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Influence of Coadministration on the Pharmacokinetics of Azimilide Dihydrochloride and Digoxin

From Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, Ohio. Dr Toothaker is currently at Akros Pharma Inc, Princeton, New Jersey; Mr Corey is currently at Human Genome Sciences, Inc, Rockville, Maryland; Ms Valentine is currently at DemandTec, Inc, San Francisco, California; and Dr Parekh is currently at Wyeth Consumer Healthcare, Richmond, Virginia.

Address for reprints: Gary A. Thompson, PhD, Clinical Pharmacology and Pharmacokinetics, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040-9462.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The influence of coadministration on digoxin and azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between azimilide blood concentrations and QT_c prolongation was characterized by an E_max model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL_r (P = .0325), with no change in CL_o. Digoxin pharmacokinetics was unaffected by azimilide, except for a 21% increase in C_max (P = .0176) and a 10% increase in AUC (P = .0121). Digoxin coadministration increased the apparent EC₅₀ with no effect on E_max, consistent with competitive inhibition (K_i = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.

Key Words: Azimilide • digoxin • pharmacokinetics/pharmacodynamics • QT_c • drug interaction

Azimilide pharmacokinetics has been assessed following intravenous and oral administration.² Following intravenous administration, mean azimilide pharmacokinetic parameters include total clearance = 0.136 L/h/kg, renal clearance = 0.013 L/h/kg, steady-state volume of distribution = 12.9 L/kg, and a terminal exponential half-life = 71.4 hours. Azimilide plasma protein binding is about 94%,³ is concentration independent over the range observed clinically, and is predominately bound to albumin, with minor binding to ₁-acid glycoprotein.^4,5 These parameters indicate that azimilide has a low extraction ratio (low capacity clearance) with a steady-state volume of distribution consistent with extensive tissue distribution. Because of the low clearance and large volume of distribution, azimilide has a long terminal exponential half-life of about 3 to 4 days. Following oral administration, azimilide is completely absorbed, with peak blood concentrations occurring at approximately 7 hours. When azimilide is administered following a high-fat meal, no change in extent of absorption is observed, although peak blood concentration decreases approximately 19%.⁶

Azimilide clearance is primarily due to metabolic processes, with renal clearances accounting for only approximately 10%. Metabolites include F-1292 (4-chlorophenylfuroic acid), F-1292 ß-acyl glucuronide, a desmethyl metabolite, a carboxylic acid metabolite, an N-oxide metabolite, and other metabolites formed following cleavage of azimilide. Formation of F-1292 via cleavage accounts for approximately 35% of azimilide's total clearance, with cytochrome P450 3A4/5 and cytochrome P450 1A1 accounting for approximately 15% and 25% of azimilide's total clearance, respectively.⁷ Azimilide's major metabolite in plasma is a carboxylic acid moiety (F-1292), which does not possess cardiovascular activity.^8,9 Minor metabolites also found in plasma include desmethyl azimilide (NE-10171 base), azimilide N-oxide (NE-10835), and azimilide carboxylate (NE-11178). These metabolites have approximately 20%, 11%, and 0% of azimilide's class III antiarrhythmic activity in vitro, respectively.⁹ Since plasma concentrations of these latter metabolites are generally less than 10% of azimilide, they do not measurably contribute to azimilide antiarrhythmic activity.¹⁰

Digoxin is a cardiac glycoside indicated for the treatment of congestive heart failure and control of supraventricular tachyarrhythmias.¹¹ Following oral administration, digoxin is 75% absorbed, with peak plasma concentrations occurring at 1.2 hours.^11,12 It is a p-glycoprotein substrate, whose bioavailability may be altered by substrates/inhibitors/inducers of p-glycoprotein.^12-15 Digoxin is primarily renally cleared with a terminal exponential half-life of 36 hours.¹¹

Since digoxin is likely to be given concomitantly to patients being treated with azimilide dihydrochloride, the potential for a pharmacokinetic or pharmacodynamic interaction upon coadministration was assessed in this study.

