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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Ayalasomayajula, Dr Yeh, Dr Vaidyanathan, Mr Flannery, Dr Howard, Dr Bedigian); Novartis Pharma AG, Basel, Switzerland (Dr Dieterich); and Novartis Institutes for Biomedical Research Inc, Cambridge, Massachusetts (Dr Dole).
Address for reprints: William P. Dole, MD, Novartis Institutes for Biomedical Research Inc, 400 Technology Square, Building 605-820, Cambridge, MA 02139.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1%) were similar or lower than placebo (4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.
Key Words: Aliskiren • moxifloxacin • QT interval • cardiac repolarization
Although there is a strong relationship between large increases (>60 milliseconds) in QT interval and the occurrence of drug-associated TdP,5 even modest increases in QT interval have been associated with TdP and sudden death.3,6 Consequently, detection of relatively small QT prolongations above the normal circadian variation over the course of 24 hours becomes important in assessing the risk of any new drug to induce proarrhythmia.7,8 Study design and methodology are critical because the QT interval shows a high degree of spontaneous variability in individuals and is affected by a number of different factors.9 The QT interval is heart rate dependent, with an inverse relationship. Consequently, a heart rate correction factor or function must be applied to the measured QT interval.10,11 Other important effects and variability on QT interval include age, gender, food intake, obesity, and circadian rhythm.9,12
The lack of a standardized approach to the design of studies examining QTc prolongation has, in the past, meant that the various factors affecting QTc interval were not always taken into consideration, making it difficult to assess the findings. The recent regulatory guidance developed by the International Conference on Harmonization (ICH) expert working group for adoption by regulatory bodies in Europe, Japan, and the United States was designed to address these issues by providing practical recommendations for the clinical evaluation of QT/QTc interval prolongation.7 Specifically, a placebo-controlled study designed to exclude a drug-related QTc effect of 10 milliseconds is recommended for drugs in clinical development. An active control, such as moxifloxacin, is included to determine and document the sensitivity of the experimental conditions of the study and the analysis techniques and procedures. ECGs are acquired in digital format to facilitate high-resolution measurement of the QT interval. Multiple ECGs at each time point (replicates) are obtained to improve the precision of the QTc point estimate.
Aliskiren is the first in a new class of oral direct renin inhibitors approved for the treatment of hypertension.13 Aliskiren has demonstrated effective blood pressure lowering in patients with mild-to-moderate hypertension in both short-term studies14-17 and long-term trials (up to 52 weeks) with aliskiren alone or in combination with hydrochlorothiazide.18,19 Aliskiren treatment was well tolerated, and standard ECG monitoring during all of these clinical trials showed no evidence of any adverse effects of aliskiren treatment on cardiac conduction or repolarization.20
Preclinical studies suggest a low risk of TdP with aliskiren. Aliskiren did not affect any action potential measures (including duration, repolarization, and instability) at concentrations up to 100 µmol/L (61 µg/mL) in an isolated rabbit heart assay. In an in vitro study using cloned human ether-a-go-go-related gene (hERG) channels expressed in mammalian cells, only supratherapeutic doses of aliskiren exhibited inhibition of IKr, the rapidly activating delayed rectifier potassium current (IC25 671 µmol/L). The risk of TdP with aliskiren is therefore very low, given that maximum plasma concentrations of aliskiren following a 300-mg oral dose are in the nanomolar range (500 nmol/L or 300 ng/mL). Findings from other hERG studies also suggest that drugs showing weak channel blockade (IC50 >100 µmol/L) are unlikely to be associated with TdP.5
The aim of the present study was to examine the effects of aliskiren on the ECG in healthy subjects by measuring changes in PR, QRS, and QT intervals at baseline and following drug administration. This study was designed in accordance with the latest regulatory guidance7 and examined the effects of aliskiren and placebo on cardiac repolarization and conduction using time-matched analysis of the change in QTc, PR, and QRS interval over the 23 hours following dosing. Secondary assessments included baseline-averaged analysis across the dosing interval. Aliskiren was examined at the highest approved therapeutic dose for hypertension (300 mg) and a 4-fold higher dose (1200 mg); moxifloxacin (400 mg), which is associated with a relatively small increase in QTc interval, was included as a positive control.21
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Prior to the treatment period (days 1-7), subjects underwent an initial assessment to establish baseline parameters (day –1). Following an overnight fast of at least 10 hours, all subjects received placebo at 0730 to 0830 hours and then underwent a series of ECG assessments over the following 23 hours. Subjects then received the assigned study medication for 7 days, administered in the morning following an overnight fast. On days 1 to 6, medication was administered at 0700 to 0800 hours, while on day 7 it was administered at the same time (±15 minutes) as on day –1. Subjects were confined to the study center from 2 days before the first dose of study medication until 48 hours after the last dose (ie, day –2 to day 9). Subjects then returned to the center to give blood samples for plasma drug concentrations on day 10 (72 hours after the last dose) and for a study completion assessment 4 to 8 days after the last dose of study drug (days 11-15).
