Gary A. Thompson, PhD, Clinical Pharmacology and Pharmacokinetics, Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040–9462, USA. Tel.: + 1513 622 3058; Fax: + 1513 622 5333; E-mail: firstname.lastname@example.org
Aims To assess the influence of severe renal impairment on azimilide pharmacokinetics.
Methods A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22–28 and 10 days, respectively.
Results Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h−1 kg−1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h−1 kg−1, 95% confidence interval on the ratio 0.67, 1.36) was observed.
Conclusions Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.
Azimilide dihydrochloride is a Class III antiarrhythmic, which is being developed for use in prolonging the time to recurrence of atrial fibrillation and flutter and as adjunctive therapy in patients with an implantable cardioverting defibrillator .
Following intravenous administration, azimilide undergoes extensive metabolism with approximately 10% excreted unchanged in urine . Total clearance is 0.136 l h−1 kg−1, renal clearance is 0.013 l h−1 kg−1 (consistent with filtration and active secretion), steady-state volume of distribution is 12.9 l kg−1; and terminal exponential half-life is 71.4 h. Following oral administration, azimilide is completely absorbed with peak blood concentrations occurring at approximately 7 h.
Azimilide metabolic clearance is mediated via multiple pathways including cleavage (30%) CYP 1A1 (up to 25%) and CYP 3A4 (up to 25%) . F-1292, the major metabolite of azimilide in plasma, is formed by cleavage of the azomethine bond and does not possess cardiovascular activity . Minor metabolites in plasma include desmethyl azimilide, azimilide N-oxide and azimilide carboxylate, which have approximately 20%, 11% and 0% of the Class III antiarrhythmic activity of the parent drug in vitro, respectively . Since plasma concentrations of these three metabolites are generally less than 10% of azimilide, they do not contribute measurably to antiarrhythmic activity .
The target population for azimilide therapy includes patients with renal impairment. Although a decrease in renal clearance is commonly expected in renal impairment , alterations in metabolic clearance have also been observed [5, 6]. Therefore, the purpose of this study was to investigate the influence of severe renal impairment on azimilide pharmacokinetics.
This was an open-label, single dose study conducted in subjects with chronic, stable severe renal impairment (creatinine clearance: 10–40 ml min−1) and in healthy volunteers (creatinine clearance within age-adjusted normal limits). For each renally impaired subject, a healthy volunteer was enrolled who was matched by age (± 10 years), weight (± 15%), and gender.
The study was conducted at the Orlando Clinical Research Center (Orlando, FL, USA) and at the Center for Clinical Research (Austin, TX, USA). All procedures were conducted in accordance with the Declaration of Helsinki and its amendments. The protocol and written consent form were approved by the Columbia Park Medical Center Institutional Review Board (Orlando, FL, USA) and the Research Consultants’ Review Committee (Austin, TX, USA). All subjects signed informed consent forms prior to participation and were institutionalized 1 day prior to and for 48 h after dosing.
Twenty-four subjects were enrolled and all completed the study. Subject characteristics (mean ± s.d.) for the renally impaired group were: age = 51 ± 11 years; weight = 82.5 ± 18.3 kg; and creatinine clearance = 23 ± 10 ml min−1. Eleven of the 12 participants were male; two were Hispanic, five were African American and five were Caucasian. Subject characteristics (mean ± s.d.) for subjects with normal renal function were: age = 52 ± 11 years; weight = 84.1 ± 13.4 kg; and creatinine clearance = 109 ± 30 ml min−1. Eleven of the 12 participants were male, one was African-American and 11 were Caucasian.
Subjects fasted from 10 h prior to and for 4 h after dosing. Subjects were orally administered 125 mg azimilide dihydrochloride (tablet) with 240 ml water. Blood samples (sodium heparin) were collected prior to dosing and at 0.5, 1, 4, 5, 6, 7, 8, 10, 12, and 24 h, as well as 2, 3, 4, 5, 7, 10, 13, 16, 19 and 22 days after dosing. Additional blood samples were obtained on days 25 and 28 in renally impaired subjects. Azimilide plasma protein binding was assessed at 7 h. Urine samples were pooled over 24 h intervals prior to and for 10 days after dosing. Samples for azimilide and metabolite analyses were frozen at −20 °C until analysed except for F-1292, which was stored at −80 °C. Creatinine clearance was determined from the first 24 h urine sample after dosing and a 12 h serum creatinine concentration.
Safety assessments included electrocardiography, vital signs, clinical laboratory tests, haematology and subject interviews. Whether spontaneously reported by the subject or determined by the clinical investigator, all adverse events (AEs) occurring subsequent to drug administration were documented and categorized as mild, moderate or severe, based on the investigator's clinical judgement. Causality was also classified by the clinical investigator as either doubtfully, possibly or probably drug-related.
