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Raltegravir Thorough QT/QTc Study: A Single Supratherapeutic Dose of Raltegravir Does Not Prolong the QTcF Interval

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Iwamoto, Dr Kost, G. C. Mistry, Dr Wenning, S. A. Breidinger, Dr Stone, Dr Gottesdiener, Dr Bloomfield, Dr Wagner) and Orlando Clinical Research Center, Orlando, Florida (Dr Marbury).

Address for reprints: Marian Iwamoto, MD, PhD, Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900; e-mail: marian_iwamoto{at}merck.com.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC₉₅ = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C_max of 20 µM raltegravir was attained, 4-fold higher than the C_max at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.

Key Words: Raltegravir • HIV-1 integrase inhibitor • QTc interval • thorough QT • ECG

Raltegravir (formerly known as MK-0518) is a novel HIV-1 antiretroviral agent that targets HIV-1 integrase, the enzyme that catalyzes the stepwise process that results in the integration of the HIV-1 DNA into the genome of the host cell.^2,3 Raltegravir has potent in vitro activity against HIV-1, exhibiting a 95% inhibitory concentration (IC₉₅) of 31 nM in the presence of 50% human serum.⁴ It is active against a wide range of wild-type and multidrug-resistant HIV-1 clinical isolates and has potent activity against viruses using CCR5 and/or CXCR4 coreceptors for entry.^5,6 Initial results of a 10-day monotherapy proof-of-concept study demonstrated raltegravir to have potent antiretroviral activity as short-term monotherapy and to be generally well tolerated at doses of 100 to 600 mg administered twice daily.⁷ Based on these data, as well as initial pharmacokinetic data,⁸ the 400-mg dose administered twice daily was selected to move forward in phase III investigation. In phase II and III studies, which included patients with advanced HIV-1 infection harboring triple-class resistant virus, raltegravir demonstrated a rapid, potent, and sustained antiretroviral effect with dose administration of 400 mg twice daily up to 48 weeks and was characterized with a favorable tolerability profile.^9-12 At this dose, the mean C_max was 4.5 µM, and the mean AUC was 14 µM·h.⁷

Recently, an association was identified in 24 patients with QT interval prolongation and/or torsade de pointes who were taking protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) using the Food and Drug Administration's (FDA's) adverse event reporting system.¹³ The investigators demonstrated that lopinavir, nelfinavir, ritonavir, and saquinavir caused dose-dependent block of human ether-a-go-go-related gene (hERG) channels heterologously expressed in HEK293 cells in vitro. In addition, lopinavir demonstrated inhibition of repolarizing potassium current (IKr) channels in neonatal mouse cardiac myocytes.

The potential risk of raltegravir to cause delayed ventricular repolarization in humans was investigated using several nonclinical assays consistent with the ICH S7B guidelines.¹⁴ Raltegravir was not associated with any changes in mean arterial blood pressure, heart rate, and PR, QRS, and QTc intervals, as assessed in an anesthetized vagotomized dog model and a highly sensitive conscious dog QTc prolongation telemetry model.¹⁵ In the 2 in vivo cardiovascular models, maximal exposures of 17.5 µM and 20.6 µM were attained in the anesthetized vagotomized dog model and the conscious dog telemetry model, respectively (unpublished data). An in vitro evaluation of the effects on hERG current demonstrated only marginal inhibition of hERG current at the highest testable concentration (100 µM) (unpublished data). Overall, these nonclinical results suggested that the risk presented by raltegravir for QT interval prolongation in humans at therapeutic concentrations is likely to be very low. Furthermore, this conclusion was consistent with human electrocardiogram (ECG) data collected in the initial phase I raltegravir clinical program⁸ in which single doses up to 1600 mg and multiple doses up to 800 mg twice daily did not show any evidence or consistent pattern for treatment-related increases in QTc interval.