The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol was approved by the local ethics committee/institutional review board (Independent Investigational Review Board Inc, Plantation, Florida), and all subjects provided informed written consent before participating in any study procedures.
Subjects
Subjects aged 18 to 65 years and in good health, as determined from their past and current medical history, physical examination, ECG, and laboratory tests at screening, were included in this study. Subjects had to weigh at least 50 kg and be within ±15% of normal body weight according to the Metropolitan Life Insurance tables. In addition, vital signs had to be within predefined limits at screening (oral body temperature 35.0°C -37.5°C; systolic blood pressure [SBP] 90-140 mm Hg; diastolic blood pressure [DBP] 50-90 mm Hg; pulse rate 50-90 bpm), and subjects had to show no evidence of postural hypotension (defined as >20 mm Hg decrease in SBP or a reduction in SBP 20 mm Hg associated with dizziness, light-headedness, or syncope within 3 minutes of moving from the supine to standing position).
Exclusion criteria included smoking; use of any prescription or over-the-counter medication (except for acetaminophen) or a significant illness within 2 weeks prior to dosing; medical history of clinically significant ECG abnormalities (defined as PR >240 milliseconds, QRS >110 milliseconds, or QTcB >450 milliseconds for men or >470 milliseconds for women); a family history of a prolonged QT interval syndrome; history of palpitations or fainting spells, acute or chronic bronchospastic disease, or autonomic dysfunction; clinically significant drug allergy; history or evidence of drug or alcohol abuse over the previous 12 months; or any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of the study drug. Female subjects had to be using adequate contraception.
Study Assessments
ECG assessments. ECGs were extracted in triplicate from a continuous 24-hour 12-lead ECG (Holter monitoring), which was obtained as a single tracing on day –1 and day 7 using a Mortara H-12 plus digital recorder (Mortara Instruments, Milwaukee, Wisconsin) and analyzed by a central facility (Electronic Research Technology, Philadelphia, Pennsylvania). ECGs were extracted predose (0 hours) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 23 hours postdose. The time points were chosen to provide ECG assessments across the dosing interval, with frequent evaluations covering the maximum plasma concentration of aliskiren based on the pharmacokinetic-pharmacodynamic profile of aliskiren at steady state. Recordings were made after the subject had been resting supine for 15 minutes. At each time point, 3 ECGs were extracted in 20-second windows (eg, 0-20, 21-40, and 41-60 seconds). RR, PR, QRS, and QT interval durations were determined from lead II by manual measurement using a high-resolution digitized ECG measurement system. For each ECG tracing, the interval duration was averaged across 3 cycles, and then the values from each of the 3 tracings were averaged to give the subject's mean interval duration at that time point.
The QTc interval was derived using Fridericia's formula (QTcF = QT.RR–1/3) and an individualized correction formula (QTcI) to correct for changes in heart rate. The individualized correction was based on each subject's QT-RR relationship at baseline, applying a log-linear correction (QT.RR–b), where b is the estimated slope (or correction factor) of the model Log(QT) = a + b*Log(RR).
Safety and tolerability assessments. Adverse events reported during the study were recorded and evaluated by the investigators for severity and possible relationship to study medication. Use of concomitant medications and significant nondrug therapies was also recorded. Evaluation of standard blood chemistry in addition to hematology and urine analyses was performed at screening, baseline, and 24 hours after dosing on day 7, while physical examination and vital signs assessments were performed at screening, baseline, and the end-of-study visit.
Aliskiren pharmacokinetics. Aliskiren pharmacokinetics were determined to evaluate any potential relationships between aliskiren exposure and changes in ECG intervals. Blood samples for plasma aliskiren concentrations were collected predose (0 hours) and at 3 hours postdose on days –1, 3, and 5. On day 7, blood samples were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose. Samples were collected into lithium-heparin tubes and centrifuged at 3°C to 5°C for 15 minutes at approximately 800g, and the plasma was removed and stored at –20°C or lower prior to analysis.
