Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin

DIAB-5944; No. of Pages 9 diabetes research and clinical practice xxx (2014) xxx–xxx

Contents available at ScienceDirect

Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres

Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin Ling He a,*, Prachi Wickremasingha a, James Lee a, Ben Tao a, Jeanne Mendell-Harary a, Joseph Walker a, Douglas Wight b a b

Daiichi Sankyo Pharma Development, Edison, NJ, USA Milestone Pharmaceuticals, Montreal, Que´bec, Canada

article info

abstract

Article history:

Aims: Drug interactions with bile acid sequestrants are primarily due to the potential of

Received 29 August 2013

these agents to bind to concomitant drugs. Six clinical studies were performed to determine

Received in revised form

the effects of colesevelam on the pharmacokinetics of aspirin, atenolol, enalapril, phenyto-

5 November 2013

in, rosiglitazone, and sitagliptin.

Accepted 21 December 2013

Methods: All six studies enrolled healthy subjects aged 18–45 years. The phenytoin study

Available online xxx

used a single-dose, three-period crossover design (phenytoin alone, phenytoin simultaneously with colesevelam, and phenytoin 4 h before colesevelam). The other studies used a

Keywords:

two-period crossover design (test drug alone and test drug simultaneously with coleseve-

Drug–drug interactions

lam). Colesevelam (3750 mg once daily) was dosed throughout the pharmacokinetic sam-

Colesevelam

pling period. After each single dose of the test drug, serial blood samples were collected for

Antihypertensive agents

determination of plasma drug concentrations and calculation of pharmacokinetic param-

Hypoglycemic agents

eters.

Anticonvulsants

Results: For all six test drugs, 90% CIs for geometric least-squares mean ratios of AUC and Cmax for the measured analytes were within specified limits, indicating no interaction between the test drug and colesevelam. Conclusions: Aspirin, atenolol, enalapril, rosiglitazone, and sitagliptin may be taken with colesevelam. Although the phenytoin study indicated no pharmacokinetic interaction, phenytoin should continue to be taken 4 h before colesevelam in accordance with current prescribing information. # 2014 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Bile acid sequestrants have been used for a number of years for the treatment of adults with primary hyperlipidemia [1], while the bile acid sequestrant colesevelam is additionally indicated to improve glycemic control in adults with type 2 diabetes

mellitus (T2DM) [2]. Bile acid sequestrants are not systemically absorbed and therefore do not interact with drugs systemically, but there is the potential for medications taken concomitantly to be bound by the bile acid sequestrants in the gastrointestinal tract, thereby reducing absorption and decreasing therapeutic efficacy [3]. Colesevelam has greater bile acid-binding capacity than the first-generation bile acid

* Corresponding author at: Daiichi Sankyo Pharma Development, 339 Thornall Street, Edison, NJ 08837, USA. Tel.: +1 732 590 5193; fax: +1 732 906 5690. E-mail address: [email protected] (L. He). 0168-8227/$ – see front matter # 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.12.033 Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

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sequestrants colestipol and cholestyramine [4], which hypothetically could influence its propensity for binding to other drugs and causing drug–drug interactions [5]. Data on potential drug–drug interactions with colesevelam are available for 28 drugs based on testing of in vitro binding, in vivo drug interaction studies with colesevelam, and/or postmarketing reports consistent with potential drug–drug interactions; a complete listing is included in the colesevelam United States prescribing information [2]. Drug–drug interaction profiles are of particular importance when making treatment decisions for patients with T2DM, who may take multiple medications to manage their many comorbidities [6–8]. The American Diabetes Association recommends that patients with T2DM receive pharmacotherapy for the management of glycemic control, hypertension, and dyslipidemia, and for primary prevention of cardiovascular disease [9]. As the number of prescribed medications in a patient’s regimen increases, the risk of drug–drug interactions correspondingly increases [10,11]. The purpose of this paper is to report on a series of recent drug–drug interaction studies that showed no pharmacokinetic interactions. This series of studies was performed to determine the effects of colesevelam on the single-dose pharmacokinetics of aspirin, atenolol, enalapril (a prodrug that is metabolized in vivo to enalaprilat, the pharmacologically active chemical form, by various esterases), rosiglitazone, and sitagliptin, medications that may be commonly prescribed in patients with T2DM. In addition, a study was performed to determine the effects of colesevelam on the single-dose pharmacokinetics of phenytoin. This was based on postmarketing reports consistent with potential drug–drug interactions (increased seizure activity or decreased phenytoin levels) in patients concomitantly receiving colesevelam with phenytoin [2], a compound with a narrow therapeutic index (the ratio between the upper and lower limits of the therapeutic range) [12].

