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CLINICAL STUDIES |
From Exploratory Clinical Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Address for reprints: Denise B. Serra, Exploratory Clinical Development, 435/1159, One Health Plaza, East Hanover, NJ 07936-1080.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Darifenacin • overactive bladder • QT interval • cardiac repolarization
During the past decade, increasing regulatory scrutiny has focused on noncardiac drugs that affect cardiac function, particularly those that delay cardiac repolarization because of a blockade of ion channels. Such delay is manifested on a surface electrocardiogram (ECG) as prolongation of the QT interval, which represents the time taken for electrophysiological depolarization and repolarization of the ventricles. Many structurally unrelated drugs in different therapeutic classes have been found to prolong the QT interval, including terodiline (previously indicated for unstable bladder and withdrawn in 1991), moxifloxacin, terfenadine, astemizole, grepafloxacin, droperidol, lidoflazine, sertindole, levomethadyl and cisapride.10-12 QT prolongation is a cause for concern because it has been associated with the development of potentially life-threatening polymorphic ventricular tachyarrhythmia, or torsades de pointes (eg, as reviewed by Roden).10 Risk factors for such drug-induced arrhythmia include female gender, older age, hypokalemia, bradycardia, and polypharmacy.10,11
The objective of this study was to evaluate conclusively the effects on QT interval of once-daily administration of therapeutic and supratherapeutic doses of darifenacin (to steady state) in healthy volunteers. Because QT intervals correlate with heart rate, treatment effects should be evaluated at a standard heart rate, normally 60 beats per minute. The most commonly used correction formulae, Bazett and Fridericia, were explored to obtain corrected QT (QTc). However, Fridericia correction (QTcF) was preselected as the primary QTc because of deficiencies in Bazett correction (QTcB).13-15
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The supratherapeutic (75 mg) dose of darifenacin was chosen to give 
5 times the mean steady-state exposure observed in CYP2D6 poor metabolizers receiving 15 mg (the highest therapeutic dose), thus exceeding the worst-case scenario of overexposure to darifenacin. Based on the clinical pharmacokinetics of controlled-release darifenacin (half-life, 13-19 hours with chronic dosing),19 6 days of study drug administration was estimated to achieve 98% of steady-state levels. To better reflect OAB treatment demographics and to ensure adequate representation of CYP2D6 polymorphism, subjects were stratified during enrollment by gender, age (18-44 and 45-65 years) and CYP2D6 phenotype (poor and extensive metabolizers), resulting in 8 cohorts. Within each cohort, subjects were randomized evenly to the 4 treatment arms. Exclusion criteria included cardiac disease, blood pressure outside 90-180/50-100 mm Hg, resting heart rate exceeding the range 50 to 100 beats per minute, body weight more than 15% outside normal for height and frame size, and relevant findings in physical examination, routine laboratory tests or ECG including a QTc interval (Bazett formula) greater than 470 milliseconds (women) or greater than 450 milliseconds (men).
CYP2D6 Phenotype/Genotype Determination
Subjects were classified as phenotypic CYP2D6 poor metabolizers if their plasma dextromethorphan: dextrorphan ratio was greater than 0.30, 2 hours after ingestion of 60 mg dextromethorphan (30 mL Robitussin-DM syrup). CYP2D6 genotype was determined in a blinded fashion by Genaissance Pharmaceuticals Corporation (Morrisville, NC) using polymerase chain reaction (PCR) with genomic DNA isolated from whole blood and primers specific for alleles *3, *4, *6, *7, and *8. The occurrence of allele *5, a complete deletion of the CYP2D6 locus, was assessed using long-range PCR with heterozygote status determined by signal intensity. Alleles *3 through *8 are classified as null alleles20 and, in the absence of other alleles, were predicted to confer poor metabolizer phenotype. As a result of a protocol amendment partway through the screening phase, some subjects were also genotyped for alleles *10 and *17 using PCR with allele-specific primers. Alleles *10 and *17 are classified as decreased-activity alleles20 and were predicted to confer extensive metabolizer phenotype. Alleles not amplified in the above tests were assumed to confer extensive metabolizer phenotype. Functional phenotype was the deciding criterion for CYP2D6 stratification.
Study Conduct
This study was conducted in accordance with the Declaration of Helsinki21 and good clinical practice as described in the US Code of Federal Regulations and the Arkansas Research Institution Review Board. After determination of CYP2D6 phenotype, subjects participated in a 21-day screening period before randomization. Subjects were then confined to the study site (Arkansas Research, 207 Rebsamen Park Road, Little Rock, Ark) for a 1-day placebo run-in (day-1) followed by a 6-day treatment period (days 1-6). No medication other than the study drug was allowed from 14 days before the study to study end.
