- Email: [email protected]
A phase i, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults
Clinical Therapeutics/Volume 29, Number 4, 2007
A Phase I, Randomized, Open-Label, Crossover Study of the Single-Dose Pharmacokinetic Properties of Guanfacine Extended-Release 1-, 2-, and 4-mg Tablets in Healthy Adults Dennis Swearingen, MD1; Michael Pennick, BSc2; Amir Shojaei, PhD3; Andrew Lyne, MSc, Cstat2; and Kimberly Fiske, BS3 1MDS Pharma Services, Phoenix,Arizona; 2Shire PharmaceuticalDevelopment Ltd., Chineham, United Kingdom; and 3Shire DevelopmentInc., Wayne, Pennsylvania ABSTRACT
Background: Guanfacine is an %-adrenoreceptor agonist used to treat children and adults with attention-deficit/ hyperactivity disorder. An extended-release formulation of guanfacine is currently under development. Objective: The objective of this study was to assess the single-dose pharmacokinetic properties and dose proportionality of guanfacine extended-rdease (GXR) tablets after oral administration in healthy adults. Methods: This was a Phase I, randomized, openlabel, single-dose, crossover trial of GXR 1-, 2-, and 4-mg tablets in healthy adults. In the lead-in period (period 1), subjects received a single GXR 1-mg tablet, and then were randomized to receive single GXR 2- or 4-mg tablets during 4 separate weekly visits. Vital signs were monitored, blood samples were obtained, and subjects underwent electrocardiography (ECG) before dose administration and at regular intervals over 96 hours. The pharmacokinetic parameters of C.... AUC0_t, and AUC0_~ were determined after each dose of GXR in all subjects. Summary statistics for the concentration-time data were analyzed to assess between-dose linearity. An analysis-of-variance model was constructed to test the concentration-time data for dose proportionality. Tolerability was assessed at each visit through the analysis of standard serology tests; urinalysis/drug screen reports; and physical examination, including height and weight measurements; vital-sign data; and ECG findings. Results: The total study enrollment was 52 subjects, including 28 men (53.8%) and 24 (46.2%) women. The subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-54 years) and a mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120.0 kg). Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Three subjects were discontinued by the study investigators because of noncompliance with study procedures or use of concomitant medicaApril 2007
tions. Forty-nine subjects completed the study. Mean (SD) values for guanfacine plasma concentrations with GXR 1, 2, and 4 mg, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for Cmax; 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL • h -1 for AUC0_t; and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL • h -1 for AUC0~. Mean (SD) tl/2 values were 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 mg, respectively. The geometric mean ratios for C . . . . AUC0_t, and AUC0_~ were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in Cmax between GXR 1 and 2 mg. All treatment-emergent adverse events (AEs) were assessed as mild or moderate and resolved without treatment with the exception of headache in 3 subjects and 1 case of lower back discomfort, which resolved with therapy. Left rib pain was reported in 1 subject, but it is unknown if it had resolved, since the subject was lost to followup. No subjects withdrew from participation or were discontinued by the study investigators as a result of AEs. The most common treatment-emergent AE, somnolence, occurred in 33 (63.5%) of 52 subjects. All mean vital-sign measurements and mean ECG parameters remained within normal limits after dosing and no marked changes from baseline measurements were noted. Mean values for all test results of hematology and serum chemistry panels were within
The article was presented as an abstract at the 35th Annual Meeting of- the American College of- Clinical Pharmacy, October 26-29, 2006, St. Louis, Missouri.
Accepted for publicationJanuary 23, 200Z doi:l 0.1016/].clinthera.2007.04.016 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2007 Excerpta Medica, Inc.
61 7
Clinical Therapeutics
the reference range at completion of the study, with no significant changes from baseline. Conclusions: In these 49 healthy adult subjects, the single-dose pharmacokinetic properties of GXR 1-, 2-, and 4-mg tablets appeared to be statistically linear; that is, increases in mean C. . . . AUC0_t, and AUC0~ of guanfacine were proportional to dose, with the exception of the increase in mean Cmax between GXR 1 and 2 mg. All doses appeared to be well tolerated, with no serious AEs or withdrawal or discontinuation from study participation due to AEs reported. (Clin Ther. 2007;29:617-625). Copyright © 2007 Excerpta Medica, Inc. Key words: guanfacine, SPD503, attention-deficit/ hyperactivity disorder, ADHD, pharmacokinetics, stimulant, 0~2-adrenoceptor agonist.
INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders affecting children. Prevalence estimates vary, but according to data from the National Survey of Children's Health, -8% of US children were diagnosed with ADHD in 2003, and -56% of these children were treated with medication. 1 Prevalence appears to be higher in boys, with ADHD affecting an estimated 9% and 3% of elementary-school-aged boys and girls, respectively.2 Three subtypes of ADHD are recognized by health care professionals. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), 3 patients with ADHD may have symptoms that are of the predominantly hyperactive-impulsive type, predominantly inattentive type, or the combined type. Psychostimulant medications are the mainstay of therapy for patients with ADHD. 4-6 Although >80% of these patients receive stimulant drugs, <40% are reported to exhibit fully normal behavior with treatment. 4 Additionally, -30% of patients either do not respond to or cannot tolerate long-term therapy with these agents. 7,s An additional concern is that stimulants are classified by the US Drug Enforcement Administration as Schedule II controlled substances, which require a written prescription, in triplicate in some states, with every new prescription and refill. 9 Although stimulant drugs have been reported to be efficacious in controlling some symptoms of ADHD in -70% of patients, 7 concerns about the potential effects 618
of their long-term use, such as substance abuse and the slowing of growth in height and weight, have prompted investigators to examine the use of nonstimulant therapies. 7 Several classes of nonstimulant drugs appear to be efficacious in patients with ADHD, 7 including tricyclic antidepressants (eg, imipramine, desipramine), bupropion, and the 0~2-adrenoceptor agonists clonidine and guanfacine. 7 Norepinephrine has been reported to regulate prefrontal cortex functioning (PCF) through %-adrenoceptors, apparently modulating arousal and sensory sensitivity, as well as the processing of analytic thinking and reasoning. 1° Thus, the noradrenergic effects of psychostimulants, especially amphetamines, may be important for effective treatment of ADHD. The major effect of the stimulant methylphenidate, for instance, is increased synaptic concentration of dopamine through the blocking of presynaptic dopamine reuptake. Amphetamines work similarly, while also increasing the release of dopamine and norepinephrine. 11 The nonstimulant 0~2-adrenoceptor agonist guanfacine has been reported to enhance PCF in rats, monkeys, and humans; in patients with ADHD, guanfacine may ameliorate prefrontal cortical deficits. 12 Specifically, guanfacine appears to act primarily on the 0~2-adrenoceptors in the prefrontal cortex, enhancing working memory, cognitive function, and attentiveness. 13 Although the dopaminergic effects of amphetamines may be essential for attention, the noradrenergic effects of these drugs and of nonstimulant therapies targeting 0~2-adrenoceptors may increase attention and enhance executive function and working memory.1° Biochemical evidence from studies in rats has indicated that low oral doses of methylphenidate, which produce plasma concentrations in rats comparable to those in patients with ADHD, may have a greater effect on norepinephrine than on dopamine in subcortical structures. 14 Recent research suggests that low oral doses of methylphenidate may improve performance of PCF tasks in rats and mice due, in part, to 0~2adrenoceptor stimulation. 15 Consistent with this view, clinical trials have found that the 0~2-adrenoceptor guanfacine was associated with improvement in symptom scores and performance of PCF-regulated tasks in children 16-1s and adults 19 with ADHD as measured by the Connors' Continuous Performance Test (Par Inc., Lutz, Florida). These findings suggest that guanfacine may have a role in the treatment of ADHDrelated symptoms. Volume 29 Number 4
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Clinical trials have found immediate-release guanfacine to be well tolerated and effective in controlling symptoms of ADHD in adults and children. 16-19 In an open-label, controlled, 1-month trial in 13 children with ADHD (mean age, 11.1 years), children receiving immediaterelease guanfacine as monotherapy (titration range, 0.54 mg/d) had significantly greater improvement in symptom severity scores for hyperactivity and inattention than those receiving placebo (P < 0.01). lr In an g-week, placebo-controlled trial of guanfacine in children with ADHD and comorbid tic disorders (mean age, 10.4 years; range, 7-14 years), scores for commission and omission errors on the Connors' Continuous Performance Test decreased by 22% and 17%, respectively, in children receiving immediate-release guanfacine 1.5 mg compared with increases of 29% and 31%, respectively, in scores for placebo recipients (P = 0.01 and P = 0.04, respectively), is The children receiving guanfacine also had a 31% reduction in total tic scores on the Yale Global Tic Severity Scale compared with 0% improvement in the placebo group (P < 0.001). is In a 6-week, double-blind, placebocontrolled, crossover trial in 17 adults with ADHD, patients receiving immediate-release guanfacine (mean [SD] dose, 1.10 [0.60] mg) had improvements in symptom scores similar to those of patients receiving dextroamphetamine (mean [SD] dose, 10.2 [7.4] mg). 