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DRUG INTERACTIONS |
From Lilly-NUS Centre for Clinical Pharmacology, Singapore (Dr Soon, Ms Yuen, Dr Wise); Eli Lilly and Company, Indianapolis, Indiana (Dr Kothare, Dr Park, Dr Mace); and Eli Lilly and Company, Windlesham, United Kingdom (Dr Linnebjerg).
Address for reprints: Danny Soon, MBBS, Lilly-NUS Centre for Clinical Pharmacology, Level 6, Clinical Research Centre, MD 11, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore; e-mail: soon_danny{at}lilly.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Exenatide • warfarin • drug interaction • international normalized ratio
After subcutaneous administration, exenatide is rapidly absorbed, usually reaching peak concentrations 2 hours postadministration. Peak plasma exenatide concentrations after a 10-µg dose are approximately 200 pg/mL.6 Exenatide is primarily eliminated by renal mechanisms (glomerular filtration, followed by peptidic degradation in the tubules).7,8 After a single subcutaneous dose, it exhibits a short half-life of approximately 2.5 hours. Pharmacokinetic/pharmacodynamic modeling and empirical assessments from early clinical studies supported a twice-daily dosing regimen.9 Because of its relatively short half-life, significant systemic accumulation is not observed with repeated twice-daily dosing. As exenatide is a peptide, enzyme-based drug interactions such as those with cytochrome P450 (CYP) isoenzymes are not expected, and no in vitro metabolism studies or animal metabolism studies have been conducted.
Because of slowing of gastric emptying, exenatide is expected to alter the absorption of orally administered concomitant medications, typically resulting in a minor reduction of maximum plasma concentration (Cmax) by about 10% to 20% and a prolonged time of maximum concentration (tmax) by 1 to 2 hours.10-12 Drug exposures are not expected to be significantly altered, although to date, one study that evaluated the interaction between exenatide and lovastatin was the only study that demonstrated a significant reduction in area under the plasma concentration–time curve (by 40%).13 The exact reasons for this reduction are unknown.
Warfarin is a widely used anticoagulant, and its main mode of action is in the inhibition of the regeneration of vitamin K–dependent clotting factors (factors II, VII, IX, and X) from their oxidized form.14 Warfarin, taken as a racemic mixture of R- and S-enantiomers, is well absorbed after oral administration, reaching peak concentrations approximately 4 hours after dosing. The more potent S-warfarin form (up to 5 times the anticoagulant potency of R-warfarin) is metabolized primarily by CYP2C9, and hence the pharmacokinetics and pharmacodynamics of warfarin may be affected by reduced function of this enzyme resulting from genetic polymorphism. Warfarin has a narrow therapeutic ratio with risk of bleeding in overdose and risk of thromboembolic events with underanticoagulation. Thus, the therapeutic efficacy of warfarin is measured as the international normalized ratio (INR) of the prothrombin time, with the usual therapeutic range being 1.5 to 4.0 for anticoagulant effects, depending on the disease state being treated.15 After a single dose of racemic warfarin, the INR peak generally occurs within 24 hours, and the warfarin effects on INR persist for a period of 2 to 5 days.