Plasma concentrations of aliskiren were determined by an HPLC/MS/MS method. The assay consisted of a solid-phase extraction on Oasis MCX cartridges using an automated system, followed by reversed-phase high-performance liquid chromatography using a MetaSil Basic 5-µm column (Metachem, Palo Alto, California).23 Detection was performed by MS/MS with electrospray ionization (ESI) using a TSQ Quantum Discovery (Thermo Finnigan, San Jose, CA) or an API 3000 (Applied Biosystems, Foster City, CA) mass spectrometer. The general settings used were as follows: selected reaction monitoring, positive ion mode, ESI interface; temperature 350°C for TSQ Quantum or 500°C for API 3000; mass resolution 0.7 amu; and scan time 0.20 seconds (TSQ Quantum) or 0.50 seconds (API 3000). The masses for aliskiren were precursor ion m/z 552 and product ion m/z 436. The lower limit of quantification for the assay was 0.5 ng/mL. The internal standard for this assay was [gem dimethyl-d6] aliskiren, a derivative of aliskiren. Within-study assay validation at nominal concentrations of 0.5, 1.0, 8.0, 80.0, and 400 ng/mL showed an assay precision (coefficient of variation) of 3.1% to 12.7% and a bias of –9.8% to 6.4%.
The area under the plasma concentration-time curve (AUC0-
), maximum observed plasma concentration (Cmax), and the time to reach Cmax (tmax) for both aliskiren groups were estimated using noncompartmental analysis (WinNonlin version 4.1; Pharsight Corp, Mountain View, CA), and descriptive statistics were presented for the pharmacokinetic parameters.
Statistical Analyses
Sample size. For the time-matched analysis, a total sample size of 232 subjects (58 per treatment group) was sufficient to show no QT prolongation from baseline (ie, upper 90% confidence limit for the difference in change in QT between treatment and placebo at any time point was less than 10 milliseconds) with 
80% power if the true mean difference was 3 milliseconds. For the baseline-averaged analysis, a sample size of 180 subjects (45 per treatment group) was needed to show no QT prolongation from baseline with 80% power if the true mean difference was 3 milliseconds.
QTc analyses. Central tendency analysis of the QTc interval data was performed by time-matched and baseline-averaged analysis. The time-matched analysis of the QTc interval was the primary study analysis, and 2 different methods were used to calculate the mean change from baseline. In the first method, the change from baseline was calculated by subtracting the average QTc value across all time points at baseline (day –1) from the day 7 value at each time point. In the second method, the average QTc value at each time point on day –1 was subtracted from the corresponding day 7 value. For the baseline-averaged analysis, the mean QTc values at baseline and day 7 were calculated from all of the time points. The maximum change from baseline, based on the maximum QTc value across all 14 time points for each subject, was also analyzed.
The primary endpoint for both time-matched and baseline-averaged analyses was the mean change in QTc interval from baseline. For these analyses, an analysis of variance-based t test on change from baseline was used to compare each active treatment versus placebo and generate a 90% confidence interval (CI) for each comparison. The threshold used to define no clinically relevant prolongation of the QTc interval was a mean difference of <5 milliseconds and a corresponding upper 90% CI of <10 milliseconds.7
Other cardiac conduction intervals (PR, QRS, and RR) were evaluated by time-matched analysis, baseline-averaged analysis, and maximum change analysis, as for the QTc data. The relationship between Cmax and AUC0- of aliskiren and QTcF and QTcI intervals observed at tmax was also examined.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Of the 298 subjects who received study medication, 20 discontinued prior to the end of the study. The number of discontinuations was similar across the 4 groups (aliskiren 300 mg, n = 4; aliskiren 1200 mg, n = 5; moxifloxacin, n = 7; placebo, n = 4), and the reasons for discontinuation were adverse events (8 subjects), withdrawal of consent (7 subjects), administrative problems (3 subjects), and lost to follow-up (2 subjects). All subjects who received at least 1 dose of study medication were included in the safety analysis (n = 298); individuals with an ECG assessment at baseline (day –1) and day 7 were included in the QT analysis (n = 283).
