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Assessment of the Pharmacokinetic Interaction Between the Novel DPP-4 Inhibitor Linagliptin Andasulfonylurea,Glyburide,Inhealthysubjects

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Assessment of the Pharmacokinetic Interaction Between the Novel DPP-4 Inhibitor Linagliptin Andasulfonylurea,Glyburide,Inhealthysubjects 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 andaSulfonylurea,Glyburide,inHealthySubjects Ulrike GRAEFE-MODY1,*, Peter ROSE2,ArneRING2,KerstinZANDER2, Mario IOVINO2 and Hans-Juergen WOERLE1 1Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany 2Boehringer 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 © 1day)on the relative bioavailability of either compound in healthy subjects (n = 20, age 18­55 years). Coadmin- istration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC¸,ss and Cmax,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 AUC0­¨ and Cmax 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 Introduction ¥ ¤GLP-1¥.3 Linagliptin attains maximum plasma concentra- Type 2 diabetes mellitus ¤T2DM¥ is a progressive disease tions approximately 1.5 h after dosing at a dose of 5 mg.4¥ associated with worsening hyperglycemia, increased periph- The non-specific protein binding of linagliptin is in the region eral insulin resistance, impaired insulin secretion, and of 70®80%.5¥ In addition, linagliptin binds tightly to DPP-4, reduced pancreatic Ç-cell mass.1¥ Combining two oral which is, however, saturated at low linagliptin concen- 6¥ hypoglycemic agents generally provides greater reductions trations, with an EC50 of 2.82 nM. Due to this tight binding in blood glucose concentrations and/or more sustained to DPP-4, protein binding is concentration dependent and, periods of glycemic control than monotherapy.2¥ Therefore, at very low concentrations, less than 1% of the total combinations of linagliptin and sulfonylureas such as linagliptin is unbound in plasma. Linagliptin therefore shows glyburide appear to be rational. target-mediated, nonlinear disposition kinetics.7,8¥ It has a Linagliptin ¤BI 1356¥ is a novel oral dipeptidyl peptidase-4 long terminal half-life of over 130 h, which is related to the ¤DPP-4¥ inhibitor, which at a clinical dose of 5 mg reduces tight binding to DPP-4 and which is not sensitive to changes blood glucose concentrations by preventing the rapid in absorption or elimination of unbound linagliptin caused by 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. 123 124 Ulrike GRAEFE-MODY, et al. extrinsic factors. The accumulation half-life, which deter- study; if they had an alcohol or drug abuse problem; if they mines the time to attain steady-state conditions, is relatively smoked more than 10 cigarettes, 3 cigars, or 3 pipes per short at 11.4 h for a 5-mg dose.9¥ Thus, linagliptin steady day, or if they could not refrain from smoking for the state is reached by the third day of administration.9¥ duration of the trial. Subjects were also not permitted to Elimination of linagliptin primarily occurs via non-renal take any herbal remedies within 10 days of the start of pathways, and metabolism was shown to play a subordinate dosing and throughout the study. In the case of adverse role with all metabolites being pharmacologically inactive.10¥ events ¤AEs¥ in need of treatment, concomitant therapy was In vitro, linagliptin does not inhibit any CYP enzymes other permitted. In the case of clinical signs of hypoglycemia or a than being a weak to moderate inhibitor of CYP3A4,10¥ blood glucose level below 55 mg/dL ¤g3.1 mmol/L¥, which did not translate into clinically relevant interactions glucose was to be administered stepwise as appropriate. during a sensitive CYP3A4 study in a clinical interaction For minor pain, paracetamol was allowed. Female subjects study.11¥ No indications of biologically relevant changes in of child-bearing age ¤and their male partners¥ were excluded cytochrome P450 activity were observed in rats following unless willing and able to use appropriate barrier contra- repeated once-daily oral administration of 6 or 60 mg/kg ception. A number of restrictions were imposed on the linagliptin for 4 days. In addition, no evidence of enzyme subjects, including avoidance of excessive physical activity induction ¤CYP1A2, 2B6, or 3A4¥ was found in human during the course of the study and abstention from alcoholic hepatocytes ¤unpublished data¥. Therefore, linagliptin is not beverages, caffeine, juices of certain fruits ¤e.g., apples, an inducer of hepatic cytochrome P450. oranges, and grapefruits¥, methylxanthine-containing drinks Glyburide and other sulfonylureas produce their hypo- or foods ¤coffee, tea, cola, energy drinks, chocolate, etc.