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Clinical Statistician, Tibotec BVBA, Mechelen, Belgium
Clinical Statistician, Tibotec BVBA
Director of Clinical Pharmacology, Department of Human Pharmacokinetics, Tibotec Inc., Yardley, PA
Clinical Pharmacokineticist, Tibotec BVBA
Senior Manager, Global Clinical Operations, Tibotec BVBA
Head of Pharmacology, Tibotec BVBA
Senior Director, Global Clinical Development, Tibotec BVBA
Director, Global Clinical Development, Etravirine Clinical Lead, Tibotec BVBA
Reprints: Mrs. Peeters, Tibotec BVBA, Gen De Wittelaan, L11B 3, 2800, Mechelen, Belgium, fax 32 15 444 291, mpeeter7{at}tibbe.jnj.com
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Abstract |
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OBJECTIVE: To evaluate the effect of 2 etravirine dosing regimens on QT/corrected QT interval (QTc) in HIV-negative volunteers and assess pharmacokinetic and additional safety parameters.
METHODS: A double-blind, double-dummy, randomized, placebo- and active-controlled, 4-period crossover trial was conducted in 41 HIV-negative volunteers. Participants received 4 regimens: etravirine 200 mg twice daily, etravirine 400 mg once daily, moxifloxacin 400 mg once daily (positive control), and placebo in separate 8-day sessions, with each followed by a washout period of 14 or more days. On days –1, 1, and 8 of each session, ECGs were recorded at 11 time points over 12 hours. Pharmacokinetic profiles of etravirine regimens were evaluated and safety was assessed.
RESULTS: Thirty-seven subjects completed the study. For etravirine, the upper limit of the 90% CIs of mean time-matched differences in QTc determined using Fridericia's formula (QTcF) was below 10 msec at all time points, the threshold for prolonged QT as defined by regulatory guidelines. The maximum mean (90% CI) difference of time-matched changes in QTcF versus placebo on day 1 was +0.1 msec (–2.6 to 2.9), –0.2 msec (–2.6 to 2.1), and +10.1 msec (7.3 to 12.8) for etravirine 200 mg twice daily, etravirine 400 mg once daily, and moxifloxacin, respectively. On day 8, these values were +0.6 msec (–2.1 to 3.3), –1.0 msec (–4.4 to 2.5), and +10.3 msec (6.8 to 13.9), respectively. Etravirine produced no clinically significant changes in other ECG parameters. No significant differences between males and females were observed. Both etravirine regimens had similar pharmacokinetic exposure and safety profiles.
CONCLUSIONS: Etravirine does not prolong the QTc interval. No clinically relevant ECG changes were observed in HIV-negative volunteers. Short-term dosing of etravirine in HIV-negative volunteers was generally safe and well tolerated.
Key Words: electrocardiogram, etravirine, QT interval, safety, tolerability
Published Online, April 29, 2008. www.theannals.com, DOI 10.1345/aph.1K681
A number of antiretrovirals used to treat HIV-1 infection have been associated with adverse cardiac events, including prolonged QT interval.9-11 Prolongation of the QT interval can increase the risk of life-threatening arrhythmias, including torsade de pointes and ventricular fibrillation, possibly leading to sudden death.12 Because of the potentially serious health implications, investigational medications are often assessed for cardiac safety during drug development. Current International Conference on Harmonisation (ICH) guidelines recommend that testing of a new therapy includes a thorough QT/corrected QT interval (QTc) trial.13
Preclinical and clinical trial data have provided no evidence for clinically relevant adverse cardiac effects with etravirine. Several in vitro and in vivo tests have demonstrated that etravirine showed no relevant effects on cardiac electrophysiology or hemodynamic parameters (data on file). Data obtained from clinical trials showed no relevant changes in electrocardiogram (ECG) parameters, including QTc interval.5-8
Although clinical trials have not shown an association between etravirine and cardiac events or changes in ECG parameters, these trials were not specifically designed to study the effect of etravirine on cardiac repolarization in humans. The aim of this study was, therefore, to evaluate the effect of 2 clinically relevant etravirine dosage regimens on QT interval in healthy volunteers. The effect on other ECG parameters, pharmacokinetics, and additional safety and tolerability parameters were also assessed.