ECG Assessments
QTc. At baseline, mean QTcF values were similar across the 4 treatment groups at each of the 14 study time points during the 23-hour assessment period. In all 4 groups, QTcF intervals showed a similar circadian rhythm over the assessment period, with the highest and lowest mean values at 0900 to 1000 hours and 1600 hours, respectively (1-2 hours and 8 hours, respectively, after the initial assessment). The mean QTcF interval in the 4 groups ranged from 394 to 397 milliseconds at the lowest values and 405 to 407 milliseconds at the highest values. The mean QTc interval at baseline was significantly greater in female than in male subjects in each treatment group (P < .01). The baseline-averaged QTcF interval ranged from 408 to 412 milliseconds for female subjects compared with 385 to 396 milliseconds for male subjects in the 4 treatment groups; similar values were observed for QTcI (female, 406-413 milliseconds; male, 392-395 milliseconds).
Following administration of study medication, the mean QTcF interval was consistently longer across the posttreatment assessment period in the moxifloxacin group than in either the aliskiren groups or the placebo group. A comparison of each active treatment versus placebo using time-matched analysis (using the average baseline value for baseline subtraction) showed a significant prolongation in QTcF interval following moxifloxacin dosing (Figure 1a; Table II). The placebo-adjusted mean increase in QTcF from baseline exceeded 5 milliseconds at all assessments except at 14 hours after dosing. The greatest mean increases in QTcF were observed during the first 4 hours after dosing, with a second peak apparent at 8 hours postdose. In contrast, time-matched analysis showed no prolongation of QTcF interval with either aliskiren 300-mg or aliskiren 1200-mg dosing compared with placebo (Figure 1a; Table II). Placebo-adjusted mean values and upper 90% CIs were within the predefined limits (<5 milliseconds and <10 milliseconds, respectively) at all time points with only 1 exception: at 23 hours postdosing in the aliskiren 1200-mg group, the mean QTcF was greater than the 5-millisecond limit (mean 5.2 milliseconds; 90% CI 2.2, 8.1 milliseconds). Similar findings were observed for QTcI interval.
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Time-matched analysis showed that neither aliskiren 300 mg nor 1200 mg was associated with QTcI prolongation, whereas significant prolongation was observed with moxifloxacin treatment (Figure 1b; Table II). As with QTcF data, placebo-adjusted QTcI values exceeded the limits only at 23 hours postdosing in the aliskiren 1200-mg group (mean 5.0 milliseconds; 90% CI 2.0, 8.1 milliseconds).
Analysis using individual time-matched values for baseline subtraction (the second analysis method) produced comparable placebo-adjusted changes in QTcF and QTcI. Moxifloxacin showed QT prolongation at all time points except 14 hours postdose, while only the mean QTcF and QTcI values for aliskiren 1200 mg at 23 hours were outside the limits indicating prolongation (5.8 and 5.2 milliseconds, respectively).
Baseline-averaged analysis of the QTc data, based on the mean QTc interval averaged across all 14 postdosing time points, showed no significant prolongation of either QTcF or QTcI interval on day 7 with aliskiren 300-mg or 1200-mg treatment. In the aliskiren 300-mg group, placebo-adjusted mean (90% CI) changes of 1.3 milliseconds (–0.8, 3.4) in QTcF interval and 0.4 milliseconds (–1.9, 2.7) in QTcI interval were observed. In the aliskiren 1200-mg group, values were 1.5 milliseconds (–0.6, 3.6) and 1.4 milliseconds (–0.8, 3.7) for QTcF and QTcI, respectively. In contrast, moxifloxacin resulted in a significant (P < .001) prolongation of the QTc interval, producing mean placebo-adjusted increases of approximately 10 milliseconds for both QTcF and QTcI.
Analyses of QTc interval data by gender showed similar results for male and female subjects. Time-matched analysis showed that moxifloxacin was associated with significant QTc prolongation, with increases outside the limits at most postdosing time points in both male and female subjects. The increases in female subjects tended to be larger than in male subjects during the first 8 hours postdose; the largest increase in QTcF (3 hours postdose) was 19.3 milliseconds in women compared with 14.4 milliseconds in men. Aliskiren 300 mg and 1200 mg showed no QTc interval prolongation in either men or women, with values within limits at almost all time points. Baseline-averaged results were also consistent with the overall findings. Placebo-adjusted mean increases in QTcF showed QTc prolongation with moxifloxacin in both male and female subjects; increases tended to be larger in women (11.8 milliseconds) than in men (8.8 milliseconds). This compared with increases of 1.2 and 1.3 milliseconds for male and female subjects, respectively, with aliskiren 300 mg, and 1.8 milliseconds (men) and 1.0 milliseconds (women) with aliskiren 1200 mg.