The purpose of this thorough QTc (TQT) study was to provide a more rigorous assessment of the potential for raltegravir to prolong ventricular repolarization based on the ICH E14 guidance.¹⁶ To date, virtually all published TQT studies use both therapeutic and supratherapeutic doses in the characterization of cardiac repolarization effects.^17-20 Recently, Zhang et al²¹ performed a QTc analysis on duloxetine, escalating up to supratherpeutic dose levels with ECG evaluation at the higher dose levels. In contrast to these approaches, this article describes the utilization of a novel and more efficient study design incorporating evaluation of a single supratherapeutic dose of raltegravir, without utilization of secondary dose levels.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
Healthy male and female volunteers, between the ages of 18 and 45 years and within 30% of ideal body weight, were recruited for participation in the study. Subjects were excluded if they were smokers; infected with HIV; had a history of neurologic, pulmonary, cardiovascular, hepatic, renal, rheumatologic, hematologic, or neoplastic disease; had abnormal ECG or clinically significant laboratory findings; had recent surgery or had donated blood within 4 weeks prior to study start; or anticipated needing any prescription or nonprescription drugs during the conduct of the study. Subjects were excluded if ECG intervals/values were outside the following ranges: PR >0.20 seconds, QRS 0.12 seconds, corrected QT 450 milliseconds, RR >1.2 seconds, and resting ventricular rate <50 bpm.

Every subject gave written informed consent to participate in the study. The protocol was approved by the Independent Investigational Review Board (Plantation, Florida). The protocol was conducted in accordance with the guidelines on good clinical practice and with ethical standards for human experimentation established by the Declaration of Helsinki.

Study Design
A double-blind, randomized, placebo-controlled, double-dummy, 3-period, balanced crossover study was conducted in which 31 young, healthy, male and female subjects were enrolled. Each period consisted of a single dose of 400 mg moxifloxacin (Avelox; Bayer HealthCare, West Haven, Connecticut) with placebo to raltegravir, 1600 mg raltegravir (lactose formulation) with placebo to moxifloxacin, or placebo to both raltegravir and moxifloxacin. There was at least a 7-day washout interval between periods. The subjects received the treatments in 1 of 6 randomized sequences appropriate for a 3-period crossover design. All doses were administered in the fasted state. Twelve-lead ECGs were obtained by a Mortara H-12+ Holter recorder (Mortara Instrument, Inc, Milwaukee, Wisconsin) and were extracted by a core ECG laboratory (Covance Central Diagnostics, Reno, Nevada). Blood samples were collected at prespecified nominal time points throughout the study up to 12 hours postdose for determination of raltegravir plasma concentrations.

ECG Acquisition
Following a physical examination and the collection of blood, the Holter recorder was attached and then activated 10 minutes prior to the anticipated dosing time in each period while subjects rested quietly in the supine position. Electrocardiograms were simultaneously acquired (using dual-snap ECG electrodes) by the Mortara H-12+ Holter recorder (which continuously records and digitizes 12-lead ECGs that were used for the primary analysis) and a bedside 12-lead ECG machine (which was used for safety monitoring during the study). These dual-snap ECG electrodes were placed on the 6 standard precordial positions on the chest; limb leads were placed in the modified foreshortened position. Subjects were asked to rest quietly in a supine position for 10 minutes prior to, as well as 5 minutes following, each prespecified ECG time point (baseline predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose). In each period, a single bedside 12-lead ECG was printed and reviewed by the investigator at 2 and 4 hours postdose for safety evaluation.

ECG Analysis and Interpretation
The flash cards containing the ECG data from each Holter ECG session were analyzed in an ECG core laboratory (Covance Central Diagnostics). Each Holter ECG recording was reviewed by a technician, and a fully annotated record was compiled indicating any 10-second periods with significant artifact, technical failure, or any nonsinus beats. Once annotated, 10-second periods of the Holter recording were extracted according to prespecified time points ("extracted ECGs"). These extracted ECGs were read by a cardiologist who was blinded to treatment period, dose, and time postdose. All ECGs from a subject were read by a single cardiologist.