2.

Subjects, materials and methods

2.1.

Clinical drug interaction studies

The aspirin and atenolol studies were conducted at MDS Pharma Services, Neptune, New Jersey, USA; the enalapril and sitagliptin studies were conducted at MDS Pharma Services, Lincoln, Nebraska, USA; the phenytoin study was conducted at the Clinical Pharmacology Unit, Manipal AcuNova Kasturba Hospital Clinical Research Centre, Manipal, India; and the rosiglitazone study was conducted at Celerion [formerly MDS Pharma Services], Lincoln, Nebraska, USA. Each study enrolled healthy men and women aged 18–45 years with a body mass index of 18.0–30.0 kg/m2. Exclusion criteria varied between the studies, but the following were generally excluded: a history and/or presence of bowel obstruction (or being at risk for bowel obstruction), pancreatitis, gastrointestinal disorders within 4 weeks prior to the first dose; use of any drugs or substances known to be strong inducers or inhibitors of cytochrome P450 enzymes within 30 days prior to the first dose; and consuming or not agreeing to abstain from grapefruit/grapefruit juice from 10 days before the first dose and throughout confinement. Study details are summarized in Table 1. The dose of colesevelam for coadministration with the test drug in each study was 3750 mg (6  625 mg tablets) once daily until the plasma sampling for the test drug was completed. A quantitative structure property relationship (QSPR) model [13] based on the lipophilicity of the coadministered drug was used to predict the in vivo binding potential of colesevelam with the test drugs of interest. A two-period crossover study design was utilized in studies for the test drugs predicted by QSPR modeling to have a low potential for binding to colesevelam (aspirin [predicted binding 1.50%], atenolol [1.50%], enalapril [6.45%], rosiglitazone [16.8%], and sitagliptin

Table 1 – Study details. Test drug

Dose (mg)

Aspirin

650

Atenolol

100

Enalapril

40

Rosiglitazone

8

Sitagliptin

100

Phenytoin

300

Treatments Aspirin alone (reference) Aspirin simultaneously with colesevelam Atenolol alone (reference) Atenolol simultaneously with colesevelam Enalapril alone (reference) Enalapril simultaneously with colesevelam Rosiglitazone alone (reference) Rosiglitazone simultaneously with colesevelam Sitagliptin alone (reference) Sitagliptin simultaneously with colesevelam Phenytoin alone (reference) Phenytoin simultaneously with colesevelam Phenytoin 4 h before colesevelam

Participants enrolled, n

Participants completed, n

Pharmacokinetic sampling times

28

28

32

31

40

35

30

30

Predose and 0.08, 0.17, 0.33, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h postdose Predose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 30, and 36 h postdose Predose and 0.167, 0.333, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 h postdose Predose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 9, 12, 16, and 24 h postdose

28

27

Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, and 72 h postdose

24

24

Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 24, 36, 48, 60, 72, 96, and 120 h postdose

Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

DIAB-5944; No. of Pages 9 diabetes research and clinical practice xxx (2014) xxx–xxx