The maximum change from baseline analysis for QTc showed no significant prolongation with aliskiren 300 mg or 1200 mg but a significant (P < .001) increase with moxifloxacin treatment, consistent with the time-matched and baseline-averaged analyses. Placebo-adjusted mean increases in QTcF were 1.2 milliseconds with aliskiren 300 mg, 2.0 milliseconds with aliskiren 1200 mg and 10.9 milliseconds with moxifloxacin treatment. The corresponding QTcI values were 0.0 milliseconds, 2.3 milliseconds, and 11.3 milliseconds, respectively. Analysis of the change in QTc interval at tmax for the aliskiren groups also showed no significant QTc prolongation with either dose compared with placebo. Placebo-adjusted increases in QTcF were 2.0 milliseconds and 1.6 milliseconds for aliskiren 300 mg and 1200 mg, respectively, while the corresponding increases in QTcI were 1.6 milliseconds and 1.4 milliseconds.
Categorical analysis examining the proportion of subjects in each group with a QTc interval greater than 450 milliseconds, 480 milliseconds, and 500 milliseconds showed that few subjects in any of the 4 groups had a QTcF or QTcI interval exceeding 450 milliseconds during the study (Table III). Only 1 subject (moxifloxacin) experienced a QTc interval of >480 milliseconds, and no subject had a QTc interval >500 milliseconds during the study. An increase in QTc interval of >30 milliseconds from baseline was seen more frequently in subjects in the moxifloxacin group (15%-17%) than in the other treatment groups (3%). None of the subjects in the study had an increase of >60 milliseconds in QTcF or QTcI interval (Table III).
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Other ECG parameters. Time-matched analysis showed no significant changes from baseline in PR interval with aliskiren 300 mg, aliskiren 1200 mg, or moxifloxacin treatment compared with placebo at any time point (Figure 2). Similarly, time-matched analysis of the QRS interval showed no significant changes between any active treatment group and placebo, with the exception of a significant reduction in QRS interval with moxifloxacin compared with placebo at 5 hours postdosing (P = .035; Figure 2). Baseline-averaged analysis showed placebo-adjusted mean changes of less than 1 millisecond for PR (aliskiren 300 mg, –0.9 milliseconds; aliskiren 1200 mg, –0.3 milliseconds; moxifloxacin, +0.5 milliseconds) and QRS (aliskiren 300 mg, +0.6 milliseconds; aliskiren 1200 mg, –0.5 milliseconds; moxifloxacin, –0.7 milliseconds). All 3 active treatments reduced RR interval compared with placebo. Placebo-adjusted decreases in RR ranged from 16.3 to 44.6 milliseconds for aliskiren 300 mg, 20.6 to 69.1 milliseconds for aliskiren 1200 mg, and 1.7 to 54.8 milliseconds for moxifloxacin, with significant reductions (P < .05) versus placebo observed at 4, 12, and 9 time points after dosing, respectively.
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Pharmacokinetic Assessments
Pharmacokinetic parameters for aliskiren following daily administration for 7 days showed a median tmax of 1.9 and 1.6 hours for the 300-mg and 1200-mg doses, respectively. Cmax was approximately 4.5-fold greater with the 1200-mg dose (1115.2 ng/mL) compared with the 300-mg dose (246.1 ng/mL); AUC0- was higher in the aliskiren 1200-mg group (12487 ng •h/mL) than the 300-mg group (2158 ng •h/mL). No correlation was observed between the change in QTc interval at tmax and either AUC0- or Cmax for the aliskiren 300-mg and 1200-mg treatment groups (Figure 3).
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None of the subjects reported a serious adverse event while on study medication. One subject became pregnant during the placebo run in, which was recorded as a serious adverse event, and the subject was discontinued from the study. There were few discontinuations due to adverse events during the study (overall, n = 8 [2.7%]). Two subjects discontinued from the placebo group, 1 due to dizziness and 1 due to light-headedness and tightening in the lower chest. In the aliskiren 300-mg group, there were 3 discontinuations: 1 due to severe fatigue, 1 due to gastrointestinal events and dizziness, and 1 due to palpitations, anxiety, and an episode of vasovagal syncope. Two subjects discontinued from the aliskiren 1200-mg group (diarrhea, mild headache) and 1 from the moxifloxacin group (backache).
