International Journal of Clinical Pharmacology and Therapeutics, DOI 10.5414/CP202065
A thorough QT study of guanfacine Patrick Martin1, Lawrence Satin2, Robert S. Kahn3, Antoine Robinson1, Mary Corcoran1, Jaideep Purkayastha1, Sharon Youcha4, and James C. Ermer1
Original ©2014 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965
Development LLC, Wayne, PA, 2Independent consultant in cardiac safety, Wellington, FL, 3Genentech, San Francisco, CA, and 4Drexel University College of Medicine, Philadelphia, PA, USA
1Shire
DOI 10.5414/CP202065 e-pub: August 11, 2014
Key words guanfacine – electrocardiography – heart conduction system – heart rate – ADHD
Received October 30, 2013; accepted April 29, 2014 Correspondence to Patrick Martin, MD Vice President, Global Clinical Pharmacology and Pharmacokinetics, Shire Development LLC, 725 Chesterbrook Blvd., Wayne, PA 19087, USA
[email protected]
Abstract. Objectives: Guanfacine extended-release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984). Methods: In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals. Results: In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common. Conclusions: Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.
Introduction Guanfacine was approved by the US Food and Drug Administration (FDA) in 1986 for the treatment of hypertension [1, 2]. An extended-release formulation of guanfacine (GXR; INTUNIV®, Shire Development LLC, Wayne, PA, USA) is approved by the FDA both as monotherapy and as adjunctive therapy to psychostimulant medication, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 – 17 years [3]. The efficacy and safety of oncedaily GXR monotherapy for the treatment of ADHD has been demonstrated in children and adolescents aged 6 – 17 years in a pair of multicenter, randomized, placebo-controlled pivotal trials [4, 5], as well as in two long-term (up to 24 months) open-label trials [6, 7]. Two studies also evaluated GXR as adjunctive therapy in combination with psychostimulants [8, 9]. In one study, a 9-week, open-label, dose- escalation study of 75 subjects with ADHD and suboptimal response to a psychostimulant, significant (p 470 ms for female subjects), risk factors for TdP (e.g., heart failure, hypokalemia, family history of long QT syndrome), cardiac arrhythmia, renal impairment, concomitant medication (excluding hormonal contraception or hormone replacement therapy), a history of alcohol or substance abuse, use of tobacco, or use of excessive caffeine. Written informed consent was obtained from each subject prior to enrollment. To meet the primary objective for the current trial, it was calculated that a minimum of 48 participants were required to complete the study. Such a sample size was determined to be capable of detecting true mean differences between active and placebo groups of 5 ms (for all time points) of QTc interval (change from baseline) with 90% power (and with k = 10 time points), assuming a true standard deviation (SD) within 6 ms. This sample size was also determined to have more than 90% power to demonstrate non-superiority (1-sided, 5% type-1 error) with an acceptance limit of 10 ms for both planned analysis methods. To ensure 48 completers, enrollment of ≥ 72 subjects was planned.
Electrocardiogram assessments and QTc evaluation At screening and day –2 of each treatment period, subjects were assessed via 12-lead safety ECGs. On the morning of day –1, 30 minutes prior to the projected time of dose administration (on day 1), continuous, digital 12-lead ECGs (H-12 12lead Holter recorder, Mortara Instrument, Inc., Milwaukee, WI, USA) were obtained. The time points for ECG extraction were within 30 to 10 minutes of dose administration and within 10 minutes before each of the 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24hour time points after dose administration. A similar ECG extraction schedule was employed on days 1 and 6 of each period. A minimum of three 12-lead ECGs was extracted from the continuous ECG recording at each time point, and the primary analyses of the primary end points were based on these manually read, extracted 12-lead
5
QT study of guanfacine
ECG data. During the trial, subjects were required to be supine 20 minutes before any ECG acquisition time point, as well as supine or recumbent for 5 hours beginning 30 minutes after dose administration. HR and corrected QT were derived from the average value of the parameters measured on 3 consecutive complexes. HR correction formulas used for QT were QTcF (QT/RR1/3) and QTcNi (QT/RRBi). QTcNi was calculated for each subject individually based on extracted ECGs from continuous ECG recordings obtained on day –1 prior to dosing of study drug. For QTcNi, the relationship between QT and RR interval was assessed from the equation QT = Ai.RRBi, fitted with a log-transformed power model, using records from day –1: Log QT = Log Ai + Bi Log RR + esub + e. This regression model was fitted using a linear mixed-effects model to estimate the slope and intercept terms, with a random term for subject. QTcNi allows for a relatively HR-independent assessment of QT interval [34].
Pharmacokinetic assessments To evaluate plasma concentrations of guanfacine and moxifloxacin, blood samples for pharmacokinetic assessments were obtained within 30 and 5 minutes before dose administration on days 1 and 6, respectively. Blood samples (3 mL) were also collected within 2 minutes of the following post-dose time points on days 1 and 6: 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours. Following collection, blood samples were stored on ice for 450 ms for male subjects and > 470 ms for female subjects), QTc > 500 ms, or an increase in QTc from baseline of > 60 ms. Similarly, shift tables were created to summarize the number of subjects with post-baseline vital-sign values of potential interest. Categorical analyses were also performed for vital signs meeting predetermined criteria.
