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Effect of Exenatide on the Steady-State Pharmacokinetics of Digoxin

From the Lilly-NUS Centre for Clinical Pharmacology, Singapore (Dr Soon, Mr Chan, Ms Yeo, Ms Lim, Dr Wise); Eli Lilly and Company Limited, Lilly Research Centre, Windlesham, Surrey, United Kingdom (Dr Linnebjerg); and Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Dr Kothare, Dr Park, Dr Mace).

Address for reprints: Prajakti A. Kothare, PhD, Global PK/PD and Trial Simulations, Eli Lilly and Company, Indianapolis, IN 46285.

	ABSTRACT

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This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 µg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUC_,ss) and C_min,ss but caused a 17% decrease in mean plasma digoxin C_max,ss (1.40 to 1.16 ng/mL) and an increase in digoxin t_max,ss (median increase, 2.5 hours). Although the decrease in digoxin C_max,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Key Words: Exenatide • digoxin • gastric emptying • interaction • pharmacokinetics

Digoxin, a commonly prescribed cardiac glycoside used to treat arrhythmias and heart failure, has a narrow therapeutic window (recommended therapeutic plasma concentration of 0.8 to 2.0 µg/L).^7,8 Digoxin is a P-glycoprotein substrate that reaches peak plasma concentrations 1 to 3 hours after oral administration, and it is mainly excreted unchanged in the urine (only 16% of a dose of digoxin is metabolized).^7,9 As digoxin has a narrow therapeutic window, change in steady-state plasma concentrations may result in toxicity or loss of therapeutic efficacy. The aim of the present study was to determine the effect of exenatide on the steady-state pharmacokinetics, safety, and tolerability of digoxin.

	METHODS

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Subjects
Healthy male subjects between the ages of 21 and 50 years were permitted to enroll in the study. Subjects were required to be in good health with a body mass index (BMI) of 19 to 30 kg/m². The study was a single-center study conducted by one principal investigator at the Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore. The protocol and informed consent document were approved by the institutional review board at the National University Hospital of Singapore, in accordance with the principles described in the Declaration of Helsinki, including all amendments through the 1996 South Africa revision.¹⁰ All subjects provided written informed consent before participation.

Study Design
This study was an open-label, fixed-sequence study. Subjects who met the eligibility criteria were enrolled at an admission visit within 7 days before the first dose (day 1) for medical assessments and baseline tests. Subjects were administered a loading dose of 0.5 mg digoxin twice daily (Lanoxin 0.25-mg tablets, Glaxo SmithKline, Research Triangle Park, NC) on day 1, followed by maintenance doses of 0.25 mg digoxin once daily on days 2 through 12. On days 8 through 12, subcutaneous doses of 10 µg exenatide were also administered twice daily. Exenatide was supplied by Amylin Pharmaceuticals (San Diego, Calif) as a 0.25 mg/mL sterile solution for subcutaneous injection. Plasma and urine samples for digoxin were taken for 24 hours after the digoxin dose on days 7 and 12. Subjects returned for a poststudy visit within 14 days of the final dose of digoxin.

All digoxin doses were administered after a standard breakfast. Subjects fasted overnight after admission to the study center on days 6 and 11 until breakfast the following day. On days 8 through 12, subjects were provided with a standard breakfast 15 minutes after the morning dose of exenatide. The subjects were allocated 15 minutes to complete the breakfast, after which digoxin was administered (ie, approximately 30 minutes after exenatide administration). After the evening dose of exenatide, the subjects were provided with a snack or dinner.

Prescribed medication was not permitted for 14 days before the first digoxin dose through the final follow-up visit. Over-the-counter medication, except occasional acetaminophen, vitamins, or mineral supplements, was not permitted for 7 days before the first digoxin dose through the final follow-up visit. Concomitant medication was permitted at the discretion of the investigator. Subjects were asked to avoid consumption of alcohol and grapefruit products and to abstain from vigorous or prolonged exercise.

Pharmacokinetic Assessments
Blood samples (5 mL) for quantification of plasma digoxin concentration were collected on day 1 before the first dose of digoxin and then before the dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 24 hours after the dose on days 7 and 12. Heparinized plasma samples were analyzed for digoxin (PPD Development, Richmond, VA) using a radioimmunoassay method validated over the concentration range of 0.15 to 8.00 ng/mL. Additional blood samples (5 mL) for quantification of plasma exenatide concentration were collected on day 8 (before the first exenatide dose) and on days 11 and 12 (2 hours after the exenatide dose). The plasma assay had an accuracy of -6.48% to 1.28% as percentage difference from theoretical and a precision of 4.94% to 15.6% as percentage coefficient of variation (CV%). Plasma samples were analyzed for exenatide (Amylin Pharmaceuticals, San Diego, Calif) using a validated immunoenzymetric assay method over the concentration range 10 to 500 pg/mL.