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Methods |
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Random sequence generation was used to assign subjects in a crossover fashion to 4 treatment sessions: etravirine 400 mg administered as 100-mg tablets using either a once- or twice-daily regimen; a placebo; and a therapeutic dose of a positive control, moxifloxacin 400 mg once daily, administered as a 400-mg capsule. Treatment sessions comprised 4 tablets and 1 capsule in the morning and 2 tablets in the evening. Etravirine placebo tablets and moxifloxacin dummy capsules were used to blind administration. The total duration of treatment was 36 days (excluding the screening period, washout periods, and follow-up) and consisted of four 8-day treatment sessions, preceded by a 1-day run-in period and separated by a 14-day washout period. Follow-up was conducted 7 and 28–34 days after the last treatment.
SAMPLE SELECTION
Eighty-four healthy male and female volunteers aged 18–55 years were
enrolled and screened. An effort was made to recruit an equal number of men
and women. Eligible subjects were nonsmokers, had a body mass index of
18.0–30.0 kg/m2, and displayed a normal 12-lead ECG.
Subjects were excluded on the basis of a positive HIV-1 or -2 test; pregnancy;
history of alcohol or drug abuse; presence of hepatitis A, B, and/or C
infection; presence of a concomitant disease state; use of concomitant
medication; history of allergy or hypersensitivity to the study drugs; history
of significant skin disease; conditions influencing drug absorption or
bioavailability; presence of laboratory abnormalities; presence of cardiac
abnormalities (abnormal ECG, heart rhythm, or conduction disturbances;
presence of a risk factor for torsade de pointes); greater than grade 2
electrolyte abnormalities within 21 days prior to the first intake;
participation in a drug trial or donation of blood or plasma during the 60
days preceding first intake; and participation in multiple trials with
etravirine, dapivirine, and/or rilpivirine. All medications (with the
exception of acetaminophen, ibuprofen, and hormonal contraceptives) were
discontinued at least 14 days prior to the first drug intake.
Additional volunteers could be recruited to account for subjects who discontinued the trial pre-treatment or those prematurely withdrawn from the trial after treatment allocation for reasons other than drug tolerability or safety.
The study was approved by an independent ethics committee and was conducted in accordance with the Declaration of Helsinki. All subjects provided written informed consent.
OUTCOME MEASURES
The primary objective of the study was to evaluate the effect of etravirine
versus placebo on QT and QTc interval in HIV-negative volunteers.
Moxifloxacin, a fluoroquinolone antibiotic known to consistently induce a
prolonged QT interval without clinical complications, was used as a positive
control.
Secondary objectives were to evaluate the effect of the 2 etravirine regimens on non-QT interval ECG parameters (heart rate, PR interval, QRS width), evaluate the pharmacokinetics of the 2 regimens, link the pharmacokinetics of etravirine and QTc changes, and evaluate the safety and tolerability of etravirine.
To maximize the accuracy of the assessment of QT interval, a thorough QT/QTc study was conducted with ECGs recorded, processed, handled, and analyzed in accordance with ICH guidelines.13 ECGs (12-lead, time-matched) were collected at 11 time points (0, 0.5, 1, 2, 3, 3.5, 4, 4.5, 6, 9, and 12 h after the morning dose of each treatment session) on days –1 (predose), 1, and 8 (steady-state) and at 4 hours postdose on day 2, predose and 4 hours postdose on days 3–7, and during the follow-up visit on day 15. At each time point, 10-second recordings were taken in triplicate, approximately 1 minute apart.
ECG reports were interpreted in a blinded fashion using digital techniques by a cardiologist from a validated central ECG laboratory (MDS Pharma Services, Baillet-en-France, France). QT intervals were corrected for heart rate using Fridericia's formula (QTcF; QTc = QT/RR0.33).14 For completeness, QT interval data were also corrected for heart rate using the formulae of Bazett,15 Sagie,16 and linear and nonlinear correction methods. Results for these methods were similar; therefore, only results for Fridericia's correction method are presented here.