Pharmacokinetic Assessments
Blood samples were collected each day predose and on day 6 at 1,2,3,4,5,6,7,8,10,12,14 and 24 hours postdose. Trough measurements (ie, those immediately before dosing) were made to verify darifenacin steady-state concentrations. Darifenacin (limit of quantitation, 0.1 ng/mL) and moxifloxacin (limit of quantitation, 25 ng/mL) plasma concentrations were determined using liquid chromatography followed by mass spectrometry.22 The concentration-time curve was determined for 24 hours on day 6 to provide maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and area under the curve (AUC0-24).
ECG Recordings
Standard 12-lead ECGs, including three 10-second lead II rhythm strips, were collected digitally in triplicate on days-1 and 6 using Mortara H-12 plus equipment (Mortara Instruments, Milwaukee, Wis) at the following times: predose and 1,2,3,4,5,6,7,8,10,12,14 and 24 hours postdose. Trained analysts at a central facility (eRT, Philadelphia, PA) assessed ECGs in a blinded fashion. At each time point, 3-beat ECGs were extracted in three 20-second windows (eg, 0-20, 21-40, and 41-60 seconds). Mean interval values for each time point were determined by manual digitization of the 9 beats using a high-resolution digitized ECG measurement system.
Safety Measurements
Self-reported adverse events were recorded from the time of starting the study drug. Vital signs were measured on days -2, -1, 1, 3, 5 and 7, and samples for standard clinical laboratory evaluations were collected on days -2, 1, 4, 6, and 7, after an overnight fast.
Statistical Evaluations
The study was powered to detect a 5-millisecond change from mean baseline in QTcF at Tmax of darifenacin groups versus placebo, based on a 2-sided, 2-sample t test at 5% significance level. Variability information on QTcF at Tmax with darifenacin was derived from previous clinical pharmacology studies. Assuming a standard deviation of not more than 8 milliseconds, a sample size of 45 subjects per treatment group ensured 90% power to detect a 5-millisecond increase between darifenacin and placebo. The primary end point in this study was the change from mean baseline in QTcF at Tmax, based on the ECG recording taken at the time corresponding to each subject's Cmax. Secondary end points were mean change from baseline in QT/QTcF and maximum QT interval postdose change from baseline. End points were compared between on-drug and placebo treatments in the analysis of covariance (ANCOVA), using treatment as the model factor and baseline value as the covariate. Baseline for each subject was taken as the mean of all QTc measurements on day-1. The conclusion about a nonclinically meaningful QT-prolonging effect was based on the noninferiority test criterion that upper limit of the 90% confidence interval for the true difference compared with placebo not being greater than 8 milliseconds.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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CYP2D6 Phenotype/Genotype
CYP2D6 phenotype was assessed in 2046 subjects. A total of 58 subjects (2.8%) were identified as poor metabolizers, of whom 32 enrolled in the study. Concordance between phenotype and genotype in subjects enrolled in the study was 91% (172 of 188 subjects).
Fifteen phenotypic poor metabolizers were predicted to be extensive metabolizers based on genotype. Of these 15 subjects, 11 carried at least 1 allele not represented in the test panel, and 4 carried a null allele together with the reduced-activity allele *17. Of these 15 subjects, 14 were African American, and 1 was Caucasian. The remaining 17 phenotypic poor metabolizers in the study were correctly identified by the genotyping protocol. Of these 17 subjects, 12 were Caucasian, and 5 were African American. All 17 carried 2 null alleles (*3, *4, *5, or *6).
One phenotypic extensive metabolizer was predicted to be a poor metabolizer based on genotype. The PCR results indicated that this subject was homozygous for the null allele *4. In all cases, phenotype was the deciding criterion for CYP2D6 stratification.
Pharmacokinetics
Darifenacin trough concentrations (ie, those immediately before dosing) during the dosing period verified that steady-state pharmacokinetics was achieved by day 3 (Table II). Mean pharmacokinetic parameters on day 6 are shown in Table III. After oral administration, darifenacin plasma concentration rose slowly and reached a peak at 7 to 10 hours. The difference in mean darifenacin exposure between CYP2D6 phenotype groups was low compared with the difference between the 15 mg and 75 mg groups. Mean darifenacin exposures in CYP2D6 poor metabolizers were 1.7 times and 1.2 times greater than in CYP2D6 extensive metabolizers at 15 mg and 75 mg doses, respectively, and there was a high degree of overlap between the groups (Figure 1). In contrast, mean darifenacin exposures at the 75 mg dose were 11.3 times and 7.8 times greater than at the 15 mg dose, in CYP2D6 extensive and poor metabolizers, respectively.
