim for these services. Data from this study have previously been published, in part, as Poster No. PI-66 at the 111th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 17®20, 2010, Atlanta, GA. References 1¥ Kahn, S. E., Zraika, S., Utzschneider, K. M. and Hull, R. L.: The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia, 52: 1003®1012 ¤2009¥. 2¥ Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R. and Zinman, B.: Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 32: 193®203 ¤2009¥. 3¥ Thomas, L., Eckhardt, M., Langkopf, E., Tadayyon, M., Himmelsbach, F. and Mark, M.: ¤R¥-8-¤3-amino-piperidin-1-yl¥7-but-2-ynyl-3-methyl-1-¤4-methyl-quinazolin-2-ylmethyl¥-3,7-dihydro-purine-2,6-dione ¤BI 1356¥, a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase 4
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Absence of PK Interaction between Linagliptin and Glyburide
inhibitors. J. Pharmacol. Exp. Ther., 325: 175®182 ¤2008¥. 4¥ Hüttner, S., Graefe-Mody, E. U., Withopf, B., Ring, A. and Dugi, K. A.: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J. Clin. Pharmacol., 48: 1171®1178 ¤2008¥. 5¥ Fuchs, H., Tillement, J.-P., Urien, S., Greischel, A. and Roth, W.: Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans. J. Pharm. Pharmacol., 61: 55®62 ¤2009¥. 6¥ Retlich, S., Duval, V., Ring, A., Staab, A., Hüttner, S., Jungnik, A., Jaehde, U., Dugi, K. A. and Graefe-Mody, U.: Pharmacokinetics and pharmacodynamics of single rising intravenous doses ¤0.5 mg®10 mg¥ and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin ¤BI 1356¥ in healthy male subjects. Clin. Pharmacokinet., 49: 829®840 ¤2010¥. 7¥ Retlich, S., Duval, V., Graefe-Mody, U., Jaehde, U. and Staab, A.: Impact of target-mediated drug disposition on linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. J. Clin. Pharmacol., 50: 873®885 ¤2010¥. 8¥ Retlich, S., Withopf, B., Greischel, A., Staab, A., Jaehde, U. and Fuchs, H.: Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin ¤BI 1356¥ ® investigations in DPP-4 deficient and wildtype rats. Biopharm. Drug Dispos., 30: 422®436 ¤2009¥. 9¥ Heise, T., Graefe-Mody, E. U., Hüttner, S., Ring, A., Trommeshauser, D. and Dugi, K. A.: Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes. Metab., 11: 786®794 ¤2009¥. 10¥ Blech, S., Ludwig-Schwellinger, E., Graefe-Mody, E. U., Withopf, B. and Wagner, K.: The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab. Dispos., 38: 667®678 ¤2010¥. 11¥ Graefe-Mody, U., Huettner, S., Stähle, H., Ring, A. and Dugi, K. A.: Effect of linagliptin ¤BI 1356¥ on the steady-state pharmacokinetics of simvastatin. Int. J. Clin. Pharmacol. Ther., 48: 367®374 ¤2010¥. 12¥ Ashcroft, F. M.: Mechanisms of the glycaemic effects of sulfonylureas. Horm. Metab. Res., 28: 456®463 ¤1996¥. 13¥ Vila-Carriles, W. H., Zhao, G. and Bryan, J.: Defining a binding pocket for sulfonylureas in ATP-sensitive potassium channels. FASEB J., 21: 18®25 ¤2007¥. 14¥ Sanofi-aventis US LLC. DIAßETA¬ ¤Glyburide USP tablets¥ Prescribing information, July 2009. Available at: http://products. sanofi-aventis.us/diabeta/diabeta.pdf ¤accessed 27 Aug 2010¥. 15¥ Zharikova, O. L., Fokina, V. M., Nanovskaya, T. N., Hill, R. A., Mattison, D. R., Hankins, G. D. and Ahmed, M. S.: Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochem. Pharmacol., 78: 1483® 1490 ¤2009¥. 16¥ Zhou, L., Naraharisetti, S. B., Liu, L., Wang, H., Lin, Y. S., Isoherranen, N., Unadkat, J. D., Hebert, M. F. and Mao, Q.: Contributions of human cytochrome P450 enzymes to glyburide
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metabolism. Biopharm. Drug Dispos., 31: 228®242 ¤2010¥. 17¥ Eckhardt, M., Langkopf, E., Mark, M., Tadayyon, M., Thomas, L., Nar, H., Pfrengle, W., Guth, B., Lotz, R., Sieger, P., Fuchs, H. and Himmelsbach, F.: 8-¤3-¤R¥-aminopiperidin-1-yl¥-7-but2-ynyl-3-methyl-1-¤4-methyl-quinazolin-2-ylmethyl¥-3,7-dihydropurine-2,6-dione ¤BI 1356¥, a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 50: 6450®6453 ¤2007¥. 18¥ Graefe-Mody, E. U., Padula, S., Ring, A., Withopf, B. and Dugi, K. A.: Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr. Med. Res. Opin., 25: 1963®1972 ¤2009¥. 19¥ Kendall, D. M., Cuddihy, R. M. and Bergenstal, R. M.: Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Eur. J. Intern. Med., 20: S329®S339 ¤2009¥. 20¥ Forst, T., Uhlig-Laske, B., Ring, A., Graefe-Mody, U., Friedrich, C., Herbach, K., Woerle, H.-J. and Dugi, K. A.: Linagliptin ¤BI 1356¥, a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet. Med., 27: 1409®1419 ¤2010¥. 21¥ Tzoulaki, I., Molokhia, M., Curcin, V., Little, M. P., Millett, C. J., Ng, A., Hughes, R. I., Khunti, K., Wilkins, M. R., Majeed, A. and Elliott, P.: Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ, 339: b4731 ¤2009¥. 22¥ Karim, A., Laurent, A., Munsaka, M., Wann, E., Fleck, P. and Mekki, Q.: Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants. J. Clin. Pharmacol., 49: 1210®1219 ¤2009¥. 23¥ Kirchheiner, J., Brockmoller, J., Meineke, I., Bauer, S., Rohde, W., Meisel, C. and Roots, I.: Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin. Pharmacol. Ther., 71: 286®296 ¤2002¥. 24¥ FDA Draft Guidance on Drug Interactions. US FDA Center for Biologics Evaluation and Research ¤CBER¥, Sept 2006. Available at: http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM072119.pdf ¤accessed 13 Oct 2010¥. 25¥ Rettie, A. E. and Jones, J. P.: Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu. Rev. Pharmacol. Toxicol., 45: 477®494 ¤2005¥. 26¥ Deacon, C. F. and Holst, J. J.: Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes. Expert Opin. Investig. Drugs, 19: 133® 140 ¤2010¥. 27¥ Lewin, A. J., Arvay, L., Liu, D., Patel, S. and Woerle, H.-J.: Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Presented at the European Association for the Study of Diabetes 46th Annual Meeting, Stockholm, Sweden. 20®24 September 2010, poster no. 821.