	METHODS

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Study Design
This was a randomized, 3-way crossover study to be conducted in 18 healthy, nonsmoking male or female volunteers ranging from 18 to 40 years of age with body weights within 10% of ideal body weight. The study was conducted at Focus Clinical Development (Neuss, Germany). The protocol was approved by the Independent Ethics Committee at the clinical site, and all subjects gave written informed consent prior to enrollment in the study.

Treatments
Each subject was randomly assigned to 1 of 6 treatment sequences involving consecutive administration of all 3 treatments, with 35 days between the first dose of each treatment period. For treatment 1 (azimilide alone), 175 mg azimilide dihydrochloride was orally administered once daily on days 1 to 4, followed by 100 mg on day 5. Treatment 2 (digoxin alone) consisted of digoxin (Lanoxin) orally administered every 8 hours on day 1 (first dose of 0.5 mg, followed at 8 and 16 hours by 0.125 mg), followed by 0.25 mg orally administered daily on days 2 through 5. Treatment 3 (coadministration) was treatments 1 and 2 administered concurrently. All doses were administered with 240 mL of water. Subjects fasted overnight prior to dosing and for 4 hours after the first daily dose. Subjects were not allowed to take any other medications for 1 week prior to and during the study.

Measurements
Heparinized blood samples for measurement of blood azimilide concentrations were obtained just prior to dosing on days 1 through 5, at 7 hours postdose on days 1 through 4, and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, and 480 hours postdose on day 5. Blood samples were stored frozen at or below -20°C and protected from light until analyzed.

Blood samples for quantification of serum digoxin concentrations were obtained just prior to dosing on days 1 through 5; at 1, 2, 4, 8, 9, 12, 16, and 20 hours after the first digoxin dose on day 1; at 2 and 8 hours after the digoxin dose on days 2 through 4; and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 hours after dosing on day 5. Serum samples were stored frozen at or below -20°C until analyzed.

Urine samples for azimilide and digoxin analysis were collected over 24-hour intervals, for the duration of blood collection. Urine samples were stored at 2°C to 6°C during collection and were stored frozen at or below -20°C until analyzed.

Heart rate and electrocardiogram intervals were determined from 12-lead electrocardiogram measurements. The QT interval was corrected for heart rate using Bazett's correction.¹⁶ QT_c values were obtained just prior to dosing on days 1 through 5, 7 and 12 hours postdose on day 1, 7 hours postdose on days 2 through 4, and at 7, 24, 72, 144, and 480 hours after dosing on day 5.

Sample Assay
A sensitive and specific high-performance liquid chromatography (HPLC) assay was used to determine azimilide concentrations in blood and urine.³ In brief, lysed blood samples or urine samples were extracted with acetonitrile/methanol/ammonium acetate buffer, and the evaporated extract was reconstituted in mobile phase and injected into a reverse-phase HPLC system, with ultraviolet absorbance detection at 340 nm. The lower limit of quantitation was 5 ng/mL in blood and 100 ng/mL in urine. For azimilide in blood, the coefficient of variation (CV%) for quality control (QC) samples was less than 19.2% over the range from 10 to 750 ng/mL. For azimilide in urine, the CV% for QC samples was less than 19.9% over the range of 150 to 15000 ng/mL.

A sensitive and specific commercial enzyme-linked immunosorbent assay test kit (Boehringer Mannheim) was used to determine serum and urine digoxin concentrations. Serum or urine samples were added to tubes coated with antidigoxin antibodies, in the presence of digoxin conjugated to horseradish peroxidase. After incubation, excess reagents were removed by washing. The amount of bound complex directly affects color development, which is inversely proportional to the digoxin concentration in the sample. The lower limit of quantitation was 0.4 ng/mL in serum or urine. The CV% for serum digoxin QC samples was less than 4.8% over the range of 0.5 to 4 ng/mL. The CV% for urine digoxin QC samples was less than 8.1% over the range of 0.5 to 4 ng/mL.