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ECG Evaluations
Darifenacin treatment resulted in no significant increase in QT, QTcF, or QTcB mean change from baseline at Tmax compared with placebo (Table IV). Like-wise, plots of individual QT/QTc change from baseline at Tmax versus Cmax showed no trend to increased QT/QTc interval with increasing darifenacin exposure; the slope for simple linear regression was close to the theoretical line representing no change (Figure 2a). In contrast, moxifloxacin produced a statistically significant increase in QT/QTc at Tmax compared with placebo (QT, +20.5 milliseconds; QTcF, +11.6 milliseconds; QTcB, +6.4 milliseconds). In addition, plots of individual QT/QTc change from baseline versus Cmax showed a clear trend to increased QT prolongation with increasing moxifloxacin exposure (Figure 2b).
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Consistent with its lack of effect on QT/QTc interval at Tmax, darifenacin 15 mg and 75 mg produced no significant increase versus placebo in maximum intrasubject QT/QTc interval or mean time-averaged QT/QTc change from baseline (Table V). In contrast, moxifloxacin treatment resulted in statistically significant increases in time-averaged QT/QTc and maximum observed intrasubject QT and QTcF interval (Table V). Notably, the results for CYP2D6 poor metabolizers were consistent with those for the study population as a whole; no analysis showed more than a 3-millisecond increase in QTc interval for darifenacin versus placebo (Table VI).
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Neither darifenacin treatment nor placebo resulted in any subject exhibiting a maximum QTcF increase from baseline of more than 60 milliseconds, compared with 2 subjects (4.3%) treated with moxifloxacin (Table VII). Similarly, the proportion of subjects exhibiting a maximum QTcF increase from baseline of more than 30 milliseconds was comparable between placebo and darifenacin 15 mg and 75 mg treatment groups but was approximately double in the moxifloxacin group (20.5%, 17.4%, 18.6%, and 39.1%, respectively). No subject experienced a postdose QT/QTc interval greater than 500 milliseconds. Although maximum QTcB was more than 480 milliseconds in 1 subject in each group, this result was not reflected either in uncorrected QT or in QTcF. Furthermore, whereas maximum observed postdose QTcB was more than 450 milliseconds in 63 subjects (30-40% in each group), QTcF was more than 450 milliseconds in only 2 subjects, both women in the darifenacin 75 mg group, one CYP2D6 extensive metabolizer and one poor metabolizer, with QTcFs of 469 and 458 milliseconds, respectively. The inconsistent results for QTcB were caused by overcorrection of QT for heart rate by Bazett correction formula when heart rate is greater than 60 beats per minute, as illustrated in Figure 3, which shows a clear dependency of QTcB on heart rate.
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There were no clinically relevant mean changes in heart rate (mean changes versus placebo at Tmax were +4, +6, and -6 beats per minute in the darifenacin 15 mg, darifenacin 75 mg, and moxifloxacin groups, respectively). In addition, circadian effects were noted in plots of QT and QTcB versus time, which were attributed to their dependency on heart rate (heart rate is known to have circadian variation). In contrast, QTcF did not show a circadian effect, indicating adequate correction for heart rate (data not shown).
Safety Results
Darifenacin and moxifloxacin were generally well tolerated with no discontinuations. Adverse events were reported by 25.5% of subjects in the placebo group, 38.3% in the darifenacin 15 mg group, 65.2% in the darifenacin 75 mg group, and 45.8% in the moxifloxacin 400 mg group. The most common adverse events were dry mouth (4.3%, 19.1%, 47.8%, and 4.2%, respectively), headache (10.6%, 8.5%, 19.6%, and 22.9%, respectively), and constipation (2.1%, 6.4%, 19.6%, and 2.1%, respectively) (Table VIII). Dry mouth and constipation are expected antimuscarinic effects because of antagonism of M3 receptors, and headache is a nonspecific class effect. The majority of adverse events were mild-moderate in intensity, with none warranting discontinuation of study treatment. Headaches were the only events requiring treatment. Two subjects in the darifenacin 75 mg group reported urinary retention, which was moderate in intensity and resolved without intervention. In addition, 2 subjects reported chest pain, one in the moxifloxacin group and one in the darifenacin 75 mg group, both of which were mild-moderate in intensity and resolved during the same day without medical intervention and without any indication of cardiac ischemia. The investigator could not exclude a causal relationship with study treatment for these events. There were no clinically meaningful changes in vital signs, clinical laboratory tests, or ECGs.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The results for uncorrected QT in the overall study population followed the same pattern, with no changes in uncorrected QT interval versus placebo. The QTcB showed small (nonstatistically significant) increases in QT interval compared with placebo for darifenacin 15 mg and 75 mg at Tmax and for darifenacin 15 mg averaged over time. However, the deficiency of Bazett formula for heart-rate correction is well established15 and is corroborated in the clear relationship between QTcB and heart rate found in this study. In accordance with regulatory guidance,23 Fridericia formula was preselected for the primary outcome measure in this study.