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Regular Article Assessment of the Pharmacokinetic Interaction between the Novel DPP-4 Inhibitor Linagliptin and a Sulfonylurea, Glyburide, in Healthy Subjects Ulrike G RAEFE-M ODY 1, * , Peter R OSE 2, Arne R ING 2, Kerstin Z ANDER 2, Mario I OVINO 2 and Hans-Juergen W OERLE 1 1 Boehringer 2 Boehringer
Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day © 6 days) and single doses of glyburide (1.75 mg/day © 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 1855 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC ¸,ss and C max,ss were 101.7% [97.7105.8%] and 100.8% [89.0114.3%], respectively. For glyburide, there was a slight reduction in exposure of ³14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC 0¨ and C max were 85.7% [79.892.1%] and 86.2% [79.693.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable doseresponse relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments. Keywords: dipeptidyl peptidase-4 inhibitor; drug interaction; glibenclamide; glyburide; linagliptin; pharmacokinetics; type 2 diabetes
proteolysis of the incretin hormone glucagon-like peptide-1 ¤GLP-1¥.3¥ Linagliptin attains maximum plasma concentrations approximately 1.5 h after dosing at a dose of 5 mg.4¥ The non-specific protein binding of linagliptin is in the region of 70®80%.5¥ In addition, linagliptin binds tightly to DPP-4, which is, however, saturated at low linagliptin concentrations, with an EC50 of 2.82 nM.6¥ Due to this tight binding to DPP-4, protein binding is concentration dependent and, at very low concentrations, less than 1% of the total linagliptin is unbound in plasma. Linagliptin therefore shows target-mediated, nonlinear disposition kinetics.7,8¥ It has a long terminal half-life of over 130 h, which is related to the tight binding to DPP-4 and which is not sensitive to changes in absorption or elimination of unbound linagliptin caused by
Introduction Type 2 diabetes mellitus ¤T2DM¥ is a progressive disease associated with worsening hyperglycemia, increased peripheral insulin resistance, impaired insulin secretion, and reduced pancreatic Ç-cell mass.1¥ Combining two oral hypoglycemic agents generally provides greater reductions in blood glucose concentrations and/or more sustained periods of glycemic control than monotherapy.2¥ Therefore, combinations of linagliptin and sulfonylureas such as glyburide appear to be rational. Linagliptin ¤BI 1356¥ is a novel oral dipeptidyl peptidase-4 ¤DPP-4¥ inhibitor, which at a clinical dose of 5 mg reduces blood glucose concentrations by preventing the rapid
Received; September 3, 2010, Accepted; October 20, 2010 J-STAGE Advance Published Date: November 12, 2010, doi:10.2133/dmpk.DMPK-10-RG-091 *To whom correspondence should be addressed: Dr. Ulrike GRAEFE-MODY, Therapeutic Area Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, D 55216 Ingelheim, Germany. Tel. +49 (6132) 77-97480, E-mail: [email protected] This study was supported by Boehringer Ingelheim Pharma GmbH & Co. KG. 123
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extrinsic factors. The accumulation half-life, which determines the time to attain steady-state conditions, is relatively short at 11.4 h for a 5-mg dose.9¥ Thus, linagliptin steady state is reached by the third day of administration.9¥ Elimination of linagliptin primarily occurs via non-renal pathways, and metabolism was shown to play a subordinate role with all metabolites being pharmacologically inactive.10¥ In vitro, linagliptin does not inhibit any CYP enzymes other than being a weak to moderate inhibitor of CYP3A4,10¥ which did not translate into clinically relevant interactions during a sensitive CYP3A4 study in a clinical interaction study.11¥ No indications of biologically relevant changes in cytochrome P450 activity were observed in rats following repeated once-daily oral administration of 6 or 60 mg/kg linagliptin for 4 days. In addition, no evidence of enzyme induction ¤CYP1A2, 2B6, or 3A4¥ was found in human hepatocytes ¤unpublished data¥. Therefore, linagliptin is not an inducer of hepatic cytochrome P450. Glyburide and other sulfonylureas produce their hypoglycemic effects by stimulating the secretion of insulin from pancreatic Ç-cells.12¥ By closing ATP-sensitive K-channels in the Ç-cell plasma membrane, a messenger cascade is triggered, which promotes insulin release. Glyburide reduces KATP activity by targeting the sulfonylurea receptor SUR1.13¥ The usual starting dose of glyburide is 2.5 to 5 mg daily, while those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily.14¥ The major metabolite of glyburide is a 4-trans-hydroxy derivative; a second metabolite, a 3-cis-hydroxy derivative, has also been characterized. These metabolites contribute no significant hypoglycemic action, since they are only weakly active. Glyburide is excreted as metabolites in the bile and urine ¤approximately 50% via each route¥. The major hepatic isozymes responsible for the formation of the metabolites of glyburide are CYP3A4, CYP2C9, CYP2C8, and CYP2C19.15¥ A recent study has demonstrated that CYP3A4 is the most important of these enzymes in the metabolism of glyburide in vitro.16¥ This