For purposes of replicate extraction at each time point, an available window was centered on the nominal time point and subsequently extended forward and backward to extract 5 replicates. The first ECG was extracted as close to the center of the available window as possible, with additional replicates extracted from the next available 10-second period on either side of the nominal time point. Any 10-second periods with artifact, technical failure, or nonsinus beats, as determined above, were rejected and the 10-second period next closest in time substituted.

Once extracted, the ECGs were automatically routed to the algorithm-assisted ECG annotation system (AEA). The AEA system measured intervals on each individual lead, independently of the other leads, taking advantage of lead simultaneity to improve annotation accuracy. The program marked every QRST complex on the digital ECG. The computer algorithm and lead/beat selection software was used to deliver the annotated ECG to the cardiologist. ECG digital waveforms were transferred from the Holter device to the Digitography (Covance Central Diagnostics) digital on-screen system at 1-ms resolution. All 12 leads of each ECG were displayed simultaneously for a given 10-second ECG extracted from the recording. In each ECG, all leads were evaluated, and the lead with the longest QT interval was used for analysis. In the lead with the longest QT interval, measurements were made in 3 consecutive complexes by placing markers (annotation) on the onset and offset of the PR, QRS, and QT intervals.

To correct for the possible effect of heart rate, we used Fridericia's correction (QTcF = QT/RR^1/3). The final value for each QTcF in each ECG was determined by the average of 3 consecutive complexes. Final interval values were expressed in units rounded to the nearest millisecond. All recordings, including the annotated waveforms with interval measurements, were digitally stored.

Pharmacokinetic Assessments
Plasma samples were collected and analyzed for raltegravir concentrations. Blood samples were drawn in each treatment period at predose and at 0.5, 1, 2, 3, 4, 6, and 12 hours after dosing. Plasma samples from a subset of subjects (n = 12) were selected for pharmacokinetic analysis.

The analytical method for the determination of raltegravir in human plasma has been previously published.²² Raltegravir AUC_{0-12 h} was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. C_max and t_max were obtained by inspection of the plasma concentration data.

Safety and Tolerability
Safety and tolerability were assessed by clinical evaluation (including physical examinations, vital signs, and 12-lead electrocardiograms) and laboratory measurements (including hematology, serum chemistry, and urinalysis). Adverse experiences were monitored throughout the study. All clinical adverse experiences were evaluated in terms of intensity (mild, moderate, or severe), duration, seriousness, outcome, and relationship to study drug.

Statistical Analyses
Prior to any analysis, the QTcF value at each time point was calculated as the average of the 5 replicate QTcF values from ECGs extracted around each nominal time point. All confidence intervals for the following analyses were based on the least squares means and variance components arising from an analysis of variance (ANOVA) model appropriate for a 3-period, 3-treatment crossover design, with period, treatment, time, and treatment-by-time interaction as fixed effects and with subject as a random effect. All confidence intervals referenced the t distribution. Modeling the QTcF change-from-baseline values directly, 90% confidence intervals were constructed for the mean treatment differences (raltegravir-placebo and moxifloxacin-placebo) in change from baseline of QTcF at each time point.

Ninety-five percent confidence intervals for the geometric means of C_max and AUC were constructed using 1-sample methods as applied to the natural log-transformed values and referencing a t distribution.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Demographics and Baseline Characteristics
A total of 31 healthy male (n = 17) and female (n = 14) volunteers were enrolled in the study. All subjects were nonsmokers with a mean age of 32 years (range, 19-45 years) and weighed within±30% of ideal body weight with a mean weight of 84.2 kg (range, 60.5-103.2 kg) for men and 63.5 kg (range, 49.5-81.0 kg) for women. Of the 31 subjects enrolled, 15 were black, 8 were Hispanic, 7 were white, and 1 was Asian.