Results Subject demographics and disposition
Figure 3. A: One-sided 95% lower confidence bound for QTcNi for mean changes from baseline between moxifloxacin and placebo, double-Δ method (time-matched analysis). B: One-sided 95% upper confidence bound for QTcNi mean changes from baseline between guanfacine and placebo, double-Δ method (time-matched analysis). C: Onesided 95% upper confidence bound for QTcF mean changes from baseline between guanfacine and placebo, double-Δ method (time-matched analysis). Mean values depicted represent least squares mean. Analysis conducted in pharmacodynamic population. QTcNi = QT intervals corrected with a subject-specific method. QTcF = QT intervals corrected with Fridericia’s method.
primary endpoints. A time-averaged analysis examined the change from baseline in HR and QTc over hours 1 – 5 (the period of maximal drug concentrations) on days 1
83 adults were enrolled in the trial and were randomized to 1 of 6 treatment regimens (Figure 2). The safety population was composed of 48.2% (40/83) male subjects and 51.8% (43/83) female subjects. The mean (SD) age of subjects was 29.4 (8.61) years. Subjects ranged in weight from 52.5 to 98.0 kg (mean (SD), 73.55 (11.53) kg). The majority of subjects (63.9%; 53/83) were white. Demographic characteristics were generally similar among treatment groups. The study was completed by 73.5% (61/83) of subjects. Of the 7 subjects (8.4%) who discontinued the trial as a result of AEs, 1 did so as the result of an event (bradycardia) that occurred prior to administration of the study drug. During the trial, most subjects (89.2%; 74/83) received ≥ 1 concomitant medication. The most common concomitant medications were psyllium fiber supplement, stool softeners, and laxatives, and none of the concomitant medications was believed to affect the outcome measures.
8
Martin, Satin, Kahn, et al.
Table 1. Time-matched analysis of maximal change in QTcNi and QTcF on day 6: post-dose hours 1 – 12 (pharmacodynamic population).*
ECG parameter QTcNi
QTcF
Time (h) 1 2 3 4 5 6 8 12 1 2 3 4 5 6 8 12
Day Day 6
Treatment Guanfacine 8 mg
Day 6
Guanfacine 8 mg
Mean difference vs. placebo (ms) 2-sided 90% CI Mean difference† Lower Upper –6.86 –10.40 –3.32 –6.79 –10.32 –3.25 –7.07 –10.57 –3.57 –7.56 –10.80 –4.32 –9.28 –12.53 –6.03 –5.56 –8.60 –2.52 –7.19 –10.58 –3.80 –1.18 –4.29 1.94 2.43 –0.62 5.47 3.27 0.29 6.26 2.98 0.27 5.69 2.13 –0.66 4.93 0.08 –2.73 2.90 3.54 0.78 6.29 2.85 0.30 5.40 7.61 4.87 10.34
QTcNi = QT intervals corrected with a subject-specific method; QTcF = QT intervals corrected with Fridericia’s method; CI = confidence interval; ECG = electrocardiogram. *Analysis conducted in pharmacodynamic population. †Mean difference between least squares means.
Time-matched analyses Assay sensitivity was confirmed by moxifloxacin results. Compared with placebo, treatment with moxifloxacin was associated with QTc prolongation such that the 1-sided 95% lower confidence bound (LCB) for both QTcNi and QTcF exceeded 5 ms at the majority of time points in the maximal concentration window (hours 1 – 5; QTcNi data shown in Figure 3A). Furthermore, at 12 hours post-dose, the time point where guanfacine had the largest 1-sided 95% UCB (values for both QTcNi and QTcF were > 0 ms), the largest 1-sided 95% LCB for moxifloxacin was > 0 ms (4.72 ms for QTcNi and 4.36 ms for QTcF). Finally, at most time points between post-dose hours 1 and 12, for QTcNi and QTcF, the upper bound of the 95% 1-sided CI for moxifloxacin was > 10 ms. The results observed on day 6 for moxifloxacin were similar to those observed on day 1. Using a subject-specific correction (QTcNi), the largest 1-sided 95% UCB for guanfacine observed through hour 12 was 1.94 ms, which was observed at the 12-hour time point on day 6, following the supratherapeutic (8-mg) dose (Table 1). In the same analysis, the mean change from baseline between guanfacine and placebo at the