randomized, open-label, three-period, two-way crossover study was designed to investigate the effect of linagliptin on the pharmacokinetics of glyburide and vice versa. Methods Study participants: This study ¤internal reference number 1218.30¥ was carried out on 10 male and 10 female subjects, aged 18 to 55 years, who were healthy based on a complete medical history, vital signs, 12-lead electrocardiogram ¤ECG¥, and clinical laboratory tests. Subjects were not enrolled if they had any relevant history of renal, hepatic, cardiovascular, gastrointestinal, neurologic, metabolic, or hormonal disorders; if they had donated blood, participated in another clinical trial, or had taken any prescription or non-prescription drugs with a long ¤h24 h¥ half-life within at least 1 month ¤or ten half-lives of the respective drug, whichever was longer¥ prior to administration or during the
study; if they had an alcohol or drug abuse problem; if they smoked more than 10 cigarettes, 3 cigars, or 3 pipes per day, or if they could not refrain from smoking for the duration of the trial. Subjects were also not permitted to take any herbal remedies within 10 days of the start of dosing and throughout the study. In the case of adverse events ¤AEs¥ in need of treatment, concomitant therapy was permitted. In the case of clinical signs of hypoglycemia or a blood glucose level below 55 mg/dL ¤g3.1 mmol/L¥, glucose was to be administered stepwise as appropriate. For minor pain, paracetamol was allowed. Female subjects of child-bearing age ¤and their male partners¥ were excluded unless willing and able to use appropriate barrier contraception. A number of restrictions were imposed on the subjects, including avoidance of excessive physical activity during the course of the study and abstention from alcoholic beverages, caffeine, juices of certain fruits ¤e.g., apples, oranges, and grapefruits¥, methylxanthine-containing drinks or foods ¤coffee, tea, cola, energy drinks, chocolate, etc.¥, vegetables from the mustard green family ¤e.g., kale, broccoli, and watercress¥, and charbroiled meats for 24 h preceding the first administration of study medication and on the main study days. Citrus fruits, in particular grapefruits and Seville oranges and their juices, were not permitted for 5 days before the first administration of study medication and until after the last sample from each period was collected. The subjects were not allowed to eat any foods other than those provided by the study center while admitted to the study center. The subjects had to fast for 10 h prior to medical laboratory blood sampling and drug administration. All subjects gave written informed consent. The protocol was approved by the Ethikkommittee der Landesärztekammer Baden-Württemberg, and the study was conducted in compliance with the guidelines on good clinical practice and with ethical standards for human experimentation established by the Declaration of Helsinki ¤1996 version¥ and in accordance with applicable regulatory requirements. Study design: This was a randomized, open-label, two-way crossover, multiple-dose study in healthy subjects of linagliptin ¤1H-purine-2,6-dione,8-ª¤3R¥-3-amino-1piperidinyl«-7-¤2-butynyl¥-3,7-dihydro-3-methyl-1-ª¤4-methyl-2-quinazolinyl¥methyl«¥;14¥ Boehringer Ingelheim Pharma GmbH & Co. KG; 5 mg/day¥ and glyburide ¤Aventis Pharma Deutschland; 1.75 mg/day¥. Oral doses of linagliptin were administered alone for 5 days ¤Days 1®5 of treatment period A¥, linagliptin plus glyburide were administered for 1 day ¤Day 6 of treatment period B¥, and glyburide alone was administered for 1 day ¤Day 1 of treatment period C¥ ¤Fig. 1¥. Due to the long elimination half-life of linagliptin,4,7,8¥ treatment A was immediately followed by treatment B without a washout period. Healthy subjects were randomized ¤1:1¥ to receive one of two treatment sequences: treatment A then B followed by a drug elimination period of at least 35 days before
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Absence of PK Interaction between Linagliptin and Glyburide Treatment sequence AB_C Treatment A 5 mg linagliptin q.d. for 5 days
Treatment B 1.75 mg glyburide single dose + 5 mg linagliptin q.d. on Day 6
Washout period of ≥35 days
Treatment C 1.75 mg glyburide single dose
Treatment C 1.75 mg glyburide single dose
Washout period of ≥7 days
Treatment A 5 mg linagliptin q.d. for 5 days
Treatment B 1.75 mg glyburide single dose + 5 mg linagliptin q.d. on Day 6
Randomization
Treatment sequence C_AB
q.d., once daily
Fig. 1. Schematic diagram of trial design and dosing schedule