[1.50%]), with test drug given alone and test drug coadministered with daily colesevelam. If the QSPR model suggested that a drug had moderate or high potential to bind to colesevelam, an additional treatment period was added to evaluate the effects of the test drug given 4 h prior to colesevelam. This was the case for phenytoin (predicted binding 82.8%) [13], and therefore a three-period randomized crossover study design was utilized (i.e., phenytoin alone, phenytoin simultaneously with colesevelam, and phenytoin 4 h before colesevelam). Plasma samples for pharmacokinetic analysis were collected just prior to the first dose of medication and up to 144 h post-dose, depending on the reported half-life of the test drug. Since colesevelam is not absorbed systemically, plasma concentrations of colesevelam were not measured. For each study, the study protocol, informed consent form, and other study documents were approved by the relevant Institutional Review Board or Institutional Ethics Committee. Each study was conducted in compliance with the ethical principles that have their origin in the Declaration of Helsinki, International Conference on Harmonization Guideline E6 for Good Clinical Practice, and applicable regulatory requirement(s). Written informed consent was obtained from all participants before the start of any studyspecific procedures.

2.2. Analytical methods and concentration determinations Plasma samples were analyzed at PPD, LP, Richmond, Virginia, USA (aspirin [measured analytes were salicylic acid and acetylsalicylic acid]); MDS Pharma Services, Lincoln, Nebraska, USA (atenolol, enalapril [measured analytes enalapril and enalaprilat], and sitagliptin); Celerion [formerly MDS Pharma Services], Lincoln, Nebraska, USA (rosiglitazone); and Manipal AcuNova Kasturba Hospital Clinical Research Centre, Manipal, India (phenytoin). Plasma drug concentrations for all study drugs were determined by liquid chromatography– tandem mass spectrometry (LC–MS/MS) assays, which were validated in accordance with Guidance For Industry – Bioanalytical Method Validation (Food and Drug Administration, Center for Drug Evaluation and Research, May 2001). For all assay methods, a 1/concentration2 weighted linear regression model was used to calculate slope, intercept, and correlation coefficient of the calibration curve. Back-calculated results for study samples and quality control samples were then obtained by fitting the peak area ratio (analyte vs internal standard) to the regression equation constructed from calibration standards.

2.2.1.

Aspirin concentration determination

Reference standards were the analytes acetylsalicylic acid and salicylic acid (USP grade) and the internal standards 2acetoxybenzoic-3,4,5,6-d4 acid and 2-hydroxybenzoic-3,4,5,6d4 acid (C/D/N Isotopes, Pointe-Claire, Que´bec, Canada). A 50.0 mL human plasma (potassium oxalate/sodium fluoride) sample aliquot was fortified with 250 mL of internal standard working solution. Analytes were isolated through protein precipitation using acetonitrile. The final extract was analyzed via high-performance liquid chromatography (HPLC) with MS/ MS detection. The calibration curves ranged from 0.0200 to

3

10.0 mg/mL for acetylsalicylic acid and from 0.100 to 50.0 mg/ mL for salicylic acid.

2.2.2.

Atenolol concentration determination

Reference standards were the analyte atenolol (Cerilliant Corporation, Round Rock, TX, USA) and the internal standard d7-atenolol (C/D/N Isotopes, Pointe-Claire, Que´bec, Canada). A 0.100 mL aliquot of human plasma (K3EDTA) containing the analyte and internal standard was extracted using a liquid– liquid extraction procedure. The extracted samples were analyzed by an HPLC machine equipped with an ABjMDS Sciex API 4000 mass spectrometer. Positive ions were monitored in the multiple reaction monitoring (MRM) mode. The calibration curve ranged from 5.00 to 1500 ng/mL for atenolol.

2.2.3.

Enalapril concentration determination

Reference standards were enalapril maleate and enalaprilat (USP grade), and the corresponding internal standards, d5enalapril maleate (phenyl-d5) and d5-enalaprilat (phenyl-d5) (C/D/N isotopes), respectively. The analytes measured were enalapril and enalaprilat. A 0.200 mL aliquot of human plasma (K3EDTA) containing each analyte and internal standard was extracted using a solid phase extraction procedure. The extracted samples were analyzed by an HPLC equipped with an ABjMDS Sciex API 4000 mass spectrometer. Positive ions were monitored in the MRM mode. The calibration curves ranged from 0.500 to 100 ng/mL for enalapril and from 0.250 to 50.0 ng/mL for enalaprilat.