For each treatment and time point, the time-matched change from baseline was derived. The analysis parameter was then the time-matched change under treatment minus the time-matched change during placebo use at the corresponding time point. Additionally, as recommended by ICH E14 guidelines,13 the number of volunteers per session who had an increase in QTc interval from baseline of greater than 30 and greater than 60 msec, and the number of volunteers per regimen who had QTc interval values greater than 450, greater than 480, and greater than 500 msec were determined for each regimen. Effect of sex on QT/QTc interval was also assessed.
Samples for pharmacokinetic analysis were collected on completion of ECG measurements at each time point after dosing. On days 5–7, morning predose samples were taken. Plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method with a lower limit of quantification of 2 ng/mL. Pharmacokinetic analysis was done with WinNonlin Professional 4.1 (Pharsight Corporation, Mountain View, CA) using a noncompartmental model with extravascular input. Maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), and minimum plasma concentration (Cmin) were obtained by inspection of the plasma concentration–time profiles. The area under the curve (AUC) at 12 hours (AUC12h; twice-daily regimen) and 24 hours (AUC24h; once-daily regimen) were determined using the linear trapezoidal rule.
Adverse effects were monitored continuously from the time of informed
consent until the last trial-related activity and graded according to
severity. Blood hematology, blood biochemistry (following overnight fasting of
10 h), and urinalysis assessment was performed on days 1, 5, and 9, and
during follow-up on day 15. Vital signs (blood pressure and heart rate) were
measured on days –1, 1, 2, and 5–9.
STATISTICAL ANALYSIS
An intent-to-treat analysis was performed on all randomized volunteers
receiving at least one dose of study treatment. Based on within-subject
variability (maximum mean change in QT/QTc interval) observed in previous
trials (data on file), a sample size of at least 34 evaluable volunteers was
calculated to be sufficient to detect a maximum mean change in QT/QTc interval
of less than 7.5 msec with a 5% significance level and 80% power. Statistical
analysis was performed using SAS version 8.2 (SAS Institute Inc., Cary, NC).
For QT/QTc and non-QT ECG interval endpoints, the observed and time-matched
change from baseline, maximum change, time-averaged change, and maximum mean
change from baseline were summarized using descriptive statistics (mean
± SD, 90% CI). The Kruskal-Wallis test was used for between-group
comparison of the active and placebo treatments. For the primary endpoint of
effect on QT/QTc interval, a negative QT/QTc interval outcome was defined as
one in which the upper limit of the 2-sided 90% CI of the largest time-matched
mean effect of the drug on QTc interval was smaller than 10
msec.13 A
subgroup analysis by sex was performed applying the same methodology.
Descriptive statistics were calculated for the plasma concentrations of
etravirine at each time point and for all derived pharmacokinetic
parameters.
A comparison between the pharmacokinetic parameters was carried out using a linear mixed-effects model (comparing etravirine twice daily and once daily); AUC was adjusted by multiplying AUC12h by 2 during twice-daily treatment for comparison with the AUC24h during the once-daily treatment. Treatment and period effects were considered significant at the 5% level, and sequence effects were considered significant at the 10% level.
Safety and tolerability data were analyzed using descriptive statistics.
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Results |
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The diurnal variation of the QTcF interval duration showed a consistent pattern on days –1, 1, and 8 for all 4 treatments. Compared with day –1, QTcF interval duration with placebo and the 2 etravirine treatments was slightly decreased on days 1 and 8, while moxifloxacin demonstrated an increased QTcF interval. The maximum mean (90% CI) difference of the time-matched changes in QTcF interval versus placebo on day 1 was +0.1 msec (–2.6 to 2.9) for etravirine 200 mg twice daily, –0.2 msec (–2.6 to 2.1) for etravirine 400 mg once daily, and +10.1 msec (7.3 to 12.8) for moxifloxacin. The observations at steady-state (day 8) were similar to those at day 1 and were +0.6 msec (–2.1 to 3.3) for etravirine 200 mg twice daily, –1.0 msec (–4.4 to 2.5) for etravirine 400 mg once daily, and +10.3 msec (6.8 to 13.9) for moxifloxacin.