treatment C ¤ABðC¥, or treatment C followed by washout of at least 7 days before treatment A then B ¤CðAB¥. Following an overnight fast, study medication was administered with approximately 240 mL of water to subjects in the standing position. Medications were administered at 0800 and all doses of study medication were witnessed. Subjects were kept under close medical surveillance onsite on all days of pharmacokinetic profiling until 25 h after drug administration ¤from the morning of Day 5 to the morning of Day 8 within treatment period AB and from the morning of Day 1 until the morning of Day 2 within treatment period C¥. Medical examination was performed at screening ¤within 21 days before administration of any study medication¥ and at the follow-up visit ¤at least 7 days after the conclusion of treatment¥. Water was allowed ad libitum except for 1 h before and after drug administration. Standardized meals were served at 1 h, 4 h, 9 h, and 13 h following drug administration on inhouse days. The observation time after the final drug administration was at least 8 days. The subjects were not allowed to lie down for 2 h following drug administration, except for medical examination, carrying out an ECG, or assessing vital signs. Pharmacokinetic assessments: For quantification of the plasma concentrations of the analyte linagliptin, blood was taken from a forearm vein into an ethylenediaminetetraacetic acid ¤EDTA¥-anticoagulant blood-drawing tube. For quantification of the plasma concentrations of glyburide, blood samples were taken from a forearm vein into Sarstedt S-Monovette plasma lithium-heparin tubes. Blood samples were taken at the following time points during treatment AB for pharmacokinetic profiling: at 15, 30, and 45 min and at 1, 1.5, 2, 3, 4, 6, 8, and 12 h following administration on Day 5 ¤linagliptin alone¥ and Day 6 ¤linagliptin and glyburide¥, and at predose or in the morning on Days 1, 3, 4, 5, 6, and 7. For treatment C, blood samples were taken for pharmacokinetic profiling at 15 min predose, at 15, 30, and 45 min, and at 1, 1.5, 2, 3, 4, 6, 8, and 12 h after administration of glyburide on Day 1, and in the morning on Days 2 and 3. The EDTA or lithium-heparin anticoagulated blood samples were centrifuged immediately at 2000®4000 ' g for 10 min at 4®8ôC. Plasma was collected in two aliquots ¤each containing at least 0.6 mL plasma¥ and frozen immediately at or below %20ôC.
Bioanalytical methods: Plasma concentration of linagliptin was analyzed using a validated high-performance liquid chromatography/tandem mass spectrometry ¤HPLCMS/MS¥ assay as described previously.17¥ The calibration curves of undiluted plasma samples were linear over the range of concentrations from 0.10 to 20.0 nmol/L for linagliptin. In-study assay validation at nominal concentrations of 0.25, 1.0, and 15.0 nmol/L yielded an assay imprecision and inaccuracy of 2.4 to 7.8% and 5.3 to 9.2%, respectively. Plasma concentrations of glyburide were analyzed by a fully validated HPLC-MS/MS method by Covance Laboratories Ltd ¤Harrogate, UK¥, using glimepiride as the internal standard. The assay included sample clean-up by protein precipitation. No interference of endogenous compounds was seen. The calibration curves of undiluted plasma samples were linear over the range of concentrations from 1.00 to 400 ng/mL using a plasma volume of 25 µL. Imprecision and inaccuracy results for glyburide at nominal concentrations of 3.0, 160.0, and 320.0 ng/mL were 5.1 to 10.4% and 0.6 to 5.0%, respectively. Plasma concentrations of linagliptin are given in nM in order to be comparable with previously published data on linagliptin4,7®9¥ ¤1 ng/mL is 2.12 nM¥, whereas plasma concentrations of glyburide are given in ng/mL for easier comparison with historical data. Pharmacokinetic methods: Pharmacokinetic analyses were carried out by non-compartmental analysis of the plasma concentration®time data using WinNonlin software ¤Pharsight Corporation, Mountain View, California¥. The maximum concentration ¤Cmax or Cmax,ss¥ and the time to maximum concentration ¤tmax or tmax,ss¥ values were obtained by inspection of the plasma concentration data. Actual sampling times were used for the pharmacokinetic analysis. The apparent terminal rate constant ¤Ð¥ was estimated by regression of the terminal log-linear portion ¤determined by inspection¥ of the plasma concentration®time profile using the last three available data points; the half-life ¤t1/2¥ was calculated as the quotient of ln¤2¥ and Ð. The area under the plasma concentration®time curve ¤AUC¥ was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The steady-state area under the plasma drug concentration®time curve over dosing interval Ø ¤AUCØ,ss¥
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
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of linagliptin was calculated using the extrapolated or interpolated concentration at time point Ø. AUC0®W of glyburide was estimated as the sum of the AUC to the last measured concentration and the extrapolated area given by the quotient of the last predicted concentration and Ð. Statistical analysis: Statistical analysis was carried out on the treated set for safety analysis and evaluation of demographics and baseline characteristics, and on the pharmacokinetic analysis set. All 20 subjects were included in the treated set. One subject withdrew after taking glyburide alone ¤treatment C¥; this subject was excluded from the pharmacokinetic analysis, resulting in 19 subjects in the pharmacokinetic set. The relative bioavailability of a single dose of glyburide with and without concurrent linagliptin and the relative bioavailability of linagliptin at steady state with and without concurrent glyburide were determined. AUC0®W, Cmax, AUCØ,ss, and Cmax,ss were natural log transformed before fitting the ANOVA model, which included effects accounting for úsequence,û úsubjects within sequences,û úperiod,û and útreatment.