12-hour time point on day 6, following the supra-therapeutic (8-mg) dose was –1.18 ms (Figure 3B). There were no overlapping CIs between guanfacine and moxifloxacin. Overall, the results of the a priori QTcNi timematched analysis were negative for guanfacine. For the QTcF analysis of guanfacine, the largest 1-sided 95% UCB was 10.34 ms (i.e., a positive result), which occurred at the 12-hour post-dose time point following administration of the 8-mg supra-therapeutic dose. This was the only time point in which the upper bound of the 95% 1-sided CI included 10 ms (Figure 3C). The largest mean difference in QTcF between guanfacine and placebo, 7.61 ms, also occurred 12 hours after administration of the 8-mg dose (day 6). As previously specified, this study was designed a priori to examine a 12-hour post-dose window per ICH E14 guidelines to evaluate effects at peak concentration for therapeutic and supra-therapeutic doses [19]. ECG data were collected up to 24 hours post-dose, and were initially extracted for the 0 – 12, as well as 24 hours, post-dose time points only. Analysis of data after 12 hours was not planned. However, based on 0- to 12-hour QTc results, hours 13 – 23 post-dose were later extracted, and
9
QT study of guanfacine
Table 2. Time-matched analysis of maximal change in QTcNi and QTcF on day 6: post-dose hours 13 – 24 (pharmacodynamic population).*
ECG parameter QTcNi
QTcF
Time (h) 13 14 15 16 17 18 19 20 21 22 23 24 13 14 15 16 17 18 19 20 21 22 23 24
Day
Treatment
Day 6 Guanfacine 8 mg
Day 6 Guanfacine 8 mg
Mean difference vs. placebo (ms) 2-sided 90% CI Mean Lower Upper difference† 0.83 –2.91 4.57 3.83 –0.29 7.95 0.04 –3.28 3.37 –0.22 –4.45 4.00 –2.17 –6.16 1.81 0.85 –3.41 5.11 –2.31 –5.70 1.08 –0.08 –4.13 3.96 –2.04 –5.92 1.83 1.34 –3.17 5.84 3.63 0.25 7.01 14.68 11.66 17.70 9.54 6.11 12.98 12.95 8.98 16.92 10.00 6.61 13.40 9.60 5.61 13.58 6.54 2.86 10.23 7.33 3.37 11.29 3.05 –0.36 6.46 6.17 2.42 9.91 3.98 –0.14 8.10 6.16 2.45 9.87 9.56 6.30 12.82 18.02 15.19 20.84
QTcNi = QT intervals corrected with a subject-specific method; QTcF = QT intervals corrected with Fridericia’s method; CI = confidence interval; ECG = electrocardiogram. *Analysis conducted in pharmacodynamic population. † Mean difference between least squares means.
hours 13 – 24 post-dose were then analyzed post hoc using a time-matched analysis. Results for the 13- through 24-hour time points were similar to those for 0 – 12 hours in that on day 6, at the 8-mg supra-therapeutic dose, QTcNi mean differences from placebo were 5 ms at hours 2 – 5 (the maximal concentration window) and, at the majority of time points, the UCB for moxifloxacin was > 10 ms, supporting assay sensitivity. Following therapeutic and supra-therapeutic doses of guanfacine, the largest 95% UCB for QTcNi was 2.79 ms, occurring at postdose hour 12 on day 6 (following guanfacine 8 mg). This time point also corresponded to the largest mean difference in QTcNi for both guanfacine doses (–0.53 ms on day 1 and –0.46 ms on day 6). For the repeated-measures analysis of QTcF following guanfacine administration, results were positive (i.e., > 10 ms) only at the 12-hour time point (1-sided 95% UCB, 10.54 ms).
Secondary pharmacodynamic analyses and categorical analysis of ECG data The results of the time-averaged analysis on days 1 and 6 during post-dose hours 1 – 12 support the results of the timematched and repeated-measures analyses. For guanfacine, the highest UCB for QTcNi was observed at hour 12 on day 6 (2.19 ms), whereas for moxifloxacin, the UCB for QTcNi was in excess of 10 ms at almost all time points on both treatment days. When analyzed by QTcF, the only time point at which the UCB for guanfacine exceeded 10 ms was on day 6 at hour 12 (10.26 ms). As expected, the UCB for moxifloxacin was > 10 ms at most time points. Analysis of the effect of study medication on QTc at subject-specific tmax demonstrated that for both QTcF and QTcNi, the UCB was 10 ms following moxifloxacin administration. In the guanfacine group, no subject exhibited a QTcNi or QTcF lasting longer than 500 ms or demonstrated an increase of
10
Martin, Satin, Kahn, et al.
> 60 ms in either corrected QT interval at any time point assessed. Additionally, a priori analysis of the extracted ECGs during the first 12 hours following guanfacine administration revealed that no guanfacine-treated subjects had a prolonged QTcNi or QTcF (defined as > 450 ms for male subjects and > 470 ms for female subjects). Additional examination of the extracted ECGs indicated there were no abnormal morphologic changes in the T-U wave complex, which can be indicative of increased risk for TdP.
Figure 4. Mean QT interval (uncorrected) at baseline and following administration of moxifloxacin (400 mg), placebo, and guanfacine (day 1, 4 mg; day 6, 8 mg).
Figure 5. Mean HR (bpm) at baseline and following administration of moxifloxacin (400 mg), placebo, and guanfacine (day 1, 4 mg; day 6, 8 mg).