Pharmacokinetic and Statistical Analysis
Pharmacokinetic parameters were determined using "noncompartmental" methods.^17,18 Maximum drug concentration (C_max) and the time at which C_max occurred (t_max) were determined by visual inspection of the individual drug concentration-time profiles. The terminal exponential rate constant (_Z) was estimated by linear least squares regression of the terminal phase of the log drug concentration-time profile. The terminal exponential half-life (t_1/2,Z) was obtained as 0.693/_Z. The area under the drug concentration-time curve over a dosing interval (AUC, 24-hour period following the day 5 dose) was determined using the linear trapezoidal rule. The area under the drug concentration-time curve over the entire dosage regimen (AUC_0-) was determined using the linear trapezoidal rule up to the last quantifiable concentration and extrapolated to infinity using the quotient of the last observed quantifiable concentration and _Z. Apparent clearance (Cl_O) was determined as dose/AUC. Apparent volume of distribution in the terminal phase (V_Z/F) was determined as Cl_O/_Z. Renal clearance (Cl_R) was determined as the amount of drug excreted in urine over the 24-hour collection interval following the day 5 dose (A_e), divided by AUC.

The influence of coadministration on azimilide and digoxin pharmacokinetics was assessed using an analysis of variance. The data for AUC and C_max were log-transformed prior to analysis. All other data were assessed for adherence to normality assumptions using the Shapiro-Wilks normality test for both the log-transformed and raw data. The models included terms for treatment, period, sequence, and subject within sequence effects, as well as first-order carryover. If the carryover effect was not significant at the = .10 level of significance, it was removed from the model. Treatment effects were assessed at the = .05 level of significance. The assumption that steady-state was attained by day 5 was assessed for both digoxin and azimilide using the model described above by comparing the day 5 AUC to the AUC_0- value adjusted for total administered dose for that treatment.

Pharmacodynamic Analysis
Because of the paucity of pharmacodynamic data, the relationship between QT_c and azimilide blood concentrations or digoxin serum concentrations was assessed using nonlinear mixed-effect modeling, with first-order conditional estimation (NONMEM, version IV).¹⁹ These relationships were assessed using a linear and an E_max model as shown in equations 1 and 2, respectively. Intersubject and intrasubject errors were assessed using an exponential error model.

(1)

(2)

where QT_c is the observed QT_c interval, K is the slope linearly relating concentration to QT_c, C is azimilide blood concentration or digoxin serum concentration observed concurrently with the QT_c, BL is the baseline QT_c, E_max is the maximum change in QT_c, and EC₅₀ is the concentration that results in one half the E_max.

For digoxin and azimilide, no apparent hysteresis was observed based on plots of QT_c versus digoxin serum concentration or azimilide blood concentration, connected by time. Therefore, an effect site equilibrium constant was not incorporated into the models. For azimilide, this observation is consistent with previous studies in which equilibrium half-lives were generally shorter than 1 minute.^20,21

Since no relationship was observed between QT_c and digoxin serum concentrations, the following mechanistic models of inhibition were used to assess the effect of digoxin serum concentrations (C_d) on the relationship between QT_c and azimilide blood concentrations: azimilide pharmacodynamics (1) competitive inhibition (effects on EC₅₀, equation 3), (2) noncompetitive inhibition (effects on E_max, equation 4), and (3) mixed inhibition (effects on both EC₅₀ and E_max, equation 5). Intra- and intersubject variability were estimated using an exponential error model.

(3)

(4)

(5)

View larger version (17K): [in this window] [in a new window]   Figure 1. Mean azimilide blood (A) and digoxin serum (B) concentration-time profiles following oral administration of 175 mg azimilide dihydrochloride daily for 4 days and 100 mg on day 5 (n = 18), 0.75 mg digoxin total dose on day 1 and 0.25 mg daily on days 2 to 5 (n = 17), or both treatments coadministered (n = 18).