2.2.4.

Rosiglitazone concentration determination

Reference standards were the analyte rosiglitazone and the internal standard d4-rosiglitazone (Celerion). A 0.050 mL aliquot of human plasma (K3EDTA) containing the analyte and internal standard was extracted using a liquid–liquid extraction procedure. The extracted samples were analyzed by an HPLC equipped with an ABjMDS Sciex API 4000 mass spectrometer. Positive ions were monitored in the MRM mode. The calibration curve ranged from 2.5 to 500 ng/mL for rosiglitazone.

2.2.5.

Sitagliptin concentration determination

Reference standards were sitagliptin phosphate and the internal standard d4-sitagliptin phosphate (Toronto Research Chemicals, Inc., North York, Ontario, Canada). Sitagliptin was the analyte measured. A 0.100 mL aliquot of human plasma (K3EDTA) containing the analyte with added internal standard was extracted using a liquid–liquid extraction procedure. The extracted samples were analyzed by an HPLC equipped with an ABjMDS Sciex API 4000 mass spectrometer. Positive ions were monitored in the MRM mode. The calibration curve ranged from 2.5 to 500 ng/mL for sitagliptin.

2.2.6.

Phenytoin concentration determination

Reference standards were the analyte phenytoin (USP grade) and the internal standard phenytoin-D10 (Toronto Research Chemicals, Inc.). A 0.400 mL aliquot of human plasma (K2EDTA) containing the analyte and internal standard was extracted using a liquid–liquid extraction procedure. The samples were injected into a liquid chromatograph equipped

Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

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with a tandem mass spectrometry detector. The calibration curve ranged from 20.03 to 10,015.00 ng/mL for phenytoin.

2.3.

Pharmacokinetic methods and endpoints

Pharmacokinetic parameters calculated in each study included maximum plasma concentration (Cmax), area under the concentration–time curve (AUC) from the time of dosing to the last measurable concentration (AUClast), AUC from the time of dosing extrapolated to infinity (AUC01), AUCextr (the percentage of AUC01 that is due to extrapolation from time to last measureable plasma drug concentration [tlast] to infinity), time of maximum plasma concentration (tmax), terminal halflife (t½), apparent terminal elimination rate constant (lZ), apparent total body clearance (CL/F), and apparent volume of distribution (V/F). The last measurable concentration in plasma (Clast) was calculated for atenolol, enalapril, rosiglitazone, and sitagliptin only. Parameters were calculated from plasma concentration using actual sampling times by noncompartmental methods. Calculations were performed using WinNonlin1 Professional (Pharsight, St Louis, Missouri, USA) version 5.0.1 for the phenytoin study and version 5.2 for the other studies. The primary endpoints were AUClast and AUC01 of salicylic acid for the aspirin study, and AUClast, AUC01, and Cmax for the other studies. Secondary endpoints included Clast, V/F, CL/F, tmax, and t½.

2.4.

Statistical methods

Pharmacokinetic parameters for each study were summarized using descriptive statistics. For the parameters of AUClast, AUC01, and Cmax, a mixed effect analysis of variance (ANOVA) model was used on the natural log-transformed data for statistical comparison between treatments, with the fixed effects of period, treatment, sequence, and the random effect of subject nested within sequence. The geometric mean ratio for the Test versus Reference (monotherapy) and corresponding 90% confidence interval (CI) were calculated by exponentiation of the difference in the least-square means (LSMs; on natural log-transformed data) between the treatments and the corresponding 90% CI for the difference between the LSMs calculated for the natural log-transformed values. Nonparametric analysis of the secondary endpoints of tmax and t½ was performed using the Hodges Lehmann estimator of the median of the differences between treatments with 90% CIs generated by the Moses method. For the primary endpoints, the ratio of geometric means derived from the ANOVA models of AUClast, AUC01, and Cmax were determined with two-sided 90% CIs to compare between treatments. For the aspirin study, no clinically significant interaction was concluded if the 90% CIs for the ratios of geometric LSM for AUClast and AUC01 values for salicylic acid were entirely contained within the range of 70–143%, based on the 32% decrease in bioavailability required to detect a clinically meaningful 10% decrease in serum thromboxane inhibition (from the correlation of serum thromboxane inhibition to an 81 mg dose of aspirin, the recommended dose for cardioprotection [14]). For the other studies, no statistically significant drug interaction was concluded if the 90% CIs for the ratios of geometric LSM for AUClast, AUC01,