During etravirine treatment, none of the upper limits of the 90% CI crossed the 10-msec threshold compared with placebo, indicating that neither etravirine dose regimen is associated with a risk of QT interval prolongation. In contrast, at several time points on days 1 and 8 during moxifloxacin treatment, the upper limit of the 90% CI exceeded the 10-msec threshold, confirming the prolonging effect on QT interval duration of moxifloxacin (Figure 1a).
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The outlier analysis demonstrated that no volunteers had an increase from baseline QTcF interval greater than 60 msec. One subject receiving etravirine 200 mg twice daily had an ECG recording that showed an increase in QTcF interval greater than 30 msec, compared with none in the etravirine 400-mg once-daily session and 1 and 2 for placebo and moxifloxacin, respectively. Etravirine intake did not result in any instances of QTcF interval greater than 500 msec (threshold of particular clinical concern13) or greater than 450 msec, compared with 3 cases of QTcF interval greater than 450 msec with moxifloxacin (7.7%) and 1 with placebo (2.6%).
Exposure to etravirine was not significantly different when the same daily dose was given once or twice a day. AUC24h values on day 8 were 15,730 ng·h/mL (n = 39) and 16,270 ng·h/mL (n = 37), with a least-squares (LS) mean ratio of 1.03 (90% CI 1.00 to 1.07) when comparing AUC24h. Following treatment with etravirine 400 mg once daily (n = 39), a ratio of LS means Cmin was 25% lower and Cmax was 44% higher than the respective parameters obtained after the administration of etravirine 200 mg twice daily (336.8 vs 446.9 ng/mL and 1322.0 vs 921.0 ng/mL, respectively). There was no apparent association between Cmax and the corresponding change in QTcF interval at day 8 (Figures 2a, 2b).
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50 beats/min,
range 40–49) was the most commonly reported ECG abnormality recorded, in
15 volunteers (36.6%). The incidence was similar for the 4 treatments. Since
this trial was performed in young healthy volunteers, 53.7% being men, this
finding is not unexpected. In general, etravirine was well tolerated. Ninety-eight percent of volunteers reported at least one adverse event, but these were generally mild to moderate. The most frequent adverse events during etravirine treatment are summarized in Table 2. One serious adverse event (inguinal hernia; not related to medication) was reported. Two volunteers discontinued the trial prematurely because of rash (grades 1 and 2). In both cases, exposure to etravirine was considered very likely to be the cause of the adverse event. Two participants reported a cardiac event (1 tachycardia, 1 palpitations). No clinically meaningful changes were observed in laboratory parameters (blood and urine) or vital signs.
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Discussion |
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A number of antiretroviral agents used to treat HIV infection have been shown to be associated with potentially life-threatening cardiac adverse events. Protease inhibitors, including atazanavir, indinavir, nelfinavir, and amprenavir, have been shown to induce clinically relevant changes in ECG parameters.9,10,17 Similarly, the NNRTI efavirenz has caused QT interval prolongation and severe ventricular arrhythmia in HIV-infected patients.18
To assess the potential of a non-antiarrhythmic drug to induce clinically relevant repolarization disturbances, ICH E14 guidelines require rigorous evaluation of QT/QTc interval prolongation and proarrhythmic potential.13 This study was specifically designed to undertake a thorough QT/QTc evaluation of etravirine in healthy adults.
A crossover design was applied to allow volunteers to act as their own controls, thereby reducing variability of differences related to intersubject variability. Sensitivity of data was ensured by the inclusion of moxifloxacin (positive control) which, when tested in healthy volunteers using standardized approaches and methods, has consistently produced mean increases in QTc interval in line with the threshold proposed in the ICH E14 guidelines.19
To establish treatment effect and ensure that ECG readings covered the extent of exposure to the 4 study treatments and encompassed any diurnal variation, a number of time points were included for the ECG measurements. The Fridericia correction factor was applied to QT interval data to correct for heart rate. This method is considered the most appropriate, as the Bazett15 formula tends to overcorrect for changes in the RR interval. Notably, the lack of effect of etravirine on QT interval was consistent, irrespective of the method of correction for heart rate.