Pharmacokinetic-related measures The pharmacokinetic parameters for both moxifloxacin and guanfacine calculated following serial blood draws on days 1 and 6 are summarized in Table 3. Plasma concentrations over time on days 1 and 6 for moxifloxacin and guanfacine are shown in Figures 6 and 7, respectively. Cmax values for guanfacine were attained at a median of 3.1 and 5.0 hours post-dose on days 1 and 6, respectively. As predicted, systemic exposure to guanfacine, as assessed by Cmax, AUClast, and AUC0–24, was 3-fold greater following the 8-mg dose on day 6 than following the 4-mg dose administered on day 1. In addition, mean tmax for guanfacine on day 6 was 5.2 hours. As previously discussed and shown in Figure 3C, mean change in QTcF values at this time point were below the threshold of concern (i.e., 10 ms).
Table 3. Pharmacokinetic parameters for guanfacine and moxifloxacin on days 1 and 6.
Day 1 n Mean (SD) Day 6 n Mean (SD)
Guanfacine AUClast (ng×h/mL)
Cmax (ng/mL)
tmax (h)
76 8.51 (1.77)
76 3.9 (1.9)
64 64 24.70 (6.10) 5.2 (2.3)
Moxifloxacin AUClast (ng×h/mL)
AUC0–24 (ng×h/mL)
Cmax (ng/mL)
tmax (h)
76 110.8 (24.4)
74 113.8 (21.7)
72 1,943.1 (463.8)
72 2.13 (1.08)
72 19,892 (4,904)
71 20,106 (4,670)
64 370.3 (101.3)
63 376.9 (102.1)
57 2,003.4 (477.4)
57 1.78 (0.89)
57 20,767 (4,396)
57 20,794 (4,402)
AUC0–24 (ng×h/mL)
Cmax = maximum plasma concentration; tmax = time of Cmax; AUClast = area under the plasma drug concentration-time curve from time zero to the time of last quantifiable concentration; AUC0–24 = area under the plasma drug concentration-time curve from time zero to 24 hours; SD = standard deviation.
QT study of guanfacine
11 dose than following the 4-mg dose (6.0% vs. 1.3%, respectively). Most TEAEs reported during treatment with guanfacine (78.9%) were mild in severity. Severe TEAEs were experienced by 2 (2.6%) guanfacine-treated subjects: 1 case each of syncope and constipation.
Figure 6. Mean ± SD moxifloxacin plasma concentrations in subjects receiving 400 mg of moxifloxacin on days 1 and 6 (pharmacokinetic population); SD = standard deviation.
Figure 7. Mean ± SD guanfacine plasma concentrations in subjects receiving 4 mg of guanfacine on day 1 and 8 mg of guanfacine on day 6 (pharmacokinetic population); SD = standard deviation.
AEs and additional safety measures The incidence of TEAEs among subjects receiving guanfacine, moxifloxacin, and placebo was 100%, 63.9%, and 57.4%, respectively. Common TEAEs (≥ 5%) occurring in subjects receiving guanfacine are summarized in Table 4. Among guanfacine-treated subjects, only vomiting occurred substantially more frequently following the 8-mg
Cardiac TEAEs were rare during the study. Three events of bradycardia were reported, all occurring during guanfacine treatment. Two events were reported during the upward titration period (from guanfacine 4 mg to 8 mg during days 2 – 5), and the remaining event was reported on day 6 (guanfacine 8 mg). Palpitations were reported by 2 subjects (2.6%; 2/76) while receiving guanfacine and 1 subject (1.4%; 1/72) while receiving moxifloxacin. Tachycardia was reported by 1 participant while receiving guanfacine (1.3%; 1/76). The placebo-adjusted least square mean change in HR at 5 hours post-dose on day 6 for guanfacine (8 mg) was –19.26 (90% CI; –21.30, –17.22). Syncope was reported as a TEAE for 2 subjects (2.6%; 2/76), both on day 1 of the guanfacine treatment period. Both events were categorized a priori as SAEs. Both TEAEs of syncope occurred in subjects receiving a single dose of 4 mg of guanfacine. Both were judged related to study drug and both resolved. One event occurred in a 38-year-old male who discontinued due to micturition syncope as well as a separate episode of moderate dizziness. The Holter recording was consistent with vasovagal syncope of the cardioinhibitory type and demonstrated a prolonged sinus pause of 14.65 seconds terminating with a normal sinus beat and followed by reflex tachycardia. The other event was a serious event of severe vasovagal syncope in a 24-year-old female that did not lead to discontinuation; the subject completed the remainder of the study. However, the Holter recording during the episode revealed only a brief run of sinus tachycardia reaching 147 beats per minute. Additionally, vasovagal syncope of the cardioinhibitory type was reported in a 44-yearold male (on day 6 of guanfacine treatment), which was also considered an SAE. The subject had received 8 mg of guanfacine. In this instance, the Holter recording demonstrated a sinus pause of 8.31 seconds terminating with a normal sinus beat and moderate reflex
12
Martin, Satin, Kahn, et al.