and Cmax values for the measured analytes were entirely contained within the range of 80–125%. Sample sizes were calculated using the 80–125% bioequivalence limits for the 90% CIs for geometric mean ratios of AUC and Cmax, assuming an expected geometric mean ratio of 0.95 for the aspirin, atenolol, enalapril, and rosiglitazone studies, 0.94 for the phenytoin study, and 0.90 for the sitagliptin study. For the aspirin study, based on the estimated intra-subject coefficient of variation (CV) of 0.16 for salicylic acid AUC [15], 24 completed subjects would have provided more than 90% power to conclude bioequivalence for salicylic acid exposure; to ensure completion of 24 subjects, 28 subjects (14 per sequence) were enrolled. For the atenolol study, based on estimated intra-subject CVs of 21% and 20% for atenolol Cmax and AUC, respectively [16], 28 completed subjects would have provided at least 90% power to conclude no significant drug interaction; to ensure completion of 28 subjects, 32 subjects (16 per sequence) were enrolled. For the enalapril study, based on estimated intra-subject CVs of 25% and 23% for enalaprilat Cmax and AUC, respectively [17], 34 completed subjects would have provided at least 85% power to conclude no significant drug interaction; to ensure completion of 34 subjects, 40 subjects (20 per sequence) were enrolled. For the rosiglitazone study, based on estimated intra-subject CVs of 22% and 14% for rosiglitazone Cmax and AUC, respectively [18], 26 completed subjects would have provided at least 85% power to conclude no significant drug interaction; to ensure completion of 26 subjects, 30 subjects (15 subjects per sequence) were enrolled. For the sitagliptin study, based on estimated intra-subject CVs of 13% and 8% for sitagliptin Cmax and AUC, respectively [19], 24 completed subjects would have provided at least 90% power to conclude no significant drug interaction; to ensure completion of 24 subjects, 28 subjects (14 subjects per sequence) were enrolled. For the phenytoin study, based on the estimated intra-subject CV of 0.16 for phenytoin Cmax, 20 completed subjects would provide 90% power to conclude no significant drug interaction; to ensure completion of 20 subjects, 24 subjects (4 subjects per sequence for 6 sequences) were enrolled.

3.

Results

The majority of subjects in each study were male, and mean age ranged from 27.4 to 34.2 years (Supplemental Table S1). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.diabres.2013.12.033.

3.1.

Aspirin

The salicylic acid and acetylsalicylic acid concentration–time curves following administration of aspirin alone and simultaneously with colesevelam are shown in Fig. 1A. The ratios of geometric LSMs and their 90% CIs for salicylic acid AUClast (ratio 98.51%; 90% CI 94.86–102.30) and AUC01 (ratio 97.15%; 90% CI 93.88–100.52) values were entirely contained within the prespecified 70–143% limits (Table 2), indicating no interaction. The corresponding values for acetylsalicylic acid also fell within this range. Median tmax of salicylic acid and

Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

DIAB-5944; No. of Pages 9 diabetes research and clinical practice xxx (2014) xxx–xxx

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Fig. 1 – Concentration–time curves for salicylic acid and acetylsalicylic acid (following administration of aspirin) (A), atenolol (B), enalapril and enalaprilat (following administration of enalapril) (C), rosiglitazone (D), sitagliptin (E), and phenytoin (F).

acetylsalicylic acid were shortened by simultaneous administration of colesevelam with aspirin (Table 3).

3.2.