To better reflect OAB treatment demographics, subjects were stratified during enrollment by gender and age with the result that 53% of the study population was female and 43% were aged 45 to 65 years. In addition, because CYP2D6 polymorphism can affect darifenacin's rate of clearance, the study population included 17% CYP2D6 substrate poor metabolizers, more than double the general prevalence.24 Subgroup analysis showed a 72% increase in mean darifenacin exposure in CYP2D6 poor metabolizers compared with extensive metabolizers at darifenacin 15 mg. It is interesting that at 75 mg (5 times higher than the maximum proposed marketed dose) mean exposure was increased by only 17% in poor metabolizers compared with extensive metabolizers. This finding probably reflects near saturation of the CYP2D6 pathway in both subgroups, with most darifenacin metabolism occurring via the CYP3A4 route. The availability of this alternative metabolic pathway indicates that CYP2D6 poor metabolizers will not be subject to disproportionate exposure compared with extensive metabolizers at high darifenacin doses.
Important, there was no increase in the QT interval with increasing darifenacin plasma concentration. Even in the cohort of CYP2D6 substrate poor metabolizers receiving the supratherapeutic dose of darifenacin, in which mean darifenacin exposure was greater than at the 15 mg dose in CYP2D6 poor metabolizers and Cmax was 68 ng/mL (6.5 times higher than in CYP2D6 poor metabolizers receiving the maximum therapeutic dose of 15 mg), there was no increase versus placebo in QTcF interval at Tmax or in maximum intrasubject QTcF interval. Indeed, the largest increase in QTcF versus placebo observed with darifenacin treatment in the CYP2D6 poor metabolizer subgroup was 1.8 milliseconds, for time-averaged QTcF in the 75 mg group. Consistent with these findings, regression trends in plots of individual changes in QTc versus Cmax showed no increase in the QT/QTc interval with increasing Cmax.
An interesting feature of this study was the poor concordance between CYP2D6 phenotype and genotype. Although the genotyping protocol correctly identified 17 of the 32 phenotypic poor metabolizers, it failed to identify 15, of whom 14 were African American. This finding suggests that the genotyping protocol used in this study is sensitive for detection of CYP2D6 poor metabolizers in the Caucasian population but may be inadequate in the African American population. Of the 13 Caucasian phenotypic poor metabolizers, 12 (92%) were identified genotypically, compared with 5 of 19 (26%) African American phenotypic poor metabolizers. This failure is likely because of the nonrepresentation in the allele test panel of reduced-activity or null alleles prevalent in the African American population.25 The misidentification of 1 phenotypic extensive metabolizer as homozygous for the null allele *4 may reflect an artifact of the PCR methodology.
Increased understanding of the importance of subtle cardiac effects has made formal studies of the QT/QTc interval an essential component in establishing the safety profile of new drugs. Such investigations are especially important when older drugs in the same class are known to prolong QT/QTc interval. In the case of antimuscarinic agents for OAB, terodiline (an antimuscarinic agent with calcium channel antagonist properties, formerly indicated for the treatment of detrusor instability) was withdrawn in 1991 after being associated with ventricular tachyarrhythmia (torsades de pointes).26,27 Subsequent ECG analysis of patients receiving terodiline without apparent cardiac symptoms revealed a significant and concentration-dependent increase in the QT interval compared with measurements made off-therapy.28
In general, the degree to which a drug increases the QT/QTc interval has been considered to be proportional to its potential to induce ventricular tachyarrhythmia.12 The US Food and Drug Administration has suggested that drugs that increase the mean QT/QTc interval by more than 20 milliseconds have a substantially increased likelihood of being proarrhythmic.12,29 Drugs that increase the mean QT/QTc interval by 10 to 20 milliseconds are of concern, and those that increase the mean QT/QTc interval by 5 to 10 milliseconds are subject to increased scrutiny. In contrast, drugs whose maximum effect is less than 5 milliseconds have not been associated with ventricular tachyarrhythmia. The absence of any significant increase in the QT/QTc interval in this study suggests that darifenacin is unlikely to cause ventricular tachyarrhythmia. The reduced potential for cardiovascular adverse effects with darifenacin is supported by evidence from clinical studies. A cardiovascular safety profile comparable to that of placebo has been reported recently in a pooled analysis of phase III trials.30
In conclusion, this study demonstrates that darifenacin, a muscarinic M3 selective receptor antagonist, does not prolong QT/QTc interval. This absence of effect is an additional benefit to darifenacin's sparing of cardiac effects observed in clinical trials and its up to 59-fold selectivity for muscarinic M3 over M2 receptors.3-5 Darifenacin is therefore not expected to negatively affect cardiac repolarization (QT interval) in the diverse OAB patient population encountered in clinical practice.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, simple linear regression.