Table 4. Summary of TEAEs that occurred in at least 5% of guanfacine-treated subjects by treatment regimen (safety population). Preferred term (MedDRA, version 11.0) Number of subjects (%) with TEAEs Dry mouth Dizziness Asthenia Constipation Headache Nausea Tinnitus Vision blurred Abdominal pain Dry eye Mucosal dryness Eustachian tube dysfunction Epistaxis Insomnia Myalgia Vomiting Dermatitis contact Diarrhea Dyspepsia Fatigue Hypoacusis Paresthesia Scotoma Abdominal distension Anxiety Hot flush Hypotension Irritability
Guanfacine (n = 76) 76 (100.0) 50 (65.8) 47 (61.8) 43 (56.6) 32 (42.1) 23 (30.3) 13 (17.1) 12 (15.8) 10 (13.2) 8 (10.5) 8 (10.5) 8 (10.5) 7 (9.2) 6 (7.9) 6 (7.9) 6 (7.9) 6 (7.9) 5 (6.6) 5 (6.6) 5 (6.6) 5 (6.6) 5 (6.6) 5 (6.6) 5 (6.6) 4 (5.3) 4 (5.3) 4 (5.3) 4 (5.3) 4 (5.3)
Moxifloxacin (n = 72) 46 (63.9) 2 (2.8) 6 (8.3) 6 (8.3) 4 (5.6) 8 (11.1) 14 (19.4) 1 (1.4) 0 5 (6.9) 4 (5.6) 0 0 0 1 (1.4) 0 4 (5.6) 8 (11.1) 2 (2.8) 1 (1.4) 1 (1.4) 1 (1.4) 1 (1.4) 0 1 (1.4) 0 1 (1.4) 0 1 (1.4)
Placebo (n = 68) 39 (57.4) 0 5 (7.4) 1 (1.5) 3 (4.4) 15 (22.1) 5 (7.4) 0 3 (4.4) 1 (1.5) 1 (1.5) 1 (1.5) 1 (1.5) 1 (1.5) 0 3 (4.4) 2 (2.9) 9 (13.2) 2 (2.9) 3 (4.4) 0 0 0 0 1 (1.5) 0 1 (1.5) 0 1 (1.5)
TEAE = treatment-emergent adverse eevent; MedDRA = Medical Dictionary for Regulatory Activities.
tachycardia. The event was determined to be unrelated to study drug and resolved. The subject completed the study. In total, 6 SAEs were reported by 5 study participants, with all events occurring during guanfacine treatment. In addition to the 3 subjects with syncope/vasovagal syncope described previously, 1 subject had SAEs of ileus and orthostatic hypotension and another reported an SAE of severe constipation. All 3 of these SAEs were considered related to the study drug and all resolved. No deaths occurred during the study. Of the 83 enrolled (and randomized) subjects, 22 subjects (26.5%) did not complete the study. Of these 22 subjects, 7 (31.8%) discontinued because of AEs, including 6 subjects who discontinued secondary to TEAEs (1 placebo-treated and 5 guanfacinetreated subjects). There were no clinically important changes in laboratory values.
Discussion The current study aimed to assess the effect of immediate-release guanfacine on the QT/QTc interval following therapeutic and supra-therapeutic doses of guanfacine as compared with placebo and a positive control (moxifloxacin). These types of studies are typically conducted in healthy adult volunteers as a routine part of clinical development to understand a medication’s effect on cardiac depolarization, as measured by the QT interval, at concentrations achieved by therapeutic and supra-therapeutic doses [19]. The guidelines define a negative thorough QT study as one in which the upper bound of the 95% 1-sided confidence interval (i.e., 95% UCB) for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms [19, 20]. To assess assay sensitivity, the use of a positive control, frequently moxifloxacin, is recommended. In view of the slight increases in QTcF and decreases in HR observed during treatment with GXR in prior late-phase safety and efficacy trials [4, 5], the current analysis strived to use a QT correction method that would provide an accurate means of evaluating the effects of guanfacine on QTc across a wide range of HRs. The subject-specific correction method (i.e., QTcNi) was chosen as the preferred correction method. As expected, moxifloxacin resulted in prolongation of QTcNi and QTcF on both day 1 and 6, demonstrating assay sensitivity and supporting the validity of the study. Following guanfacine administration, QTcNi showed no value above the upper bound of 10 ms at any time point from 0 to 12 hours post-dose. For the full 24-hour data, QTcNi results were negative for the supra-therapeutic dose of guanfacine at all time points from 13 – 24 hours except at hour 24 (17.70 ms). Although the mechanisms underlying this isolated increase in QTcNi are not completely clear, it occurred well after peak guanfacine concentration (5.2 hours post-dose) as HR was increasing toward baseline. Additional basic research is needed to understand the relative contributions of the peripheral and central nervous system (CNS) effects of guanfacine on HR, BP, and the QTc interval. In agreement with other data supporting CNS effects of guanfacine on vital
QT study of guanfacine
sign parameters [35, 36], the 12- to 24-hour QTc results of this study suggest that the plasma concentration of guanfacine (which reflects the peripheral component of its influence) is not the sole influence on the QTc. The QTc behavior at hour 24 (at the supratherapeutic dose) is different from that seen over hours 1 – 12, with results showing an increasing QTcF despite decreasing guanfacine plasma concentrations at times well past Cmax. However, guanfacine has no direct (concentration-dependent) effect on the QT interval and at hours 12 – 24, and QTcF values are reflective of changes in autonomic tone occurring as a result of decreasing systemic guanfacine concentrations following 6 days of supratherapeutic dosing. This leads to a change in autonomic tone reflected as an increase in HR toward pretreatment levels. For guanfacine, the QTcF value of the upper bound of the 95% 1-sided CI at the 12-hour post-dose time point on day 6 was above the 10-ms threshold. This time point is well outside the period of maximal concentration for guanfacine. Given the lack of a QT effect at guanfacine Cmax (~ 4 – 5 hours