Atenolol

The atenolol concentration–time curves following administration of atenolol alone and simultaneously with colesevelam are shown in Fig. 1B. The ratios of geometric LSMs and their

90% CIs for atenolol AUClast (ratio 95.47%; 90% CI 88.76–102.68), AUC01 (ratio 101.14%; 90% CI 94.91–107.78), and Cmax (ratio 93.57%; 90% CI 85.28–102.67) values were entirely contained within the prespecified 80–125% limits (Table 2), indicating no interaction. Median t½ was longer following simultaneous administration of atenolol and colesevelam than with administration of atenolol alone (14.606 vs 10.089 h; Table 3). Although apparent t½ was prolonged, the accumulation

Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

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Table 2 – Primary pharmacokinetic results of drug–drug interaction studies. Drug/Analyte

Parameter

Aspirin Salicylic acida

AUClast (mg.h/mL)

240.3

236.7

AUC01 (mg.h/mL)

245.7

238.7

Reference LSM

Cmax (mg/mL) Acetylsalicylic acid

Atenolol

Enalapril Enalaprila

Enalaprilat

7.313

7.237

AUC01 (mg.h/mL)

7.853

7.576

Cmax (mg/mL)

3.268

3.829

AUClast (ng.h/mL)

4211

4020

AUC01 (ng.h/mL)

4721

4775

Cmax (ng/mL)

433.1

405.2

AUClast (ng.h/mL)

297.2

279.3

AUC01 (ng.h/mL)

302.1

282.4

Cmax (ng/mL)

147.1

139.6

AUClast (ng.h/mL)

1036

AUC01 (ng.h/mL)

1068

101.9

AUC01 (ng.h/mL)

2994

2978

501.6

500.2

AUClast (ng.h/mL)

2911

2907

AUC01 (ng.h/mL)

3000

2991

325.8

307.5

AUClast (ng.h/mL)

181,630.8

168,374.4

AUC01 (ng.h/mL)

183,045.5

170,583.1

5739.5

5147.9

AUClast (ng.h/mL)

181,630.8

177,010.3

AUC01 (ng.h/mL)

183,045.5

179,660.0

5739.5

5224.9

Cmax (ng/mL) a

104.1

2888

Cmax (ng/mL) 4 h before colesevelam

1017

2929

Cmax (ng/mL) Phenytoin Simultaneous with colesevelam

977.5

AUClast (ng.h/mL)

Cmax (ng/mL) Sitagliptin

26.68

AUClast (mg.h/mL)

Cmax (ng/mL) Rosiglitazone

28.24

Test LSM

Ratio of test/ reference, % (90% CI) 98.51 (94.86, 102.30) 97.15 (93.88, 100.52) 94.48 (88.19, 101.21) 98.95 (94.88, 103.19) 96.47 (91.47, 101.74) 117.18 (100.84, 136.16) 95.47 (88.76, 102.68) 101.14 (94.91, 107.78) 93.57 (85.28, 102.67) 93.97 (89.89, 93.50 (89.37, 94.88 (86.83, 94.39 (89.87, 95.24 (90.47, 97.90 (91.82, 98.61 (95.59, 99.47 (96.61, 99.72 (91.05, 99.85 (98.30, 99.70 (98.20, 94.38 (88.45, 92.7 (87.8, 93.2 (88.1, 89.7 (84.6, 97.5 (92.3, 98.1 (92.8, 91.0 (85.8,

98.23) 97.83) 103.67) 99.13) 100.27) 104.39) 101.74) 102.42) 109.21) 101.42) 101.23) 100.70)

97.8) 98.6) 95.1) 102.9) 103.8) 96.6)

Primary analyte.

factors (based on a 24-h dosing interval) were similar with administration of atenolol alone and simultaneously with colesevelam (1.233 and 1.293, respectively), indicating only a small change in the effective t½.

3.3.