Model selection included assessment of diagnostic plots for unacceptable residual trends and monitoring the objective function for a significant decrease as different interaction models were assessed. For hierarchical models, a change in the minimum value of the objective function of at least 3.84 ( = .05, 1 degree of freedom) was used to define statistical significance for the addition of a single interaction term. When alternative models could not be considered as hierarchical, the change in the objective function was used only as a qualitative measure of statistical significance, and model selection was based on analysis of residuals.

	RESULTS

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Subjects
Eighteen healthy, Caucasian volunteers were enrolled in the study. Although both male and female volunteers were eligible to participate in the study, all volunteers enrolled in the study were men. Mean ± SD age was 30 ± 3.7 years (range, 25-38 years), and the mean ± SD weight was 83 ± 6.4 kg (range, 71-97 kg). All 18 subjects who enrolled in the study were administered both azimilide dihydrochloride alone and azimilide dihydrochloride in combination with digoxin. Seventeen subjects were administered digoxin alone. One subject was withdrawn from the study due to alanine aminotransferase and aspartate aminotransferase elevations.

Azimilide Pharmacokinetics
Azimilide blood concentrations were similar for azimilide administered alone or with digoxin (Figure 1a). Achievement of steady state by day 5 for both treatments was supported by AUC values for azimilide within 11% of values expected at steady state and similarity of trough blood azimilide concentrations just prior to and 24 hours after the day 5 dose.

Azimilide pharmacokinetic results are shown in Table I. Treatment differences between azimilide dihydrochloride administered alone and in combination with digoxin were generally less than 6% and were not statistically significant for any azimilide pharmacokinetic parameter except for the 36% increase in Cl_R (P = .0325, Table II). However, coadministration did not result in a significant difference for Cl_O, consistent with renal clearance accounting for less than 10% of Cl_O.

Digoxin Pharmacokinetics
Digoxin serum concentrations were similar for digoxin given alone or in combination with azimilide (Figure 1b). As shown in Figure 1b, digoxin trough serum concentrations on days 2, 3, 4, and 5 were similar, indicating that a steady state was attained for both treatments.

Digoxin pharmacokinetic results are shown in Table II. There were no significant differences between treatments for digoxin pharmacokinetics, with the exceptions of a 10% increase in AUC (P = .0121) and a 20% increase in C_max (P = .0176; Table III). Despite the significant 10% increase in AUC, the 7% decrease in Cl_O did not achieve statistical significance (P = .0643).

Pharmacodynamics
Mean QT_c versus time is illustrated for all 3 treatments in Figure 2. Changes in QT_c following drug administration differed between treatments but were similar for subjects within each treatment. The largest maximal change was seen for azimilide alone. QT_c interval increased following azimilide administration, with a mean maximal increase of 44 milliseconds (about 11% greater than baseline values) observed following the last dose of azimilide alone.

View larger version (17K): [in this window] [in a new window]   Figure 2. Mean QTc versus time following oral administration of 175 mg azimilide dihydrochloride daily for 4 days and 100 mg on day 5, 0.75 mg digoxin total dose on day 1, and 0.25 mg daily on days 2 to 5, or both treatments coadministered.

For digoxin, no relationship was observed between QT_c and digoxin serum concentrations. For azimilide, an E_max model adequately characterized the relationship between QT_c and azimilide blood concentration. For the inhibition models tested, the maximum reduction in the objective function was obtained using a competitive inhibition model (29.8-point decrease). Inclusion of an inhibition constant on the E_max term (mixed inhibition model) did not further significantly decrease the objective function. The final pharmacodynamic parameter estimates for the competitive inhibition model are summarized in Table III. Based on this model, the QT_c associated with azimilide administration is decreased approximately 2% to 4% when azimilide is coadministered with digoxin (Figure 3).