No clinically significant laboratory abnormalities or vital sign measurements were observed during the study period. Mean SBP and DBP values were similar across all 4 treatment groups at baseline (Table I). Small decreases in mean SBP and DBP from baseline were observed in the aliskiren groups over the 7-day treatment period (300 mg, 3.1/3.2 mm Hg; 1200 mg, 5.4/4.2 mm Hg), while decreases of 1.0 to 1.4 mm Hg in both mean SBP and DBP were seen in the moxifloxacin and placebo groups. Transient blood pressure reductions were also observed following aliskiren dosing, with decreases of 3.5 to 4.9 mm Hg observed at 8 hours after dosing.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The results show that, with the exception of one of the time points over the 23-hour assessment period in the aliskiren 1200-mg group, the mean changes from baseline in QTc interval and upper 90% CIs were within the predefined limits (5 milliseconds and 10 milliseconds, respectively) with both aliskiren doses compared with placebo. These findings demonstrate no clinically relevant prolongation of the QTc interval with aliskiren at up to 4 times the maximum therapeutic dose.
In contrast to aliskiren, the mean change in QTc interval and upper 90% CI with moxifloxacin compared with placebo indicated significant prolongation of the QTc interval. In earlier clinical studies, moxifloxacin 400 mg has been associated with an increase in QTc interval of 6 to 10 milliseconds,21 just above the threshold for clinically relevant QTc prolongation. Consequently, moxifloxacin is widely used as a positive control in studies examining the effects of medication on cardiac repolarization.24-28 The changes in QTc observed with moxifloxacin in the current study are a clear indication of the sensitivity of the study to detect clinically relevant increases in QTc interval.
In this study, there was no evidence of increased QTc duration with increasing aliskiren exposure. No correlation was observed between QTc interval at tmax and either Cmax or AUC0- of aliskiren. The Cmax and AUC0- values observed with aliskiren 300 mg were consistent with those reported in previous pharmacokinetic studies.29-31 In a series of drug-drug interaction studies, less than 2-fold increases in aliskiren exposure were observed with coadministration compared with aliskiren administered alone, with most studies reporting increases of <30%.31-33 Renal impairment was associated with up to 2-fold increases in aliskiren Cmax and AUC, but changes in exposure did not correlate with the severity of renal impairment29; hepatic impairment had little effect on aliskiren exposure (<20% increases).34 Thus, aliskiren exposure following administration of the approved 150- or 300-mg oral doses in clinical practice, even in the presence of concomitant medications or hepatic or renal impairment, would be expected to be well within the range reported for the 300-mg and 1200-mg doses in this study.
With moxifloxacin, the largest placebo-adjusted mean changes in QTc were observed during the first 4 hours after dosing, consistent with the pharmacokinetic profile of oral moxifloxacin, showing a tmax of 0.5 to 4.0 hours and half-life of approximately 12 hours.35-37 Moxifloxacin, in common with other fluoroquinolones, undergoes enterohepatic recirculation, with drug eliminated into the gastrointestinal tract undergoing reabsorption.38 It is possible that the second, smaller increase in mean changes in QTc interval seen at 8 hours after dosing reflects this. In a previous study, moxifloxacin showed significant QTc prolongation at tmax compared with placebo and a clear trend toward increased QTc prolongation with increasing moxifloxacin exposure.24
The results of the baseline-averaged and maximum change analyses of QTc interval are consistent with those from the primary (time-matched) analysis. Both analyses at day 7 showed no significant increase in mean QTc interval from baseline in either aliskiren group compared with placebo, whereas moxifloxacin treatment was associated with significant QTc prolongation over placebo. The increases in QTc interval with moxifloxacin observed in the current study are consistent with previous studies, which have reported placebo-adjusted mean increases in QTcF of 6.9 milliseconds24 and 9.2 milliseconds26 with moxifloxacin using baseline-averaged analysis during the 24 hours after dosing.