Patients with type 2 diabetes are at greater risk of vascular disease, which may directly or indirectly present a risk for thromboembolic events, and are therefore frequently prescribed antithrombotic therapy. This study evaluated the effect of subcutaneous exenatide (at 10 µg, the highest dose approved for use in the United States) on the pharmacokinetics and pharmacodynamics of orally administered warfarin.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was an open-label, 2-period, fixed-sequence study. Figure 1 provides an overview of the study design. Subjects received a single, oral 25-mg dose of warfarin (MarevanTM, 5 x 5-mg tablets; GlaxoSmithKline, Douglas Manufacturing Ltd, Auckland, New Zealand). In period 1 after an overnight fast, subjects consumed a standardized breakfast within a 15-minute period, followed by an oral dose of warfarin. In period 2, subjects received subcutaneous exenatide for 4 days (5 µg twice daily for 2 days, followed by 10 µg twice daily for 2 days) prior to warfarin dosing. On the fourth day of period 2, exenatide dosing was followed by a standardized breakfast 15 minutes later and by the second warfarin dose (25 mg) after an additional 5 minutes. Subjects were encouraged to complete the breakfast in 15 minutes and thus the second oral dose of 25 mg warfarin was administered approximately 35 minutes after the morning dose of exenatide on day 4. Exenatide 10 µg twice daily was then continued for another 5 days. Exenatide was administered as a sterile solution (0.25 mg/mL; Amylin Pharmaceuticals Inc, San Diego, Calif) at appropriate volumes. The second dose of warfarin was administered 5 days after the last warfarin blood sample was taken for period 1, allowing a minimum interval of 10 days between warfarin doses for washout and for INR values to return to baseline. Blood samples for R- and S-warfarin pharmacokinetic determination were taken predose and sequentially at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after the warfarin dose and for INR determination at predose, 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours after the warfarin dose for both periods. Subjects were inpatient for the first 24 hours after warfarin dosing. Blood samples up to 24 hours obtained via an indwelling cannula and subsequent samples obtained by individual venipuncture were collected into citrate tubes. Subjects were genotyped for CYP2C9.
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Pharmacokinetic Assessment
Key pharmacokinetic parameters for R- and S-warfarin were determined using standard noncompartmental methods. The Cmax and the corresponding tmax were identified from the observed data. Log-linear regression of the terminal phase yielded the terminal rate constant (
z). The area under the plasma concentration time-curve up to the last observable time point (AUC0-tlast) was calculated by the log-linear trapezoidal rule. The area under the curve from the last observable point to infinity (AUCtlast-
) was calculated by dividing the concentration at the last observable point by z. Summation of the 2 partial areas (AUC0-tlast and AUCtlast-) yielded the area under the curve to infinity AUC0-. Clearance (CL/F) was determined by dose/AUC0-, and volume of distribution (Vz/F) was calculated as (CL/F)/z. The terminal half-life (t
) was calculated as 0.693/z.
Pharmacodynamic Assessment
Pharmacodynamic parameters reported were the maximum observed INR response (INRmax), time to INRmax (INRtmax), and the area under the INR-time curve from dosing until the time of the last measurable INR value (INRAUC). INRAUC was calculated using linear trapezoidal rule.
Analytical Methods
R- and S-warfarin plasma concentrations were measured using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method at Advion BioServices Inc, Ithaca, New York. Total R- and S-warfarin in human plasma samples (0.1 mL) were diluted with citric acid containing the internal standard, (R,S)-[2H6]warfarin. The samples were centrifuged, and an aliquot was then quantified by turbo ion spray column switching, LC/MS/MS in the negative ion mode. High-performance liquid chromatography separation was carried out on a R,R-WHELK-O1 column (2.1 x 100 mm, 5 µm; Regis Technologies Inc, Morton Grove, Ill). The mass transitions of mass spectrometry detection were 307 mass-to-charge ratio (m/z) 
161 m/z [(R,S)-warfarin] and 313 m/z 256 m/z [(R,S)-[2H6]warfarin], respectively. The calibration (weighted 1/X2 linear regression algorithm) ranged from 10 to 2500 ng/mL. The intra- and interassay accuracy was assessed by determining the percentage of error observed in the analysis of quality control samples. The nominal concentration for each quality control level was subtracted from the mean concentration determined from the 3 validation runs. The residual was divided by the nominal value, converted to percentage, and expressed as percentage of deviation (%Dev). The intraand interassay accuracy (expressed as %Dev) ranged from –7.67% to 4.10% for R-warfarin and from –9.69% to 7.89% for S-warfarin for all quality control concentration levels. The intra- and interassay precision, defined by the percentage coefficient of variation (CV%) of the quality controls, ranged from 2.45% to 8.89% for R-warfarin and from 2.74% to 7.98% for S-warfarin at all quality control concentration levels. The INR was measured using a photo-optical clot detection method at NUH Referral Laboratories Pte Ltd, National University Hospital of Singapore, Singapore. The predicted P450 CYP2C9 genotype was determined through molecular genotyping of DNA purified from whole blood and analysis of CYP2C9*2 and *3 alleles (Genaissance, Morrisville, NC).