Urine samples for analysis of digoxin were collected on day 1 (before the first digoxin dose) and on days 7 and 12 at 3 time periods (0-6, 6-12, and 12-24 hours after the digoxin dose). Urine samples were analyzed for digoxin (PPD Development, Richmond, VA) using a radioimmunoassay method validated over the concentration range 1.00 to 40.0 ng/mL.

Safety Assessments
Safety assessments included monitoring of adverse events, laboratory evaluations, chest radiographs, vital signs, electrocardiograms (ECGs), physical examinations, and body weight. Twelve-lead ECGs were recorded for safety monitoring at screening, every morning before dosing with digoxin from days 1 through 12, and on day 13 before discharge. The investigator reviewed the ECG results before each subject's daily dosing. Safety control measurements of digoxin concentrations (trough levels) in plasma were performed before the digoxin dose on days 3, 6, 9, 10, and 11, and the results were made available to the investigator before digoxin dosing the following day. If a subject's plasma digoxin level exceeded 2.0 µg/L, he was discontinued from the study. Results of samples taken for safety control monitoring of digoxin levels were not included in the pharmacokinetic evaluation of digoxin.

Statistical Analyses
Fourteen subjects were required to complete the study to provide approximately 90% power to show the inclusion of the 90% confidence interval (CI) of the ratio of geometric means for digoxin area under concentration-time curve (AUC_,ss) within the interval (0.80-1.25), even if the geometric means differed by as much as 5%. This sample size was determined using an intrasubject coefficient of variation of 14% for digoxin AUC_,ss.

Steady-state pharmacokinetic parameters were calculated from the plasma digoxin concentration-time profile by noncompartmental analysis. Key parameters including the minimum and maximum observed plasma concentrations during a dosing interval at steady state (C_min,ss and C_max,ss), the corresponding sampling time (t_max,ss), and the area under the plasma concentration-time curve over the dosing interval (AUC_,ss) were reported. The AUC_,ss was calculated by the log-linear trapezoidal rule. Descriptive statistics were generated for each treatment period.

The amount of digoxin excreted unchanged in urine at steady state (Ae_,ss) was calculated over a 24-hour period. The fraction of digoxin excreted unchanged (fe) over the 24-hour period was estimated by dividing Ae_,ss by the dose administered. The renal clearance of digoxin at steady state (CL_R,ss) was calculated by dividing the Ae_,ss by AUC_,ss.

Plasma digoxin C_max,ss, C_min,ss and AUC_,ss were log-transformed and analyzed using a linear mixed effects model with treatment (digoxin or digoxin and exenatide) as a fixed factor and subject as a random factor. The mean difference between treatments, along with the 2-sided 90% CI for the difference, was back-transformed to yield the ratio of geometric means and the 90% CI for the ratio (combination vs alone). If the 90% CI of the ratio fell within the interval (0.80-1.25), the treatments were considered equivalent. Minimum, median, and maximum of the difference in the t_max,ss between the 2 treatments were reported.

	RESULTS

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Subjects
Twenty-three healthy Asian male subjects were enrolled in the study. The subjects ranged in age from 21 to 42 years (mean ± SD, 26 ± 5.4 years) with BMI ranging from 19.4 to 29.7 kg/m² (mean ± SD, 23.7 ± 2.70 kg/m²). Two subjects were discontinued from the study before completion. One subject discontinued because of a gastrointestinal infection unrelated to the study drug after receiving digoxin on days 1 through 3. The other subject discontinued because of personal reasons after receiving digoxin on days 1 through 8 and 1 dose of exenatide on day 8. Two subjects received concomitant medication during the study: One subject was treated with amoxicillin, acetaminophen, and antacids because of a gastrointestinal infection; the other subject received acetaminophen for a headache.

Digoxin Pharmacokinetics
Digoxin pharmacokinetic parameters at steady state with and without coadministration of exenatide are presented in Table I. Coadministration of exenatide caused a right shift in the plasma steady-state digoxin concentration-time profile (Figure 1). The median t_max,ss increased from 1.5 hours at day 7 to 4.0 hours at day 12 (median difference, 2.5 hours). The mean C_max,ss decreased from 1.40 to 1.16 ng/mL, resulting in a 17% decrease in mean C_max,ss. Despite the decrease in mean C_max,ss, steady-state peak digoxin plasma concentrations in the presence of exenatide remained in the putative therapeutic range (0.8 to 2.0 µg/L) in all subjects (Figure 2). As shown in Table II, the geometric mean ratio of C_max,ss was 0.82. However, the 90% CI for the geometric mean ratio ranged from 0.75 to 0.89 and therefore was slightly less than the prospectively defined equivalence range (0.80-1.25).