postdose) and the known HR effects of guanfacine, this isolated value may not be representative of a true QT effect. As previously discussed, the sensitivity of QTcF to changes in HR and the known effects of guanfacine on HR suggest that QTcNi may provide a better representation of the QT effect. The limitations of a fixed correction also may be responsible for the positive QTcF results following administration of a supra-therapeutic dose of guanfacine at all time points from hours 13 through 24 except at hours 19, 20, 21, and 22. Based on these results, the role of a fixed correction factor such as QTcF may be limited when evaluating the effect of a medication known to reduce HR, such as guanfacine, on QT intervals. For drugs without a clear effect on HR, QTcF works well. However, none of the fixed formula corrections (Bazett, Fridericia, or even the subject-specific QTcNi) is ideal for dealing with a drug such as guanfacine that has a negative chronotropic effect, with HR decreases in excess of 20 – 30 bpm at supra-therapeutic doses. The bradycardia induced by supra-therapeutic doses of immediate-release guanfacine is inherent to its pharmacology, and any study which uses sufficiently high supra-therapeutic
13 doses will demonstrate similar challenges. However, this study was compliant with the ICH E14 guidelines, and utilized the best of the available correction formulae to correct for HR. Although the study is complicated by the profound effect of guanfacine on HR, when examined as a whole, the data show that guanfacine does not increase the QTc interval nor does it behave in a manner similar to drugs that possess arrhythmogenic risk. The AE profile observed in the current trial is consistent with the known α2-agonist pharmacology of immediate-release guanfacine on HR, BP, sedation, and decreased bowel motility. The use of supra-therapeutic doses of guanfacine in addition to the aggressive titration schedule likely contributed to the high incidence of some AEs observed. In the context of both therapeutic and supratherapeutic doses of guanfacine, the incidence of bradycardia that was considered a TEAE was low and did not increase with increasing dose. Very few subjects exhibited an SBP, DBP, or pulse rate that met outlier criteria, and syncope was uncommon, even at supra-therapeutic doses of guanfacine. The 3 observed cases of syncope were consistent with micturition syncope in 1 instance and vasovagal syncope in the remaining 2 instances [37]. The plasma concentration data from the trial confirmed that the intended concentration of guanfacine was achieved by the supra-therapeutic dose. As a result of the pharmacokinetic differences between immediate-release guanfacine and GXR, it was felt that use of the immediate-release formulation in the current study would facilitate achievement of supra-therapeutic concentrations without affecting the ability to interpret QTc data since this is a concentration-related phenomenon. It should be noted, however, that the pharmacokinetic differences between immediate-release guanfacine and GXR, including a relatively delayed tmax, reduced Cmax, and reduced bioavailability of GXR, are such that dose substitution between the two guanfacine formulations on a milligram-for-milligram basis will result in differences in exposure, and therefore is not recommended in clinical practice [3]. In addition, the supra-therapeutic dose of guanfacine given in this study (8 mg) is based on concentrations that might occur in a patient
14
Martin, Satin, Kahn, et al.
who consumed a high-fat meal while also taking a potent CYP3A4 inhibitor and 4 mg of immediate-release guanfacine. However, patients should not take GXR with high-fat meals and caution should be exercised when administering GXR with CYP3A4 inhibitors, such as ketoconazole [3]. The results of the current study complement available evidence regarding the cardiac effects of GXR from trials conducted in children and adolescents with ADHD. Overall, small to modest changes in BP, pulse rate, and ECG parameters have been observed with GXR treatment (1 – 4 mg/d), but were not generally clinically meaningful [4, 5, 6, 7, 8, 38]. In short-term trials, among subjects who received GXR monotherapy, SBP, DBP, and pulse rate decreased as actual doses increased and then returned toward baseline as doses were stabilized and subsequently tapered [4, 5]. Dose-dependent decreases in BP and pulse rate were also observed when GXR was administered adjunctively to psychostimulants [8]. Similar cardiovascularrelated effects were observed in long-term, open-label trials of GXR [6, 7]. Interpretation of the results of this thorough QT study should be viewed in light of several methodological limitations. One major limitation is the ability to adequately interpret QT/QTc in drugs such as guanfacine that impact HR. Another limitation is the supratherapeutic dose of guanfacine evaluated in the current study. Although it was reflective of conditions that could, in theory, be encountered in clinical practice (i.e., co-administration of guanfacine with a CYP3A4 inhibitor and/or high-fat meals), the prescribing information for GXR encourages patients not to take the medication with high-fat meals and urges caution when administering GXR with CYP3A4 inhibitors, such as ketoconazole [3]. Therefore, the plasma concentrations of guanfacine achieved on day 6 of this study are far in excess of what would generally be seen with GXR use in routine clinical practice.