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Statistical Methods
With an intrasubject %CV of not more than 8% for warfarin AUC0- and Cmax, based on internal historical data, it was predicted that 12 subjects completing the study would provide approximately 90% probability to show the inclusion of the 90% confidence interval (CI) of the ratio of geometric means to be within 7% of the estimated ratio for warfarin AUC0- or Cmax.
The primary pharmacokinetic end points were AUC0- and Cmax for R- and S-warfarin and were log-transformed (base e) prior to analysis using a mixed-effects model.17 The model included the subject as a random effect and treatment (warfarin only or warfarin + exenatide) as a fixed effect. The least squares (LS) mean difference of warfarin pharmacokinetics between the treatments and its 90% CI were constructed. The difference and confidence limits were back-transformed to the original scale to yield the ratio of LS geometric means of the 2 treatments and its CI.
The pharmacodynamic parameters INRmax and INRAUC were log-transformed prior to analysis and were analyzed in a similar fashion. The predose INR value was found to be a significant covariate that was retained in the statistical model.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
The mean pharmacokinetic profiles for R- and S-warfarin are depicted in Figure 2, and parameters are summarized in Table I. Exenatide administration did not significantly alter the mean plasma warfarin concentration time profiles for R- and S-warfarin. The LS geometric mean ratio (warfarin + exenatide/warfarin alone) of AUC0- (90% CI) for R-warfarin was 1.11 (1.06-1.17) and for S-warfarin was 1.06 (1.01-1.11). The LS geometric mean ratio (warfarin + exenatide/warfarin alone) of Cmax (90% CI) for R-warfarin was 1.05 (1.00-1.09) and for S-warfarin was 0.97 (0.93-1.01). The 90% CIs were contained within the 0.8 to 1.25 limits that are usually used to assess significance of drug interactions (Table I). Both enantiomers displayed a slightly later tmax with the coadministration of exenatide with a median increase by 1 hour (R-warfarin) and by 2 hours (S-warfarin) (Table II). One subject experienced an episode of vomiting 45 minutes after receiving the warfarin dose in period 2. This subject's warfarin exposure (period 2) was lower in comparison to the other 15 subjects, as well as to his exposure in period 1. His data were excluded from the statistical analysis of pharmacokinetic and pharmacodynamic parameters.
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As expected, the 3 subjects with *2 or *3 haplotypes yielded a higher mean AUC0- by 16% and 69% for R- and S-warfarin, respectively (period 1) as compared to CYP2C9 wild-type homozygotes. Because of this small sample size, no further statistical analyses were done to evaluate phenotypic differences.