Azimilide, desmethyl azimilide and azimilide carboxylate were assayed simultaneously in blood and urine using a method similar to that previously reported . For this study, blood samples were subjected to solid phase extraction (C8/SCX) instead of liquid/liquid extraction. All analytes were subsequently quantified using h.p.l.c. (C8 column) with u.v. detection at 340 nm. The lower limit of quantification for each analyte in blood and urine was 5 and 50 ng ml−1, respectively and %CVs were less than 10% and less than 6%, respectively.
F-1292 and F-1292 β-acyl glucuronide (following NaOH hydrolysis) in plasma and urine were analysed using liquid-liquid extraction with subsequent quantification using h.p.l.c. (C8 column) with u.v. detection at 300 nm. F-1292 β-acyl glucuronide concentrations were determined based on differences in molecular weight adjusted F-1292 concentrations prior to and following hydrolysis. The lower limit of quantification for plasma and urine were was approximately 10 and 20 ng ml−1, respectively and %CVs were less than 11%.
Azimilide binding to plasma proteins was determined at 37 °C using equilibrium dialysis as previously described . %CVs were less than 6%.
Pharmacokinetic and statistical methods
Pharmacokinetic parameters were determined by ‘noncompartmental’ analysis [8, 9]. The maximum blood/plasma concentration (Cmax) and time to maximum concentration (tmax) were determined from visual inspection of the data. Area under the blood/plasma concentration-time curve from time 0 until the last quantifiable concentration (AUC(0,tlast) was determined by the linear trapezoidal rule. The remaining area was determined by dividing the predicted concentration at the time of the last quantifiable concentration by the terminal exponential rate constant. AUC was defined as the sum of these two areas. The terminal exponential rate constant (λz) was determined from linear regression analysis of data points during the terminal exponential phase of the blood/plasma concentration-time data. Terminal exponential half-life (t1/2,z) was calculated from the relationship t1/2,z = ln2/λz. Renal clearance (CLR) was obtained from the cumulative amount excreted in urine and the corresponding area under the blood concentration-time curve over the same interval. Oral clearance (CLo) and terminal volume of distribution (Vz/F ) were obtained using standard equations.
For each parameter, the difference in the log-transformed data for each matched subject pair was calculated. The corresponding standard error of the difference was used to construct a 95% confidence interval on the difference, and the antilogs of the confidence limits were used to obtain a 95% confidence interval for the ratio of severe renal impairment to normal renal function. Linear regression was also used to investigate relationships between various pharmacokinetic parameters and creatinine clearance .
Table 1 summarizes the pharmacokinetic parameters for azimilide and F-1292 and the statistical assessment of the influence of renal impairment. The concentrations of the other metabolites were generally below the lower limit of quantification. Figure 1 illustrates the relationships between azimilide renal (panel a) and oral (panel b) clearance and creatinine clearance (CLCr).
Table 1. Geometric mean (CV%) azimilide and F-1292 pharmacokinetic parameters in subjects with impaired and normal renal function following single dose oral administration of 125 mg azimilide dihydrochloride.
Severe renal impairment
Normal renal function
95% confidence interval
AUC is the area under the concentration-time profile from time zero to infinity; Cmax is the maximum concentration; tmax is the time that the maximum concentration occurs; t1/2,z is the terminal exponential half-life; CLo is oral clearance; CLR is renal clearance; Vz/F is the terminal volume of distribution; and fb is the fraction of drug bound to plasma proteins.
(ng ml−1 h)
(ml h−1 kg−1)
(ml h−1 kg−1)
(ng ml−1 h)
Four subjects in the renally impaired group and three subjects in healthy group had nine and five adverse events, respectively. All were mild or moderate. Only diarrhoea and headache occurred in more than one subject. Headache occurred in two healthy subjects (one considered possibly related to the drug) and diarrhoea occurred in one renally impaired and in one healthy subject.
The influence of severe renal impairment on azimilide pharmacokinetics was assessed in the present study. Since its pharmacokinetics are linear , single-dose data were adequate for this purpose .
Pharmacokinetic parameters for azimilide observed in this study for healthy subjects are consistent with those reported elsewhere . Our results indicate that the oral clearance of azimilide is not significantly affected by renal impairment. As expected, renal impairment did decrease the renal clearance of the drug. However, renal clearance only comprises about 10% of total clearance.
Following administration of azimilide, a 3.3 fold increase in F-1292 AUC was observed in subjects with severe renal impairment, and a similar increase would be anticipated at steady-state. Since no significant change in azimilide oral clearance was observed, the 3.3 fold increase probably reflects a decrease in F-1292 clearance rather than an increase in its formation clearance. Based on previous clinical studies, F-1292 is well tolerated at concentrations approximately 70 fold higher than those observed at steady-state following therapeutic dosing regimens of azimilide to patients with normal renal function. Thus severe renal impairment induced changes in F-1292 concentrations is not expected to be clinically important .
In conclusion, since azimilide blood concentrations (bound and unbound) are essentially unaffected by renal function and its metabolite F-1292 was well tolerated in a previous study at steady-state concentrations approximately 20 fold higher than anticipated in patients with renal impairment, an a priori dosage regimen adjustment is not required in these patient.