û úSubjects within sequencesû were considered random, with the other effects considered fixed. For tests on subject, period, and treatment effects, the denominator sum of squares was the sum of squares for error. For tests on sequence effects, the denominator was the sum of squares for the subjects. All other parameters were analyzed descriptively. The difference between the expected log means was estimated by the difference in the corresponding least square means ¤point estimate¥. Two-sided 90% confidence intervals ¤CIs¥ based on the t distribution were computed. These quantities underwent back-transformation to the original scale to give the point estimator ¤geometric mean¥ and interval estimates for the median intra-subject ratio between the test and reference. The study sample size was not based on a power calculation, but was considered to be adequate to characterize a potential interaction with sufficient accuracy based on previous experience gained in similar studies.11,18¥ Results Demographics: Twenty healthy Caucasian subjects, aged 19®48 years, were enrolled and 19 of these completed all of the treatment and study procedures as outlined in the study protocol. Five male and five female subjects were randomized to each sequence ¤ABðC or CðAB¥. One subject randomized to sequence CðAB discontinued the trial prematurely ¤Day 5 of treatment period A¥ because placing of the venous cannula was not possible. The participantsö mean ¤standard deviation¥ age was 35.9 ¤+10.3¥ years, mean weight was 72.7 ¤+10.8¥ kg, and mean body mass index was 23.8 ¤+2.6¥ kg/m2. Pharmacokinetic results: The geometric mean glyburide plasma concentration®time profiles with and without linagliptin are shown in Figure 2 and the geometric mean pharmacokinetic parameters are given in Table 1.
Glyburide plasma conc. [ng/mL]
Ulrike GRAEFE-MODY, et al. 180
Linagliptin + Glyburide (n = 19) Glyburide (n = 19)
150 120 90 60 30 0 0
4
8
12
Time [hours]
Fig. 2. Geometric mean glyburide plasma concentrations after administration of a single dose of 1.75 mg glyburide given alone or in combination with 5 mg linagliptin Table 1. Geometric mean (% geometric coefficient of variation) non-compartmental pharmacokinetic parameters of glyburide after oral administration of a single dose of 1.75 mg glyburide alone and in combination with 5 mg linagliptin
Parameter
Glyburide ¦ Linagliptin Test ¤n © 19¥
Glyburide
Adjusted GMR ¤90% CI¥
Reference ¤n © 19¥ Test/Reference, %
Glyburide AUC0®W ªng&h/mL«
299 ¤34.0¥
348 ¤32.7¥
85.7 ¤79.8®92.1¥
Cmax ªng/mL«
113 ¤28.2¥
131 ¤32.2¥
86.2 ¤79.6®93.3¥
tmax ªh«a
1.50 ¤1.00®2.02¥
1.50 ¤1.00®2.02¥
t1/2 ªh«
2.09 ¤53.8¥
2.28 ¤42.7¥
a
For tmax, the median and range ¤min®max¥ is given. GMR, geometric mean ratio; CI, confidence interval.
The adjusted glyburide Cmax GMR ¤glyburide ¦ linagliptin/ glyburide¥ was 86.2% ¤90% CI: 79.6®93.3%¥. The adjusted glyburide AUC0®W GMR was 85.7% ¤90% CI: 79.8® 92.1%¥. Although the lower limit of the CIs for the mean ratios fell just below the usual acceptance range of 80® 125%, the slight reduction in glyburide exposure observed ¤approximately 14%¥ when coadministered with linagliptin was not judged to be clinically relevant, and the median tmax ¤1.5 h¥ was identical for the single and combined regimens. For linagliptin, the geometric mean steady-state plasma concentration®time profiles ¤Fig. 3¥ and pharmacokinetic parameters were similar when administered alone or with glyburide ¤Table 2¥. Median tmax,ss was 1.52 h when linagliptin was given alone and 2.00 h when coadministered with glyburide, but with a similar range of 0.50 to 3.00 h for both treatments. The linagliptin AUCØ,ss and Cmax,ss GMRs ¤linagliptin ¦ glyburide/linagliptin¥ were 101.7% ¤90% CI: 97.7®105.8%¥ and 100.8% ¤90% CI: 89.0® 114.3%¥, respectively. Safety and tolerability: Linagliptin and glyburide were generally well tolerated, whether administered alone or coadministered. Only one AE was of severe intensity ¤headache at the screening visit in one subject¥. This AE occurred prior to any study medication and did not require
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Linagliptin plasma conc. [nmol/L]
Absence of PK Interaction between Linagliptin and Glyburide 18
Linagliptin + Glyburide (n = 19) Linagliptin (n = 19)
15 12 9 6 3 0 0
4
8
12
16
20
24
Time [hours]
Fig. 3. Geometric mean linagliptin steady-state plasma concentrations after administration of 5 mg linagliptin monotherapy for 5 days or in combination with 1.75 mg glyburide on Day 6
Table 2. Geometric mean (% geometric coefficient of variation) non-compartmental pharmacokinetic parameters of linagliptin at steady state following multiple oral administration of 5 mg/day linagliptin alone and in combination with a single dose of 1.75 mg glyburide
Parameter
Linagliptin ¦ Glyburide Test ¤n © 19¥
Linagliptin
Adjusted GMR ¤90% CI¥
Reference ¤n © 19¥ Test/Reference, %
Linagliptin AUCØ,ss ªnmol&h/L«
168 ¤22.8¥
166 ¤22.3¥
101.7 ¤97.7®105.8¥
Cmax,ss ªnmol/L«
12.9 ¤36.0¥
12.7 ¤31.9¥
100.8 ¤89.0®114.3¥
tmax,ss ªh«a
2.00 ¤0.500®3.00¥ 1.52 ¤0.500®3.00¥
a
For tmax,ss, the median and range ¤min®max¥ is given. GMR, geometric mean ratio; CI, confidence interval.