View larger version (14K): [in this window] [in a new window]   Figure 1. Arithmetic mean (±SE) digoxin plasma concentration versus time profiles following steady-state dosing of 0.25 mg once daily digoxin alone () or in the presence of steady-state dosing of 10 µg exenatide twice daily administered subcutaneously ().

View larger version (18K): [in this window] [in a new window]   Figure 2. Individual digoxin Cmax,ss values shown with the arithmetic mean (±SD) in the absence and presence of exenatide twice daily.

View this table: [in this window] [in a new window]   Table II Statistical Comparison of Digoxin AUC,ss, Cmin,ss and Cmax,ss for Digoxin + Exenatide (Day 12) and Digoxin (Day 7)

Coadministration of exenatide did not result in a statistically significant change in the digoxin AUC_,ss nor C_min,ss (Table II). The ratios of the geometric means of AUC_,ss and C_min,ss were 0.95 and 0.94, respectively, and the 90% CI for the ratios were fully contained within the prospectively defined equivalence range (0.80-1.25), indicating that the extent of absorption was not affected.

Estimates of renal digoxin clearance with and without exenatide coadministration were comparable (Table III), indicating that exenatide coadministration did not affect the renal clearance of digoxin. Mean plasma exenatide concentrations were similar 2 hours after the dose on days 11 and 12, suggesting that exenatide had attained steady state after 3 days of exenatide dosing.

Safety
No subject's plasma digoxin level exceeded 2.0 µg/L; thus, no subjects were discontinued from the study because of safety control monitoring of digoxin levels. The review of ECG data did not reveal any safety concerns. Of the 22 subjects exposed to exenatide, 21 subjects (95%) experienced adverse events assessed as related to exenatide. None of these events was serious, and no episodes of hypoglycemia were reported. No subjects experienced an adverse event that was assessed to be related to digoxin. The most common adverse event related to exenatide dosing was nausea followed by somnolence, abdominal distension, and vomiting. Of the subjects, 19 (86%) reported at least 1 episode of exenatide-related nausea, all of which were transient, mild, or moderate in intensity and resolved without treatment. The onset of new exenatide-related gastrointestinal events, such as nausea, attenuated from 41 events on day 8 to only 10 events on day 12. Five subjects experienced vomiting during the study. None of these subjects required antiemetic treatment. Only 1 incident of vomiting had the potential to affect the digoxin pharmacokinetic assessment. The patient experienced vomiting after the morning exenatide dosing on day 12; however, evaluation of the subject's concentration-time profile did not indicate a decrease in absorption, and this subject's pharmacokinetic profile was comparable to other subjects in the group. Thus, the subject's data were included in the pharmacokinetic analyses.

	DISCUSSION

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Exenatide and digoxin might potentially be used concomitantly in patients with type 2 diabetes and cardio-vascular disease. This study was conducted to determine the effects of subcutaneous exenatide (10 µg twice daily) dosing on the pharmacokinetics of oral digoxin (0.25 mg once daily) and to assess the safety and tolerability of their concomitant use. Subcutaneous doses of 5 and 10 µg exenatide twice daily have appeared to exert glucose control in long-term clinical studies.^2-4 This study utilized a dose of 10 µg exenatide twice daily to maximize the potential for any drug interaction. A 5-day dosing regimen was chosen to assess the safety and tolerability of coadministration of exenatide and digoxin, because the common exenatide-related adverse effects, such as nausea, have been reported to manifest within the first week of exenatide dosing.^4,6,11 The dose regimen selected for digoxin was expected to achieve therapeutic steady-state plasma concentrations in healthy subjects in approximately 7 days.⁷

Exenatide has been demonstrated to delay gastric emptying as coadministration with orally administered acetaminophen significantly reduced the overall rate of absorption of acetaminophen.⁶ A reduced rate of absorption would lead to a lower maximum concentration (C_max) and a prolonged time to maximum concentration (t_max), assuming that the elimination characteristics of the drug remained unchanged. This finding could potentially be of greater concern for drugs that have a narrow therapeutic index, such as digoxin. Accordingly, the results of this study showed that minor changes in the absorptive profile of digoxin were consistent with changes in the rate of absorption because of slower gastric emptying caused by exenatide. Coadministration of exenatide was associated with a 17% decrease in mean digoxin C_max,ss (1.40-1.16 ng/mL) and an increase in digoxin t_max,ss (median increase, 2.5 hours). Although the decrease in C_max,ss was statistically significant, it was still within the therapeutic concentration range in all of the individual subjects and, therefore, not felt to be of clinical significance.