The validity and sensitivity of the trial were enhanced by the use of HIV-negative volunteers. This allowed the effects of etravirine to be studied in the absence of concomitant medication and underlying pathology. In addition, systemic exposure (AUC) to etravirine in HIV-infected patients is generally lower than in healthy subjects20; thus, these results are conservative if extrapolated to the HIV-infected population.
Our study demonstrates no effect on QT/QTc interval outcome for etravirine 200 mg twice daily or 400 mg once daily. In comparison, moxifloxacin produced a significant effect on QT/QTc interval outcome. These findings suggest that etravirine is unlikely to induce serious arrhythmias and support data from Phase 3 trials in which no increased incidence of adverse cardiac events was observed in patients treated with etravirine.7,8
Studies looking at the effects of a number of drugs (including non-antiarrhythmics) on QT interval have shown that female sex can be a risk factor for the development of drug-induced torsade de pointes.12,21 By including as high a number of females in this study as men, the effects of etravirine on QT/QTc interval have been investigated in a potentially sensitive subpopulation. In our study, no effect of etravirine on QT/QTc interval was shown, regardless of the sex of the volunteers.
While previous clinical trials assessing the efficacy and safety of etravirine have included patients from different ethnic origins, we recognize that in this study, the population sampled was comprised almost exclusively of white participants. While race is not generally considered to be a risk factor for prolonged QT interval,22 it would be valuable to assess the effects of etravirine on QT interval in other ethnic populations.
The same daily dose of etravirine (400 mg/day) was administered in once- and twice-daily regimens. Because the tolerability of etravirine doses exceeding 400 mg/day (current formulation) has not been established, a higher-dose group was not included. While the effects of higher doses of etravirine on QT interval remain unknown, this study included the dose currently approved by the FDA (200 mg twice daily) for adults with HIV-1 infection. The exposures to 400 mg once daily were expected to be within the range covered by animal exposures, but would produce a higher Cmax compared with the 200-mg twice-daily dose used in Phase 3 trials. Data from our study show that Cmax is indeed 44% higher with once-daily etravirine dosing than with the currently recommended twice-daily dose, while daily exposure (AUC24h) is comparable. However, the increased Cmax was not associated with cardiac adverse effects.
In addition to showing a lack of proarrhythmic potential, this study provides evidence that both etravirine regimens are well tolerated in HIV-negative volunteers. This favorable tolerability is in accordance with tolerability data from clinical trials5-8,23,24 where, except for rash, adverse events were found to be comparable to those seen with placebo.5-8 In our study, 2 subjects discontinued the trial prematurely because of a grade 1 or 2 rash. The presence of a rash following etravirine administration was also reported in previous etravirine trials.7,8,23,24 According to the Phase 3 studies, rash is the only adverse event to occur more frequently with etravirine than placebo. However, the rashes are generally mild to moderate, infrequently lead to drug discontinuation, and resolve on continued treatment.
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Footnotes |
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Data from this study were presented in poster format at the European AIDS Clinical Society meeting in October 2007.
We thank volunteers who participated in the trial. We also acknowledge W Haazen MD SGS LSS, Antwerpen, Belgium (coordinating investigator); E Soers and M Gyselinckx, Janssen-Cilag, Berchem, Belgium (trial monitors); MP Bouche PRD Beerse (bioanalysis), and the Tibotec study team. The manuscript was drafted and author contributions were collated by Louise Marks (associate medical writer), Gardiner-Caldwell Communications (Macclesfield, UK); this service was funded by Tibotec.
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 P. N. Munster, E. H. Rubin, S. Van Belle, E. Friedman, J. K. Patterson, K. Van Dyck, X. Li, W. Comisar, J. A. Chodakewitz, J. A. Wagner, et al. A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer Clin. Cancer Res., November 15, 2009; 15(22): 7077 - 7084. [Abstract] [Full Text] [PDF]
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M. Malik, K. Hnatkova, A. Schmidt, and P. Smetana Electrocardiographic QTc Changes Due to Moxifloxacin Infusion J. Clin. Pharmacol., June 1, 2009; 49(6): 674 - 683. [Abstract] [Full Text] [PDF]
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