treatment intervention; all other AEs were of mild or moderate intensity. All subjects recovered and study medication intake was completed in all cases. One subject discontinued the trial prematurely as the investigational staff could not place the venous cannula. Six subjects ¤30.0%¥ reported AEs that were considered to be drug related. For linagliptin, three subjects ¤15.0%¥ reported three related AEs ¤headache in two subjects, sensation of heaviness in one subject¥. For linagliptin ¦ glyburide, four subjects ¤21.1%¥ reported five related AEs ¤hypoglycemia in two subjects, dizziness in two subjects, and somnolence in one subject¥. For glyburide, four subjects ¤20.0%¥ reported four related AEs ¤hypoglycemia in one subject and headache in three subjects¥. Two cases of hypoglycemia ¤one during glyburide monotherapy and one during combination treatment¥ required treatment with a single dose of glucose. Physical examinations, vital signs, 12lead resting ECGs, and laboratory analyses revealed no clinically relevant changes. Discussion The progressive nature of T2DM means that most patients eventually require multiple therapies to obtain adequate glycemic control.2¥ Indeed, around half of T2DM patients require more than one hypoglycemic agent within 3 years of
127
diagnosis. Moreover, despite an expanding armamentarium, around half of T2DM patients still show HbA1c levels in excess of 7%.19¥ Against this background, there is a pressing need for novel hypoglycemic drugs with distinct mechanisms of action. Glyburide and linagliptin, for example, both increase insulin secretion, but influence pancreatic Ç-cell function through distinct mechanisms. Linagliptin is safe, well tolerated, and effective as monotherapy or in combination with metformin.4,9,11,20¥ Sulfonylureas remain one of the most commonly prescribed drugs used to manage T2DM;21¥ however, as sulfonylureas can cause severe hypoglycemia, appropriate dosing is essential in clinical practice. Therefore, this study assessed the pharmacokinetics of the combination of glyburide and linagliptin in healthy volunteers. This multiple-dose study used the expected therapeutic dose of linagliptin to detect an effect on glyburide pharmacokinetics. Glyburide has a wide therapeutic window ¤clinical maintenance doses range from 1.25 to 20 mg daily¥,14¥ and in this study, the 1.75-mg dose was chosen to lower the risk of hypoglycemia. With this dose, mean maximum concentrations of 131 ng/mL were obtained, which is even higher than the 109 ng/mL observed after single-dose administration of 5 mg glyburide in a comparable study.22¥ This indicates that the exposure reached with a dose of 1.75 mg was adequate to detect a possible interaction with linagliptin. Despite comparable maximum concentrations, glyburide plasma concentrations declined more rapidly in this study than in the study by Karim et al.,22¥ resulting in concentrations falling below the lower limit of quantification of 1 ng/mL beyond 12 h. The determined apparent terminal half-lives of 2.1 and 2.3 h indicated that even increasing the assay sensitivity by a factor of 10 would not have yielded detectable concentrations beyond 24 h, and therefore would not have added significant information. However, when interpreting the concentration®time profiles, assay sensitivity was not considered to affect the overall study results and interpretation. Administration of a single oral dose of glyburide had no clinically meaningful effect on the steady-state pharmacokinetics of linagliptin in this study. Glyburide was not expected to significantly alter the pharmacokinetic profile of linagliptin or vice versa. Nevertheless, concomitant administration of glyburide and linagliptin reduced the glyburide GMRs for Cmax and AUC0®W by approximately 14%. Glyburide median tmax was comparable for both treatments. In view of the absence of a predictable plasma concentration®response relationship for sulfonylureas in general, and for glyburide in particular,23¥ a 14% reduction in glyburide exposure is considered to have no clinical relevance for the glycemic efficacy or safety of patients receiving linagliptin and glyburide concomitantly. Although CIs in the range 80®125% indicate no interaction between drugs, the clinical relevance must be judged on an individual drug basis. The FDA Draft Guidance on Drug Interactions ¤2006¥ states that úwhen the 90% CIs for systemic exposure
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
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Ulrike GRAEFE-MODY, et al.