Enalapril

The enalapril and enalaprilat concentration–time curves following administration of enalapril alone and simultaneously

Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

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Table 3 – Secondary pharmacokinetic results of drug–drug interaction studies. Drug/analyte Aspirin Salicylic acida Acetylsalicylic acid Atenolol Enalapril Enalaprila Enalaprilat Rosiglitazone Sitagliptin Phenytoin Simultaneous with colesevelam 4 h before colesevelam a

Parameter

Median reference value

Median test value

tmax (h) t½ (h) tmax (h) t½ (h) tmax (h) t½ (h)

4.000 2.744 2.000 0.542 1.500 10.089

3.000 2.677 1.134 0.893 1.500 14.606

tmax (h) t½ (h) tmax (h) t½ (h) tmax (h) t½ (h) tmax (h) t½ (h)

1.500 1.969 3.983 59.907 0.500 4.138 1.525 12.391

1.500 1.584 4.000 58.090 0.500 4.682 1.000 12.071

tmax (h) t½ (h) tmax (h) t½ (h)

8.0 13.1 8.0 13.1

8.0 12.9 7.0 13.2

Primary analyte.

with colesevelam are shown in Fig. 1C. The ratios of geometric LSMs and their 90% CIs for enalapril AUClast (ratio 93.97%; 90% CI 89.89–98.23), AUC01 (ratio 93.50%; 90% CI 89.37–97.83), and Cmax (ratio 94.88%; 90% CI 86.83–103.67) values were entirely contained within the prespecified 80–125% limits (Table 2), indicating no interaction. The corresponding values for enalaprilat also fell within this range. Following simultaneous administration of colesevelam with enalapril, median t½ of the prodrug enalapril was shorter (Table 3); however, primary and secondary pharmacokinetic parameters of the active moiety enalaprilat showed little change.

3.4.

Rosiglitazone

The rosiglitazone concentration–time curves following administration of rosiglitazone alone and simultaneously with colesevelam are shown in Fig. 1D. The ratios of geometric LSMs and their 90% CIs for rosiglitazone AUClast (ratio 98.61%; 90% CI 95.59–101.74), AUC01 (ratio 99.47%; 90% CI 96.61– 102.42), and Cmax (ratio 99.72%; 90% CI 91.05–109.21) values were entirely contained within the prespecified 80–125% limits (Table 2), indicating no interaction. Median t½ was longer with simultaneous administration of colesevelam with rosiglitazone (Table 3). Although apparent t½ was prolonged, the accumulation factors (based on a 24-h dosing interval) were similar with administration of rosiglitazone alone and simultaneously with colesevelam (1.039 and 1.047, respectively), indicating only a small change in the effective t½.

3.5.

Sitagliptin

The sitagliptin concentration–time curves following administration of sitagliptin alone and simultaneously with colesevelam are shown in Fig. 1E. The ratios of geometric LSMs and their 90% CIs for sitagliptin AUClast (ratio 99.85%; 90% CI 98.30– 101.42), AUC01 (ratio 99.70%; 90% CI 98.20–101.23), and Cmax (ratio 94.38%; 90% CI 88.45–100.70) values were entirely

contained within the prespecified 80–125% limits (Table 2), indicating no interaction.

3.6.

Phenytoin

The phenytoin concentration–time curves following administration of phenytoin alone, simultaneously with colesevelam, and 4 h before colesevelam are shown in Fig. 1F. When phenytoin was administered simultaneously with colesevelam, the ratios of geometric LSMs and their 90% CIs for phenytoin AUClast (ratio 92.7%; 90% CI 87.8–97.8), AUC01 (ratio 93.2%; 90% CI 88.1–98.6), and Cmax (ratio 89.7%; 90% CI 84.6–95.1) values were entirely contained within the prespecified 80–125% limits, indicating no interaction (Table 2). The corresponding values when phenytoin was administered 4 h before colesevelam also fell within this range (Table 2).

4.