ECG Analysis
Heart Rate and PR and QRS Intervals
Assessment of heart rate and PR and QRS interval change from baseline was performed. By inspection, there was no clinically meaningful difference of heart rate or PR and QRS intervals between the treatment groups.

QTcF
For QT interval assessment, Fridericia's correction to QT was made to correct for heart rate. The appropriateness of the correction factor (QTcF = QT/RR^1/3) was assessed via a simple linear regression of QTcF versus RR interval. Although not formally tested, an observed slope of 0 would indicate that Fridericia's correction is adequate. The performed regression resulted in a slope of –0.024 (R² = 0.022), indicating that Fridericia's correction is indeed adequate. In contrast, the regression analysis of raw QT versus RR resulted in a slope of 0.119 (R² = 0.369).

The QTcF interval placebo-adjusted change from baseline means and corresponding 90% confidence intervals are summarized in Figure 1 and Table I. The upper limit of the 90% confidence interval for the placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point examined. Categorical analyses on both the raw QTcF values and on the change-from-baseline QTcF values also provided evidence, per ICH E14 guidelines, that raltegravir does not prolong the QTc interval. After averaging the 5 replicates, no raltegravir or placebo QTcF values were >450 ms, and no raltegravir or placebo QTcF values had any individual change >30 ms. Assay sensitivity was verified, as moxifloxacin demonstrated a statistically significant increase in the placebo-adjusted mean change-from-baseline QTcF interval at the 2-, 3-, and 4-hour time points. In accordance to regulatory guidance, assay sensitivity is established with a positive control effect of 5 ms, a value representing a threshold of clinical concern.¹⁶ This was established with moxifloxacin demonstrating such an increase at the 3-hour time point. In categorical analyses for moxifloxacin QTcF intervals, 1 subject had 3 observations (2, 3, and 4 hours postdose) of QTcF values >450 ms, and 1 subject had 2 observations (3 and 4 hours postdose) of change-from-baseline QTcF values >30 ms.

View larger version (12K): [in this window] [in a new window]   Figure 1. Placebo-adjusted means and 90% confidence intervals for change from baseline QTcF interval (ms) after administration of raltegravir or moxifloxacin to young, healthy, male and female subjects.

Pharmacokinetics
The plasma raltegravir concentration profiles were evaluated in 12 subjects. The geometric mean C_max attained was 19.63 µM with a 95% confidence interval of (11.72, 32.89). The geometric mean AUC_{0-12 h} (95% confidence interval) was 63.05 µM·h (41.82, 95.05). The mean t_max was 2.0 hours. The concentration versus time profile is shown in Figure 2.

View larger version (15K): [in this window] [in a new window]   Figure 2. Comparison of the arithmetic mean plasma concentration-time profiles for young, healthy, male and female subjects administered single oral doses of a supratherapeutic dose of 1600 mg raltegravir (lactose formulation) in this study and historical data on the profile from a therapeutic dose of 400 mg twice-daily raltegravir (final market composition formulation)7 (inset: semilog scale).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This study was performed to provide a more rigorous assessment of the potential for raltegravir to prolong ventricular repolarization with a design in accordance with regulatory guidance documents¹⁶ using an innovative and more efficient approach. In the E14 guidance for industry, Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs,¹⁶ several key points were made, all of which were incorporated into this study, including (1) use of a positive control (moxifloxacin), (2) effect of raltegravir at exposures that are multiples above the expected therapeutic concentrations, (3) potential methods for reducing variability in the measurement of the QTcF interval using replicate ECGs and a centralized core laboratory to measure QTcF interval manually, and (4) utilization of the 10-ms cut point described in the guidance as the threshold below which the upper arm of the 95% one-sided confidence interval (of the placebo-corrected change in QTc interval from baseline) must have fallen in order for the study to be considered negative.