Conclusion The current randomized, double-blind, placebo- and positive-controlled study assessed the effects of guanfacine on QT/QTc interval in accordance with ICH guidelines. The inclusion of a moxifloxacin treatment
period demonstrated assay sensitivity and study validity. The AE profile observed in the current trial is consistent with the known pharmacology of guanfacine and was likely associated with rapid titration to a supra-therapeutic dose. As anticipated, treatment with guanfacine was associated with decreases in HR, which limits the interpretability of results employing a fixed correction method such as QTcF. During post-dose hours 1 – 12, at concentrations approximately twice the steady-state Cmax of the highest recommended therapeutic dose in children with ADHD, guanfacine did not prolong the QT interval, after correction for HR using the individualized correction method (QTcNi). Based on this study, guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.
Acknowledgments Clinical research was funded by the sponsor, Shire Development LLC. Under direction from the authors, Jennifer Steeber, PhD, formerly of SCI Scientific Communications & Information (SCI), provided writing assistance for this publication. Editorial assistance in the form of proofreading, copy editing, and fact checking was also provided by SCI. Additional editorial support was provided by Wilson Joe, PhD, of MedErgy. Jonathan Rubin, MD, MBA; Carla White, BSc, CStat; Edward Johnson, Michael Kahn, and Gina D’Angelo, PharmD, MBA, from Shire, also reviewed and edited the manuscript for scientific accuracy. Shire Development LLC provided funding to SCI and MedErgy for support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in the International Journal of Clinical Pharmacology and Therapeutics was made by the authors independently.
Conflicts of interest Patrick Martin is an employee of Shire and holds stock and/or stock options in Shire.
15
QT study of guanfacine
Lawrence Satin is a cardiac consultant for Shire and was the Chief Medical Officer at Cardiocore at the time of the study. Robert S. Kahn is an employee of Genentech, Inc. and was the Director of Medical Affairs, Charles River Clinical Services Northwest, at the time of the study. Antoine Robinson is an employee of Shire and holds stock and/or stock options in Shire. Mary Corcoran is an employee of Shire and holds stock and/or stock options in Shire. Jaideep Purkayastha is an employee of Shire and holds stock and/or stock options in Shire. Sharon Youcha was an employee of Shire at the time of the study and previously held stock and/or stock options in Shire. James C. Ermer is an employee of Shire and holds stock and/or stock options in Shire. This study was supported by Shire Development LLC, Wayne, PA, USA.
References Guanfacine hydrochloride [package insert]. Corona, CA: Watson Laboratories, Inc.; 2008. [2] US Food and Drug Administration. Tenex drug details. http://www.accessdata.fda.gov/scripts/cder/ drugsatfda/index.cfm. Accessed January 8, 2013. [3] INTUNIV® (guanfacine) extended-release tablets [package insert] Wayne, PA: Shire Pharmaceuticals Inc.; 2013. [4] Sallee FR, McGough J, Wigal T, Donahue J, Lyne A, Biederman J; SPD503 STUDY GROUP. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009; 48: 155-165. CrossRef PubMed [5] Biederman J, Melmed RD, Patel A, McBurnett K, Konow J, Lyne A, Scherer N; SPD503 Study Group. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008; 121: e73-e84. CrossRef PubMed [6] Sallee FR, Lyne A, Wigal T, McGough JJ. Longterm safety and efficacy of guanfacine extended release in children and adolescents with attentiondeficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009; 19: 215-226. CrossRef PubMed [7] Biederman J, Melmed RD, Patel A, McBurnett K, Donahue J, Lyne A. Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD. CNS Spectr. 2008; 13: 1047-1055. PubMed [8] Spencer TJ, Greenbaum M, Ginsberg LD, Murphy WR. Safety and effectiveness of coadministration
[9]
[10]
[11]
[12]
[13]
[1]
[14]
[15]
[16]
[17]
[18]
of guanfacine extended release and psychostimulants in children and adolescents with attentiondeficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009; 19: 501-510. CrossRef PubMed Wilens TE, Youcha S, Lyne A, Grannis K, Childress A, Findling R. A multisite placebo-controlled trial of morning or evening dosed extended-release guanfacine in combination with psychostimulants in children and adolescents with ADHD. Presented at: Society of Biological Psychiatry’s 66th Annual Meeting; May 20-22, 2010; New Orleans, LA, USA. 2010. Uhlén S, Wikberg JE. Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H] RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound. Eur J Pharmacol. 1991; 202: 235-243. CrossRef PubMed Buccafusco JJ, Lapp CA, Westbrooks KL, Ernsberger P. Role of medullary I1-imidazoline and alpha 2-adrenergic receptors in the antihypertensive responses evoked by central administration of clonidine analogs in conscious spontaneously hypertensive rats. J Pharmacol Exp Ther. 1995; 273: 1162-1171. PubMed Arnsten AF, Scahill L, Findling RL. alpha2-Adrenergic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: emerging concepts from new data. J Child Adolesc Psychopharmacol. 