As is conventional in clinical pharmacological studies, this study was conducted in healthy volunteers to reduce the influence of confounding factors, such as concurrent medications and diseases. A crossover design was chosen to reduce the impact of variability with each subject serving as his own control in the statistical analysis. Patients with diabetes are likely to have complex medical conditions that require many concomitant medications that have the potential to interact with digoxin pharmacokinetics. In addition, a larger range of observed steady-state concentrations is plausible given that digoxin pharmacokinetics is variable (bioavailability ranging from 60% to 90%). Nonetheless, dosage adjustment for digoxin in the presence of exenatide is not anticipated in that monitoring of drug concentrations would be routinely conducted with digoxin therapy in clinical practice. Therapeutic drug monitoring would identify patients with subtherapeutic levels of drug exposure that could potentially and theoretically occur given the narrow therapeutic window of digoxin. The possibility of pharmacodynamic interactions in patients, especially those that might be observed only during extended periods of treatment, cannot be evaluated in this study and may require further study.

The half-life of digoxin is reported to be approximately 40 hours.¹² Because the sampling duration in this study was 24 hours, estimating the digoxin half-life in this study would not have been scientifically valid. However, a visual inspection of the digoxin steady-state pharmacokinetic profile suggests that the postabsorptive phase was not altered by subcutaneous administration of exenatide. Coadministration did not produce a statistically significant change in the overall 24-hour steady-state exposure (AUC_,ss) to digoxin and C_min,ss.

Exenatide coadministration did not affect the renal clearance of digoxin. This is consistent with the change in the early part of the digoxin plasma concentration-time profile that reflects a delay in absorption rather than an alteration of an elimination pathway.

Subcutaneous doses of 10 µg twice daily exenatide, coadministered with oral doses of 0.25 mg once daily digoxin for 5 days, were generally well tolerated in this study. The incidence of gastrointestinal events related to exenatide was expected. Nausea that decreases over time has been the most commonly reported side effect in exenatide clinical trials.^2,3,4,11 Gradual dose escalation of exenatide has been demonstrated to reduce the proportion of subjects who experience nausea.¹³ No dose escalation of exenatide was performed during this study and may have contributed to the incidence of nausea reported during the study. In addition, the incidence of nausea could have been affected by the fact that this study was conducted in healthy subjects instead of patients with type 2 diabetes. Consistent with the induction of tolerance to exenatide side effects,^4,11,13 the incidence of gastrointestinal disorders decreased with repeated dosing of exenatide during this study. As described in the results section, the occurrence of vomiting was unlikely to impact the digoxin pharmacokinetic assessment.

In conclusion, the pharmacokinetic profile of digoxin in this study was similar to previously published reports.^7,8 Exenatide administration did not cause changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae, based on the known pharmacokinetic properties of digoxin. Minor changes in the plasma digoxin absorptive profile in the presence of exenatide were consistent with its action of slowing gastric emptying. Thus, dosage adjustment for digoxin in the presence of exenatide does not appear to be warranted, based on pharmacokinetic considerations.

	ACKNOWLEDGEMENTS

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The authors thank Dr Jennifer Witcher for her scientific input provided during protocol development and April Boney for her assistance in the preparation of the manuscript.

DOI: 10.1177/0091270005278806

	REFERENCES

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3. Kendall DM, Riddle MC, Zhuang D, Kim DD, Fineman MS, Baron AD: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in patients with type 2 diabetes mellitus treated with metformin and a sulfonylurea. Diabetologia. 2004;47(suppl 1): A279.

4. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes mellitus. Diabetes Care. 2004;27: 2628-2635.[Abstract/Free Full Text]

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6. Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88: 3082-3089.[Abstract/Free Full Text]

7. Lanoxin Tablets (digoxin) [Package Insert]. In Physician's Desk Reference. 57th ed. Montvade, NJ: Medical Economics; 2003: 1579-1582.

8. Cauffield JS, Gums JG, Grauer K. The serum digoxin concentration: ten questions to ask. Am Fam Physician. 1997;56: 495-503, 509-510.[Medline] [Order article via Infotrieve]

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11. Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D, Baron AD. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003;26: 2370-2377.[Abstract/Free Full Text]

12. Ooi H, Wilson SC. Pharmacological Treatment of Heart Failure. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York, NY: The McGraw-Hill Companies Inc; 2001: 901-932.

13. 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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