In this study, a single supratherapeutic dose of study drug was investigated to achieve high concentrations and thus assess maximal effects. The dose (1600 mg) was selected to provide plasma levels several-fold higher than the projected therapeutic dose of 400 mg. In addition, an alternate formulation of raltegravir was used in this study, a formulation that was used in early phase I studies and provides a higher peak-to-trough ratio relative to the final market composition formulation.⁸ Plasma levels of raltegravir were sufficiently high (19.63 µM), 4-fold in excess relative to the mean C_max value (4.5 µM) attained after single-dose administration of the 400-mg final market composition formulation.⁷ A comparison of the concentration-time profiles obtained in this study with the supratherapeutic dose to historical data for the profile from the standard 400-mg twice-daily regimen is shown in Figure 2. Raltegravir is metabolized primarily by glucuronidation via the UGT1A1 isozyme²³ and is only moderately influenced by potent inhibitors of UGT1A1, with raltegravir concentrations increasing 2-fold or less.^24,25 Furthermore, raltegravir is cleared primarily by hepatic metabolism,²³ and plasma concentrations are not meaningfully affected by moderate hepatic impairment (unpublished data). Therefore, the dose of 1600 mg with the raltegravir lactose formulation satisfied the criteria to assess a dose that provides plasma concentrations higher than that of the anticipated efficacious dose and sufficiently provides margins above potential increases in raltegravir concentrations when dosed with agents causing increases in exposures.

The raltegravir plasma concentrations at 6 hours after administration of a 1600-mg dose resulted in plasma concentrations of 3 µM, which was roughly comparable to the C_max of the projected clinical dose of 400 mg, with no evidence of an effect on the QTc interval. If an effect were evident, hysteresis would have been examined, providing important information regarding delayed ventricular repolarization effects, an effect perhaps not readily evident with examination at lower doses. In addition, if an effect on the QTc interval was seen, a pharmacokinetic-pharmacodynamic (QTc) model would have been constructed, including investigation of possible hysteresis, in which an effect on QTc at therapeutic concentrations would have been estimated.

Overall, this study design of a single dose-level administration provided adequate assessment of raltegravir QTc prolongation in an efficient manner and was scientifically sufficient to test the hypothesis. The approaches described support that single supratherapeutic dose administration is a generalizable study design and can be implemented widely. Use of modeling and simulation could characterize concentration effects and thus could replace the clinical QTc investigation at the therapeutic dose. In addition, concentration effect modeling could be advantageous in the analysis of small overall signal at high exposure. However, it is acknowledged that the approach has limitations. For raltegravir, accumulation of parent drug is minimal, allowing for sufficient assessment after single-dose administration⁸; however, metabolites may have been more fully assessed with regard to QTc interval effect with multiple-dose administration if accumulation was evident. One single metabolite was identified in the clinical characterization of the metabolites of raltegravir.²³ The relative plasma concentration of the metabolite was less than half that of parent and, furthermore, was cleared rapidly. Although pharmacokinetics of the metabolite were not characterized after multiple-dose administration, there is little evidence to support that accumulation would have been present. Investigation of a range of doses would have allowed for assessment of a dose response or characterization of a U-shaped response, if an effect was seen. However, despite the lack of characterization of a dose response, the supratherapeutic dose of raltegravir sufficiently characterized maximal effects, which is of most value with regard to identification of safety issues.

Data from this study support that in this rigorous assessment of the QTc interval, raltegravir does not prolong ventricular repolarization. Administration of the active comparator moxifloxacin prolonged the QTcF interval, establishing the sensitivity of the assay. These data support continued development of raltegravir and add to the favorable characteristics of the raltegravir safety profile. Furthermore, a single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors acknowledge David Hreniuk (Merck Research Laboratories) for his expert assistance in the conduct of the clinical study and Neal Azrolan (Merck Research Laboratories) for his assistance with preparation of the manuscript.

Financial disclosure: Merck & Co, Inc, is developing raltegravir. Authors who are employees of Merck may own stock and/or stock options in the company. Authors who are not employees of Merck have received grant support, consultant fees, and/or lecture honoraria.

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TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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