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Safety and Tolerability
Subcutaneous doses of exenatide were generally well tolerated by healthy male subjects when administered at 5 µg twice daily for 2 days, followed by 10 µg twice daily for 7 days. The most frequently reported individual adverse events considered to be related to exenatide were nausea, somnolence, headache, and lethargy, and most of these events occurred in the 24-hour period after the first 5-µg or 10-µg dose. Fifteen episodes of nausea were reported: 13 were mild, 1 was moderate, and 1 was severe. All episodes of nausea occurred within 5 hours of exenatide dosing and were generally reported across the entire exenatide dosing period. The duration of nausea ranged from 1.5 hours to approximately 8 days. All other drug-related adverse events were reported by 3 subjects during the multiple dosing period of exenatide. When 10 µg exenatide was coadministered on day 4 with 25 mg warfarin and a standardized meal, 3 subjects reported episodes of mild or moderate vomiting between 1 and 3 hours after the morning dose of exenatide. Standardized meals were given only on day 4 of the exenatide-dosing period, and there were no reports of vomiting in the 3 previous days of exenatide dosing. One subject had another occurrence of vomiting that lasted for approximately 15 hours after the evening dose of exenatide on day 7. There were no episodes of abnormal bleeding, and no subjects were discontinued on the basis of elevated INR >5. No clinically significant changes in vital signs or laboratory values were noted.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, in the presence and absence of exenatide, was fully contained within the 0.8 to 1.25 bioequivalence limits. Therefore, the coadministration of exenatide with warfarin did not produce any clinically significant changes in warfarin pharmacokinetics. In a previous study using acetaminophen to explore the impact of exenatide on gastric emptying, the rate (but not the extent) of acetaminophen absorption was slowed. Acetaminophen median tmax was approximately 1 hour when given at the same time as exenatide but was increased by 4 hours when given 1 hour after exenatide and was not altered when acetaminophen was dosed at least 1 hour prior to exenatide.10 In a separate study,11 the coadministration of exenatide with digoxin, another drug with a narrow therapeutic index, resulted in a 17% decrease in the mean Cmax of digoxin. This reduction in Cmax was not clinically significant because all subjects' digoxin concentrations remained within the therapeutic range. Also, the renal clearance of digoxin was not altered by the coadministration of exenatide.
In the current study, no significant differences were observed in warfarin plasma concentration–time profiles in the presence or absence of exenatide. Thus, the delayed gastric emptying resulting from exenatide therapy does not appear to significantly alter the pharmacokinetics of narrow therapeutic index drugs such as digoxin and warfarin.
Thus far, interactions with exenatide have been shown to be related to changes in the rate of absorption of concomitant oral drugs rather than a change in their metabolic profile.11-13,18 Warfarin acts as an anticoagulant by inhibiting the production of vitamin K–dependent clotting factors. In the mixed racemic form, the S-warfarin enantiomer is responsible for the majority of the anticoagulant activity. The S-enantiomer is a substrate for the liver enzyme CYP2C9, and its pharmacokinetics is well known to be dependent on to CYP2C9 functional status. Because of this property,19 S-warfarin is a commonly used in vivo probe of CYP2C9 activity.20 The lack of interaction between exenatide and S-warfarin pharmacokinetics in this study demonstrates a lack of effect of exenatide on CYP2C9-mediated drug metabolism.
It has previously been suggested that a single 25-mg dose of warfarin is an appropriate dose to detect an interacting effect on INR and has been used by others for the investigation of drug interactions with warfarin.21-23 In the current study, the mean INRmax attained with a single 25-mg oral dose of warfarin prior to exenatide was 1.95, with a range of 1.2 to 2.7, which is within the clinically relevant range normally used in anticoagulant therapy. The coadministration of exenatide with warfarin did not result in significantly altered anticoagulant action in these subjects, with the maximal (INRmax) and overall (INRAUC) anticoagulant effect remaining similar in both treatment phases.
In routine clinical use, warfarin anticoagulant effect is often altered by other extrinsic factors, such as concomitant medications, dietary habits, nutritional state, illness, and compliance with treatment. International normalized ratio monitoring of patients undergoing warfarin therapy is performed so that the narrow therapeutic index of the warfarin therapy is maintained. In the current study, the mean change in the maximal and overall anticoagulant effect was a decrease of approximately 12% and 6%, respectively, in the presence of exenatide. Furthermore, as the resultant mean effect was a decrease in anticoagulant effect rather than an increase, this interaction is not likely to produce an increase in unsafe bleeding. Hence, with the routine anticoagulation monitoring received by patients on warfarin therapy, this minor change in anticoagulant effect is unlikely to result in clinically significant issues.