2007; 17: 393-406. CrossRef PubMed Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007; 129: 397-410. CrossRef PubMed Scholtysik G, Regli F, Bruckmaier RM, Blum JW. The alpha2-adrenoceptor agonists xylazine and guanfacine exert different central nervous system, but comparable peripheral effects in calves. J Vet Pharmacol Ther. 1998; 21: 477-484. CrossRef PubMed Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 1988; 8: 4287-4298. PubMed Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1996; 53: 448-455. CrossRef PubMed Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995; 34: 50-54. CrossRef PubMed Scahill L, Aman MG, McDougle CJ, McCracken JT, Tierney E, Dziura J, Arnold LE, Posey D, Young C, Shah B, Ghuman J, Ritz L, Vitiello B. A prospective open trial of guanfacine in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006; 16: 589-598. CrossRef PubMed
Martin, Satin, Kahn, et al. [19] US Department of Health and Human Services. The clinical evaluation of QT/QTC interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs: E14. http://www.fda.gov/ downloads/RegulatoryInformation/Guidances/ ucm129357.pdf. Accessed June 15, 2011. [20] Shah RR. Drugs, QTc interval prolongation and final ICH E14 guideline: an important milestone with challenges ahead. Drug Saf. 2005; 28: 10091028. CrossRef PubMed [21] Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Prog Cardiovasc Dis. 2001; 43 (Suppl 1): 1-45. PubMed [22] Patterson S. D. Investigating drug-induced QT and QTc prolongation in the clinic: a review of statistical design and analysis considerations: Report from the Pharmaceutical Research and Manufacturers of America QT Statistics Expert Team. Drug Inf J. 2005; 39: 243-266. [23] Damle B, Fosser C, Ito K, Tran A, Clax P, Uderman H, Glue P. Effects of standard and supratherapeutic doses of nelfinavir on cardiac repolarization: a thorough QT study. J Clin Pharmacol. 2009; 49: 291-300. CrossRef PubMed [24] Bloomfield DM, Kost JT, Ghosh K, Hreniuk D, Hickey LA, Guitierrez MJ, Gottesdiener K, Wagner JA. The effect of moxifloxacin on QTc and implications for the design of thorough QT studies. Clin Pharmacol Ther. 2008; 84: 475-480. CrossRef PubMed [25] Malik M, Hnatkova K, Ford J, Madge D. Nearthorough QT study as part of a first-in-man study. J Clin Pharmacol. 2008; 48: 1146-1157. CrossRef PubMed [26] Dixon R, Job S, Oliver R, Tompson D, Wright JG, Maltby K, Lorch U, Taubel J. Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects. Br J Clin Pharmacol. 2008; 66: 396-404. CrossRef PubMed [27] Malik M, Andreas JO, Hnatkova K, Hoeckendorff J, Cawello W, Middle M, Horstmann R, Braun M. Thorough QT/QTc study in patients with advanced Parkinson’s disease: cardiac safety of rotigotine. Clin Pharmacol Ther. 2008; 84: 595-603. CrossRef PubMed [28] Iwamoto M, Kost JT, Mistry GC, Wenning LA, Breidinger SA, Marbury TC, Stone JA, Gottesdiener KM, Bloomfield DM, Wagner JA. Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. J Clin Pharmacol. 2008; 48: 726-733. CrossRef PubMed [29] Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf. 2008; 31: 67-77. CrossRef PubMed [30] Hulhoven R, Rosillon D, Letiexhe M, Meeus MA, Daoust A, Stockis A. Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study. Eur J Clin Pharmacol. 2007; 63: 1011-1017. CrossRef PubMed [31] Malhotra BK, Glue P, Sweeney K, Anziano R, Mancuso J, Wicker P. Thorough QT study with recommended and supratherapeutic doses of tolterodine. Clin Pharmacol Ther. 2007; 81: 377-385. CrossRef PubMed
16 [32] Weiss YA, Lavene DL, Safar ME, Simon AC, Loria Y, Georges DR, Milliez PL. Guanfacine kinetics in patients with hypertension. Clin Pharmacol Ther. 1979; 25: 283-293. PubMed [33] Florian JA, Tornøe CW, Brundage R, Parekh A, Garnett CE. Population pharmacokinetic and concentration--QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. J Clin Pharmacol. 2011; 51: 1152-1162. CrossRef PubMed [34] Extramiana F, Maison-Blanche P, Cabanis MJ, Ortemann-Renon C, Beaufils P, Leenhardt A. Clinical assessment of drug-induced QT prolongation in association with heart rate changes. Clin Pharmacol Ther. 2005; 77: 247-258. CrossRef PubMed [35] Scholtysik G. Pharmacology of guanfacine. Br J Clin Pharmacol. 1980; 10 (Suppl 1): 21S-24S. CrossRef PubMed [36] van Zwieten PA, Timmermans PB. Pharmacology and characterization of central alpha-adrenoceptors involved in the effect of centrally acting antihypertensive drugs. Chest. 1983; 83 (Suppl): 340-343. PubMed [37] Vaddadi G, Corcoran SJ, Esler M. Management strategies for recurrent vasovagal syncope. Intern Med J. 2010; 40: 554-560. CrossRef PubMed [38] Connor DF, Findling RL, Kollins SH, Sallee F, López FA, Lyne A, Tremblay G. Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial. CNS Drugs. 2010; 24: 755-768. PubMed