¥, glycemic effects by stimulating the secretion of insulin from vegetables from the mustard green family ¤e.g., kale, pancreatic Ç-cells.12¥ By closing ATP-sensitive K-channels broccoli, and watercress¥, and charbroiled meats for 24 h in the Ç-cell plasma membrane, a messenger cascade is preceding the first administration of study medication triggered, which promotes insulin release. Glyburide and on the main study days. Citrus fruits, in particular reduces KATP activity by targeting the sulfonylurea receptor grapefruits and Seville oranges and their juices, were not SUR1.13¥ The usual starting dose of glyburide is 2.5 to 5 mg permitted for 5 days before the first administration of study daily, while those patients who may be more sensitive to medication and until after the last sample from each period hypoglycemic drugs should be started at 1.25 mg daily.14¥ was collected. The subjects were not allowed to eat any The major metabolite of glyburide is a 4-trans-hydroxy foods other than those provided by the study center while derivative; a second metabolite, a 3-cis-hydroxy derivative, admitted to the study center. The subjects had to fast for has also been characterized. These metabolites contribute no 10 h prior to medical laboratory blood sampling and drug significant hypoglycemic action, since they are only weakly administration. active. Glyburide is excreted as metabolites in the bile and All subjects gave written informed consent. The protocol urine ¤approximately 50% via each route¥. The major was approved by the Ethikkommittee der Landesärzte- hepatic isozymes responsible for the formation of the kammer Baden-Württemberg, and the study was conducted metabolites of glyburide are CYP3A4, CYP2C9, CYP2C8, in compliance with the guidelines on good clinical practice and CYP2C19.15¥ A recent study has demonstrated that and with ethical standards for human experimentation CYP3A4 is the most important of these enzymes in the established by the Declaration of Helsinki ¤1996 version¥ and metabolism of glyburide in vitro.16¥ in accordance with applicable regulatory requirements. This randomized, open-label, three-period, two-way Study design: This was a randomized, open-label, crossover study was designed to investigate the effect of two-way crossover, multiple-dose study in healthy sub- linagliptin on the pharmacokinetics of glyburide and vice versa. jects of linagliptin ¤1H-purine-2,6-dione,8-ª¤3R¥-3-amino-1- piperidinyl«-7-¤2-butynyl¥-3,7-dihydro-3-methyl-1-ª¤4-meth- Methods ¥ yl-2-quinazolinyl¥methyl«¥;14 Boehringer Ingelheim Pharma Study participants: This study ¤internal reference GmbH & Co. KG; 5 mg/day¥ and glyburide ¤Aventis number 1218.30¥ was carried out on 10 male and 10 female Pharma Deutschland; 1.75 mg/day¥. subjects, aged 18 to 55 years, who were healthy based on a Oral doses of linagliptin were administered alone for 5 complete medical history, vital signs, 12-lead electrocardio- days ¤Days 1®5 of treatment period A¥, linagliptin plus gram ¤ECG¥, and clinical laboratory tests. Subjects were not glyburide were administered for 1 day ¤Day 6 of treatment enrolled if they had any relevant history of renal, hepatic, period B¥, and glyburide alone was administered for 1 day cardiovascular, gastrointestinal, neurologic, metabolic, or ¤Day 1 of treatment period C¥¤Fig. 1¥. Due to the long hormonal disorders; if they had donated blood, participated elimination half-life of linagliptin,4,7,8¥ treatment A was in another clinical trial, or had taken any prescription or immediately followed by treatment B without a washout non-prescription drugs with a long ¤h24 h¥ half-life within at period.
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