A limitation of this study is that it was performed in healthy Asian male volunteers aged 22 to 50 years and only single doses of warfarin were given. Age, gender, race, Vitamin K Epoxide Reductase C1 (VKORC1) haplotype, and CYP2C9 polymorphisms are important known factors determining the maintenance dose of warfarin.24 It should be noted however, that in this crossover study, the subjects acted as their own controls and the impact of the preceding factors would be substantially mitigated. In translating the findings of this study into a relevant observation for the target population (ie, patients with type 2 diabetes and under long-term dosing), one needs to consider the known mechanistic basis for this interaction. As previously described, the effect of exenatide on the pharmacokinetics of concomitantly orally administered drugs appears to be chiefly a delay of tmax and a decrease in Cmax, effects consistent with a slowing in gastric emptying. Based on the known pharmacology and disposition of exenatide, a metabolism-based interaction is not expected. Indeed, no clinically relevant changes in warfarin clearance were observed. The only change in the pharmacokinetic profile was a minor shift in the absorption profile. For low therapeutic index therapies, such as warfarin, there is usually greater concern that an interacting drug may cause increased drug exposure, resulting in toxicities, and less concern with decreased efficacy. Given the observed change in exenatide pharmacokinetic profile, this is not likely to be a risk associated with concomitant exenatide therapy. Because this was a study with healthy volunteers, multiple dosing with warfarin was not performed. Exenatide also exhibits similar pharmacokinetics in healthy volunteers as in patients with type 2 diabetes6,10; hence, it is unlikely that patients with type 2 diabetes will behave in a significantly different manner from healthy volunteers with regard to this interaction.
Subcutaneous doses of exenatide (5 µg twice daily for 2 days, followed by 10 µg twice daily for 7 days) were generally well tolerated. All subjects reported drug-related adverse events, the most common being gastrointestinal in nature. The majority of the events were mild to moderate in severity, and the highest incidences of events occurred in the 24-hour period after the first 5-µg or 10-µg dose. Nausea that decreases over time has been the most common side effect reported with exenatide in clinical trials,2,3,25 and this side effect was observed to be less severe with a gradual dose escalation of exenatide.26
Genotyping results from the present study revealed that 13 of 16 subjects were wild-type genotype, 1 subject was of the *2 haplotype, and 2 subjects were the *3 haplotype. Compared to wild-type, subjects homozygous and heterozygous for CYP2C9 *3, when given oral warfarin, have been shown to have 90% and 66% lower clearance of S-warfarin, respectively.27 Veenstra and coworkers have also associated subjects with the *2 and *3 haplotype with reduced warfarin doses, longer times of warfarin dosing to reach stable blood concentrations, and increased risk of bleeding at generally prescribed warfarin dosages.18 Other drugs that have demonstrated lower clearance in subjects who possess the CYP2C9*2 or *3 allele include phenytoin and glipizide.28 In this study, the *2 and *3 haplotype subjects demonstrated a trend toward higher warfarin exposures of approximately 16% and 69% for R- and S-warfarin, respectively, compared with wild-type. This finding is expected; however, because of the small sample size, it is difficult to draw a firm conclusion from these data.
In conclusion, no significant changes in warfarin pharmacokinetics (R- or S-warfarin) were observed when a single dose of warfarin was coadministered with exenatide to healthy individuals. The changes in INR were small in magnitude and in a direction that is unlikely to cause a safety concern.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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4. Kolterman OG, Kim DD, Shen L, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62: 173-181.
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11. Kothare PA, Soon DK, Linnebjerg H, et al. Effect of exenatide on the steady-state pharmacokinetics of digoxin. J Clin Pharmacol. 2005;45: 1032-1037.
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24. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106: 2329-2333.
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26. Fineman MS, Shen LZ, Taylor K, Kim DD, Baron AD. Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes. Diabetes Metab Res Rev. 2004;20: 411-417.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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