ratios fall entirely within the equivalence range of 80®125%, standard Agency practice is to conclude that no clinically significant differences are present. This is, however, a very conservative standard and a substantial sample would need to be studied to meet it.û24¥ In this study with glyburide, there is no safety issue in terms of toxicity, as the exposure to the drug was reduced when coadministered with linagliptin. In terms of efficacy, a 14% reduction in exposure was considered not clinically relevant as there is a high interindividual variability with this drug.16,23¥ Any inhibitory effects of linagliptin on metabolizing enzymes ¤such as cytochromes¥ or efflux transporters ¤e.g., P-gp¥ that are involved in the absorption, disposition, or elimination of glyburide would be expected to result in an increase of glyburide exposure. Because a minor reduction in glyburide exposure was observed resulting from linagliptin co-medication, any relevant inhibitory effects on these enzymes or transporters can be excluded. The data from this study demonstrate that linagliptin had no relevant effect on the CYP2C9-metabolized drug glyburide, and therefore it appears that linagliptin would be unlikely to affect the pharmacokinetics of other drugs primarily metabolized by this pathway. CYP2C9 contributes to the metabolism of several widely used agents, including non-steroidal anti-inflammatory drugs, oral anticoagulants, and oral hypoglycemics.23,25¥ As linagliptin did not alter the pharmacokinetics of glyburide, pharmacokinetic interactions with other sulfonylureas ¤such as glipizide¥ and other drugs primarily metabolized by CYP2C9 are not expected. A recent study on the contribution of human cytochrome P450 enzymes to glyburide metabolism found that the primary enzyme involved in the metabolism of glyburide in vitro was CYP3A4.16¥ When linagliptin was incubated with recombinant human P450 enzymes, the only enzyme that was active in metabolizing linagliptin was CYP3A4.10¥ In the present study, if linagliptin were competitively inhibiting the metabolism of glyburide by CYP3A4 in vivo, an increase in glyburide levels would have been expected, in contrast to the 14% decrease in exposure reported here. A drug®drug interaction study between linagliptin and simvastatin ¤a CYP3A4 substrate¥ reported no clinically relevant effect on the pharmacokinetics of simvastatin and concluded that linagliptin coadministration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates. This study involved healthy volunteers, and the hypoglycemic effects of linagliptin were not investigated. Nevertheless, no hypoglycemia emerged in this cohort of healthy subjects with normoglycemia during treatment with linagliptin alone. The two cases of hypoglycemia occurred with glyburide monotherapy and combination treatment. This suggests that glyburide was responsible for the hypoglycemia. Multiple doses of linagliptin as monotherapy and with a single dose of glyburide were well tolerated. This is in agreement with the excellent tolerability of linagliptin
seen in previous clinical studies involving healthy subjects and patients with T2DM.4,9®11,18,26¥ In a recently reported phase III study of linagliptin as add-on therapy to a sulfonylurea in patients with inadequately controlled T2DM, linagliptin produced a statistically significant and clinically relevant reduction in HbA1c from baseline compared with sulfonylurea plus placebo after 24 weeks of treatment.27¥ The study patientsö sulfonylurea drug was administered during the entire trial duration ¤including washout and placebo run-in periods¥ in an unchanged dosage and linagliptin was added to this background therapy at a once-daily dose of 5 mg. The incidence of hypoglycemia was low and occurred at a similar rate in the two treatment arms ¤5.6 vs. 4.8% for the combination of sulfonylurea and linagliptin or placebo, respectively¥. Therefore, adding linagliptin to sulfonylurea treatment did not increase the risk of hypoglycemia, and the results of this 24-week trial indicate that linagliptin can be used safely as an add-on therapy in patients with insufficient glycemic control receiving treatment with a sulfonylurea.27¥ In summary, steady-state concentrations of linagliptin have no relevant impact on the pharmacokinetics of glyburide. The minor changes in glyburide pharmacokinetics observed in the present study are not expected to meaningfully alter the glycemic efficacy or safety of glyburide. Linagliptin was well tolerated as monotherapy and in combination with glyburide, with no drug®drug interaction potential with medications metabolized predominately by CYP2C9 or CYP3A4. Acknowledgments: Boehringer Ingelheim would like to thank the subjects and staff who participated in this study. This work was supported by Boehringer Ingelheim. Writing and editorial assistance was provided by Stephanie Milsom of PHASE II International, which was contracted by Boehringer Ingelheim for these services. Data from this study have previously been published, in part, as Poster No. PI-66 at the 111th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 17®20, 2010, Atlanta, GA. References 1¥ Kahn, S. E., Zraika, S., Utzschneider, K. M. and Hull, R. L.: The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia, 52: 1003®1012 ¤2009¥. 2¥ Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R. and Zinman, B.: Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 32: 193®203 ¤2009¥. 3¥ Thomas, L., Eckhardt, M., Langkopf, E., Tadayyon, M., Himmelsbach, F. and Mark, M.: ¤R¥-8-¤3-amino-piperidin-1-yl¥7-but-2-ynyl-3-methyl-1-¤4-methyl-quinazolin-2-ylmethyl¥-3,7-dihydro-purine-2,6-dione ¤BI 1356¥, a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase 4
Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX)
Absence of PK Interaction between Linagliptin and Glyburide
inhibitors. J. Pharmacol. Exp. Ther., 325: 175®182 ¤2008¥. 4¥ Hüttner, S., Graefe-Mody, E. U., Withopf, B., Ring, A. and Dugi, K. A.: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J. Clin. Pharmacol., 48: 1171®1178 ¤2008¥. 5¥ Fuchs, H., Tillement, J.-P., Urien, S., Greischel, A. and Roth, W.: Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans. J. Pharm. Pharmacol., 61: 55®62 ¤2009¥. 6¥ Retlich, S., Duval, V., Ring, A., Staab, A., Hüttner, S., Jungnik, A., Jaehde, U., Dugi, K. A. and Graefe-Mody, U.: Pharmacokinetics and pharmacodynamics of single rising intravenous doses ¤0.5 mg®10 mg¥ and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin ¤BI 1356¥ in healthy male subjects. Clin. Pharmacokinet., 49: 829®840 ¤2010¥. 7¥ Retlich, S., Duval, V., Graefe-Mody, U., Jaehde, U. and Staab, A.: Impact of target-mediated drug disposition on linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. J. Clin. Pharmacol., 50: 873®885 ¤2010¥. 8¥ Retlich, S., Withopf, B., Greischel, A., Staab, A., Jaehde, U. and Fuchs, H.: Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin ¤BI 1356¥ ® investigations in DPP-4 deficient and wildtype rats. Biopharm. Drug Dispos., 30: 422®436 ¤2009¥. 9¥ Heise, T., Graefe-Mody, E. U., Hüttner, S., Ring, A., Trommeshauser, D. and Dugi, K. A.: Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes. Metab., 11: 786®794 ¤2009¥. 10¥ Blech, S., Ludwig-Schwellinger, E., Graefe-Mody, E. U., Withopf, B. and Wagner, K.: The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab. Dispos., 38: 667®678 ¤2010¥. 11¥ Graefe-Mody, U., Huettner, S., Stähle, H., Ring, A. and Dugi, K. A.: Effect of linagliptin ¤BI 1356¥ on the steady-state pharmacokinetics of simvastatin. Int. J. Clin. Pharmacol. Ther., 48: 367®374 ¤2010¥. 12¥ Ashcroft, F. M.: Mechanisms of the glycaemic effects of sulfonylureas. Horm. Metab. Res., 28: 456®463 ¤1996¥. 13¥ Vila-Carriles, W. H., Zhao, G. and Bryan, J.: Defining a binding pocket for sulfonylureas in ATP-sensitive potassium channels. FASEB J., 21: 18®25 ¤2007¥. 14¥ Sanofi-aventis US LLC. DIAßETA¬ ¤Glyburide USP tablets¥ Prescribing information, July 2009. Available at: http://products. sanofi-aventis.us/diabeta/diabeta.pdf ¤accessed 27 Aug 2010¥. 15¥ Zharikova, O. L., Fokina, V. M., Nanovskaya, T. N., Hill, R. A., Mattison, D. R., Hankins, G. D. and Ahmed, M. S.: Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochem. Pharmacol., 78: 1483® 1490 ¤2009¥. 16¥ Zhou, L., Naraharisetti, S. B., Liu, L., Wang, H., Lin, Y. S., Isoherranen, N., Unadkat, J. D., Hebert, M. F. and Mao, Q.: Contributions of human cytochrome P450 enzymes to glyburide
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metabolism. Biopharm. Drug Dispos., 31: 228®242 ¤2010¥. 17¥ Eckhardt, M., Langkopf, E., Mark, M., Tadayyon, M., Thomas, L., Nar, H., Pfrengle, W., Guth, B., Lotz, R., Sieger, P., Fuchs, H. and Himmelsbach, F.: 8-¤3-¤R¥-aminopiperidin-1-yl¥-7-but2-ynyl-3-methyl-1-¤4-methyl-quinazolin-2-ylmethyl¥-3,7-dihydropurine-2,6-dione ¤BI 1356¥, a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 50: 6450®6453 ¤2007¥. 18¥ Graefe-Mody, E. U., Padula, S., Ring, A., Withopf, B. and Dugi, K. A.: Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr. Med. Res. Opin., 25: 1963®1972 ¤2009¥. 19¥ Kendall, D. M., Cuddihy, R. M. and Bergenstal, R. M.: Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Eur. J. Intern. Med., 20: S329®S339 ¤2009¥. 20¥ Forst, T., Uhlig-Laske, B., Ring, A., Graefe-Mody, U., Friedrich, C., Herbach, K., Woerle, H.-J. and Dugi, K. A.: Linagliptin ¤BI 1356¥, a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet. Med., 27: 1409®1419 ¤2010¥. 21¥ Tzoulaki, I., Molokhia, M., Curcin, V., Little, M. P., Millett, C. J., Ng, A., Hughes, R. I., Khunti, K., Wilkins, M. R., Majeed, A. and Elliott, P.: Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ, 339: b4731 ¤2009¥. 22¥ Karim, A., Laurent, A., Munsaka, M., Wann, E., Fleck, P. and Mekki, Q.: Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants. J. Clin. Pharmacol., 49: 1210®1219 ¤2009¥. 23¥ Kirchheiner, J., Brockmoller, J., Meineke, I., Bauer, S., Rohde, W., Meisel, C. and Roots, I.: Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin. Pharmacol. Ther., 71: 286®296 ¤2002¥. 24¥ FDA Draft Guidance on Drug Interactions. US FDA Center for Biologics Evaluation and Research ¤CBER¥, Sept 2006. Available at: http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM072119.pdf ¤accessed 13 Oct 2010¥. 25¥ Rettie, A. E. and Jones, J. P.: Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu. Rev. Pharmacol. Toxicol., 45: 477®494 ¤2005¥. 26¥ Deacon, C. F. and Holst, J. J.: Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes. Expert Opin. Investig. Drugs, 19: 133® 140 ¤2010¥. 27¥ Lewin, A. J., Arvay, L., Liu, D., Patel, S. and Woerle, H.-J.: Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Presented at the European Association for the Study of Diabetes 46th Annual Meeting, Stockholm, Sweden. 20®24 September 2010, poster no. 821.
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