Discussion

In this series of single-dose clinical studies performed to determine the effects of colesevelam on the pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin, no pharmacokinetic changes meeting the prespecified criteria for a drug–drug interaction were observed. The results of the current studies add to the existing body of study data supporting the favorable drug–drug interaction profile of colesevelam [20]. Fewer medications have demonstrated potential drug–drug interactions with colesevelam than with cholestyramine (Table 4) [2,21–37]. Previous studies have demonstrated an absence of clinically significant drug–drug interactions with concomitant administration of colesevelam with fenofibrate [38], pioglitazone [37], lovastatin [39], digoxin, metoprolol, quinidine, valproate, warfarin, and verapamil [40]. The current study utilized the results of QSPR modeling to predict the likelihood of observing drug–drug interactions, and to modify the design of the studies accordingly. Predicted

Please cite this article in press as: He L, et al. Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2013.12.033

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Table 4 – Medications associated with potential drug– drug interactions with the bile acid sequestrants cholestyramine [21–36] and colesevelam [2,37], based on in vitro binding or in vivo interaction studies. Cholestyramine Digitalis/digoxin Estrogens and progestins Glipizide Hydrocortisone Penicillin G Phenobarbital Phenylbutazone Propranolol Rosiglitazone Simvastatin Tetracycline Thiazide diuretics Thyroxine Tricyclic antidepressants Valproic acid Warfarin Other drugs that undergo enterohepatic circulation (e.g., naproxen, phenprocoumon, sulindac) a

Colesevelam Cyclosporine Ethinyl estradiol and norethindrone Glimepiride Glipizide Glyburide Levothyroxine Metformin ERa (increases exposure) Olmesartan medoxomil

Extended-release.

binding was 82.8% for phenytoin and 1.50–16.8% for the other tested drugs [13]. In general, our observed data were consistent with the predictions of the QSPR modeling, suggesting that this may be a useful tool to screen for the potential for drug– drug interactions. The QSPR model is based on in vitro and physicochemical properties of the medications and does not include in vivo factors. Therefore, this model suggests which compounds show low risk for interaction with colesevelam and which may be at higher risk for interaction. Although our pharmacokinetic study has shown that the peak and total exposure of phenytoin is not altered when administered with colesevelam, concomitant use of phenytoin and colesevelam should remain in accordance with United States prescribing information for colesevelam. At present, the prescribing information indicates that phenytoin should be taken at least 4 h before colesevelam, based on the narrow therapeutic index of phenytoin and postmarketing reports consistent with potential interactions [2,12].

5.

Conclusions

Aspirin, atenolol, enalapril, rosiglitazone, and sitagliptin may be taken together with colesevelam. Although no pharmacokinetic-based drug–drug interaction between phenytoin and colesevelam is apparent, concomitant use of phenytoin and colesevelam should remain in accordance with colesevelam United States prescribing information, with phenytoin administered at least 4 h before colesevelam.

Author contributions P.W., L.H., J.M-H., J.L., B.T., D.W., and J.W. designed the studies, analyzed the data and contributed to discussions. L.H., D.W. and

P.W. conducted the studies. L.H. provided the assay support for the studies. L.H., J.L., B.T., J.M-H., and J.W. are employees of Daiichi Sankyo Pharma Development, the sponsor of these DDI studies, and P.W. was an employee of Daiichi Sankyo Pharma Development at the time that the studies were conducted. D.W. was an employee of MDS Pharma Services or Celerion Inc. at the time that these studies were conducted.

Conflicts of interest None.

Acknowledgments The studies were supported by Daiichi Sankyo, Inc. Robert Schupp, PharmD, and Sushma Soni of inScience Communications, Springer Healthcare, provided medical writing support funded by Daiichi Sankyo, Inc. The authors would like to acknowledge Richard Scheyer, MD, and Giorgio Sendali, MD, of Daiichi Sankyo Pharma Development for their participation in the studies as medical monitors; Mukesh Kumar, MBBS, MD, of Daiichi Sankyo India Development; Robert Noveck, MD, PhD, FCP, Frank Lee, MD, Srinivas Shenoy B, MBBS, MD, Satish Kumar, MBBS, MD, Daniel Weiss, MD, and Scott Rasmussen, MD, for their participation in the studies as principal investigators; Hamim Zahir, PhD, of Daiichi Sankyo Pharma Development for contributing to the study design; and SaeHeum Song, PhD, of Daiichi Sankyo Pharma Development for assistance with pharmacokinetic calculations and helpful discussion regarding interpretation of the data.

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