Female subjects had a significantly longer QTc interval at baseline in this study, consistent with the known effects of gender on QT interval duration.22 Evidence also suggests that women are more susceptible to drug-induced QT interval prolongation and TdP than men,39 with 65% to 75% of drug-induced TdP occurring in women.40,41 For a number of drugs, there is substantial evidence for gender differences in the risk of QT prolongation and TdP.40 No differences were observed between male and female subjects in the effects of aliskiren on QTc interval prolongation, although the increases in QTc interval in the moxifloxacin group tended to be larger in female subjects than in male subjects. The differing susceptibility to QT interval prolongation raises the possibility that drug effects could be underestimated if only small numbers of female subjects are included in the study population. Indeed, a recent study evaluated the risk of QTc prolongation with duloxetine solely in female subjects because of their increased exposure to the drug and increased susceptibility for QT prolongation.28
The correction factor used to adjust the QT interval for heart rate has the potential to affect study findings, given the potentially small changes in QT interval examined. In the European Amiodarone Myocardial Infarction Trial, QTc prolongation with amiodarone ranged from 15 to 30 milliseconds depending on the correction factor used,10 representing a considerable variation in the risk assessment for TdP.8 Bazett's correction factor is still widely used in clinical trials, although it has been shown to overcorrect at high heart rates and undercorrect at low heart rates.5,42 Fridericia's formula provides a more accurate method of correcting heart rate,11,43 but as with all correction factors that use a set QT-RR relationship, it will not be optimal for all subjects because of individual variation in the QT-RR relationship. Adjustments based on correction factors (QTcI) derived from the individual's own QT-RR data are designed to overcome these limitations. Guidance from the ICH recommends the use of several correction factors, including Fridericia and individualized formulae.7 In the current study, there was good agreement between the QTcF and QTcI data. However, this will not necessarily be the case for all populations, particularly those with a high degree of heart rate variation or in cases in which there is a large difference in heart rate between baseline and treatment periods. In these cases, QTcF may not provide adequate heart rate correction for all subjects; a correction factor based on individual patient data may provide a more accurate assessment of changes in QTc interval duration.
Although there is no clear consensus regarding the upper limit above which the QTc interval is of particular concern, QTc intervals >500 milliseconds carry a greater risk of triggering ventricular arrhythmias, including TdP.8 The ICH guidelines recommend QTc values exceeding 450, 480, and 500 milliseconds and increases of >30 milliseconds and >60 milliseconds from baseline for categorical analyses.7 In the current study, none of the subjects experienced a QTc interval >500 milliseconds or an increase >60 milliseconds from baseline, and only 1 subject had a QTc interval >480 milliseconds (moxifloxacin group). QTc intervals >450 milliseconds or increases of >30 milliseconds were infrequent in both aliskiren groups (3%), occurring at a similar or lower incidence than with placebo.
Although the recent focus of cardiac safety studies has been on QTc interval, changes in PR and QRS intervals may indicate a potentially important effect of treatment on cardiac conduction. In the current study, aliskiren and moxifloxacin treatment did not affect cardiac conduction, as shown by the lack of significant changes in the PR and QRS intervals compared with placebo across the assessment period. The decreases in RR interval seen with aliskiren treatment compared with placebo may reflect a small baroreceptor-mediated change in sympathetic activity in response to the effects of renin inhibition in healthy normotensive subjects.
Aliskiren was well tolerated during the study at the 300-mg dose, the maximum dose approved for the treatment of hypertension, with the most common adverse events being headache, dizziness, and diarrhea. Adverse events were mostly mild or moderate in intensity and were consistent with the adverse event profile observed in clinical trials involving patients with hypertension.14 Aliskiren has been shown to be generally well tolerated in hypertensive patients at the maximum approved dose of 300 mg in both short-term15,16 and long-term clinical trials.18,19 Gastrointestinal events (mainly diarrhea, loose stools, and nausea) were relatively common with the 1200-mg aliskiren dose.
In conclusion, aliskiren administered at the highest approved therapeutic dose (300 mg) and a 4-fold higher dose (1200 mg) had no effect on cardiac repolarization (QTc interval) or conduction (PR and QRS intervals) following daily dosing for 7 days in healthy volunteers.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was supported by Novartis Pharma AG, Basel, Switzerland. All of the authors are employees of Novartis and thus are eligible for stock and stock options.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10): 1013-1022.
2. Yap YG, Camm J. Risk of torsades de pointes with non-cardiac drugs: doctors need to be aware that many drugs can cause QT prolongation. BMJ. 2000;320(7243): 1158-1159.
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