View larger version (74K): [in this window] [in a new window]   Figure 3. Predicted QTc as a function of azimilide blood and digoxin serum concentrations.

	DISCUSSION

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Azimilide Cl_O was unchanged when coadministered with digoxin, although there was a statistically significant increase (36%) in azimilide Cl_R. Azimilide renal clearance is consistent with clearance via glomerular filtration and active secretion, although reabsorption cannot be excluded. Based on these renal clearance mechanisms for azimilide, an increase in renal clearance could occur if plasma protein binding is decreased. Although not assessed in the current study, changes in azimilide plasma protein binding would not be expected to occur since digoxin is not highly plasma protein bound (20% to 30%)¹¹ and did not appear to occur since other parameters in this study that are highly dependent on plasma protein binding showed no changes on coadministration (eg, oral clearance). Alternatively, an increase in azimilide renal clearance may also result from an increase in renal blood flow. Although digoxin has been reported to increase renal blood flow in patients with heart failure, its effect on renal blood flow in healthy subjects is unclear.^22-24 Regardless of the mechanism, since Cl_R accounts for only about 10% of Cl_O^2,3,6,20,21 and no change in oral clearance was observed, the change in Cl_R is not expected to be clinically important.

For digoxin, there was a statistically significant increase in the rate and extent of absorption when coadministered with azimilide, with C_max (rate) increased by about 21% and a 10% increase in AUC (extent). These changes in digoxin pharmacokinetics on coadministration with azimilide may be related to a decrease in p-glycoprotein-mediated export of digoxin from intestinal tissue, consistent with in vitro results indicating that azimilide is a weak inhibitor of p-glycoprotein-mediated transport in the rat intestine (IC₅₀ = 50 µg/mL).²⁵ However, these changes in AUC and C_max are also not likely to be clinically important since they were not associated with altered tolerance and are much less than the differences in commercially available dose sizes.

Azimilide prolonged the QT_c interval in all subjects. The effect of azimilide on the QT_c interval was similar to that observed in previous studies in which the predicted E_max ranged from 23% to 28% change from baseline, while EC₅₀ ranged from 432 to 566 ng/mL.^20,21 The range of EC₅₀ was similar to that observed for peak steady-state azimilide blood concentrations achieved with 100 mg/d of azimilide dihydrochloride.²¹ The observed prolongation in QT_c was slightly less upon coadministration with digoxin. This difference in QT_c prolongation appeared to be related to a 2-fold increase in the apparent EC₅₀ for azimilide when administered with digoxin, with no change in E_max. These changes are consistent with a competitive inhibition model (K_i = 0.899 ng/mL for digoxin). Based on these parameter estimates and the upper limit of digoxin plasma concentrations commonly observed in patients (0.5-2.0 ng/mL),²⁶ the QT_c associated with azimilide administration would decrease approximately 2% to 4% when coadministered with digoxin.

In conclusion, coadministration of azimilide and digoxin results in a 10% to 20% increase in digoxin serum concentrations and a 2% to 4% decrease in QT_c prolongation as compared with azimilide alone. Based on the magnitude of these changes, azimilide and digoxin coadministration is unlikely to result in clinically significant changes in efficacy and cardiovascular safety (QT_c), based on comparison with the profiles observed when each drug is administered alone.

	ACKNOWLEDGEMENTS

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The authors would like to acknowledge assistance from Rita Hust, MD, Laurent and the staff of Focus Clinical Development (Neuss, Germany) for their excellent work during the clinical conduct of the study. Procter & Gamble Pharmaceuticals provided funding for this study.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Toothaker, R. D. Articles by Powell, J. H. Search for Related Content PubMed PubMed Citation Articles by Toothaker, R. D. Articles by Powell, J. H. Social Bookmarking                   What's this?