19 Mean (SD) total scores on the DSM-IV symptom checklist for the dextroamphetamine and guanfacine groups versus placebo group were 24.2 (12.0) and 22.3 (8.2), respectively, versus 30.4 (10.6) (P < 0.05). Compared with placebo recipients, both treatment groups had significantly greater improvement in Stroop Color subscale scores, however, only the guanfacine group had a significantly greater improvement in Stroop Color-Word task scores (P < 0.01). Based on the need for nonstimulant treatment options and initial positive reports of the efficacy and tolerability of immediate-release guanfacine for the treatment of ADHD symptoms, a once-daily formulation-guanfacine extended-release ([GXR] Shire Pharmaceutical Development code, SPD503)--is currently in development. Extended-release formulations offer greater dosing convenience than immediate-release formulations because they permit once-daily dosing; thus, there is the potential for improved treatment compliance with GXR. Tolerability and treatment effect may be improved because of fewer fluctuations in peak-to-trough plasma concentrations of guanfacine. Moreover, GXR could potentially provide effective symptom control throughout the day. April 2007
In the present study, the single-dose pharmacokinetic parameters, tolerability profile, and bioequivalence of GXR tablets manufactured at 2 different sites were examined in healthy adults (Pharmaceutics International Inc., Hunt Valley, Maryland and Shire US Manufacturing Inc., Owings Mills, Maryland). For the purpose of this article, the pharmacokinetic data for GXR tablets from each of these 2 manufacturers were pooled for analysis of dose proportionality. However, a discussion of the bioequivalence of GXR tablets from 2 different manufacturers is not within the scope of this article. SUBJECTS AND METHODS This was a Phase I, randomized, open-label, crossover study examining the single-dose pharmacokinetic parameters of GXR 1-, 2-, and 4-mg tablets. Institutional review board (IRB) approval (MDS Pharma Services IRB, Lincoln, Nebraska) was received to conduct the study, and written informed consent was obtained from all subjects.
Subjects Healthy men and women aged 18 to 55 years were recruited by the MDS facility in Phoenix, Arizona, through IRB-approved advertisements. Fifty-two volunteers were identified for study participation with -12 additional volunteers identified as backup subjects. A total of 52 subjects were enrolled. Subjects with any specific cardiac condition (including systolic/ diastolic blood pressure >140/>90 mm Hg or abnormal electrocardiographic [ECG] findings) or a family history of cardiac abnormalities were excluded from the study. Pregnant women and subjects using concomitant medications or illicit drugs also were excluded. Additional exclusion criteria were use of any investigational drug <30 days before study entry; donation of >500 mL blood or plasma <30 days before the first dose of the study drug; any plasma donation <7 days before the first dose of the study drug; treatment with any drug affecting the hepatic cytochrome P450 enzyme system <30 days before the first dose; hemoglobin level <12.0%; abnormal thyroid function; or clinical abnormality deemed significant in the opinion of the physician investigator. Subjects fasted overnight before receiving each dose of the study drug in all periods of all sequences. The study began with a lead-in period in which all subjects were administered a single GXR 1-mg tablet 619
Clinical Therapeutics with 240 mL of water. Subjects were then randomly assigned to 1 of 4 dosing sequences, each consisting of 4 treatment periods separated by a 7-day washout period. In periods 2 and 3, subjects were administered GXR 2-mg tablets; GXR 4-mg tablets were administered in periods 4 and 5. Thirteen subjects were randomized to each treatment sequence. Subjects who completed the study received all 3 doses of GXR. Subjects were given doses in a confined research facility that was supervised by clinical staff. Subjects arrived at the research facility 12 to 18 hours before each scheduled dose and remained for 48 hours until the first collection of blood samples. Subjects returned to the facility for the 72- and 96-hour collections. Subjects received a total sum compensation for all visits.
Blood Sample Collection Vital signs were monitored, blood samples were obtained, and ECG data were collected before dose administration for all subjects in all treatment periods and sequence groups. Monitoring of vital signs was repeated at 6, 7, 8, 9, 10, 24, 48, 72, and 96 hours after dose administration; ECG data were collected at 6, 7, 8, 9, 10, and 96 hours after doses were dispensed; and blood samples were obtained at 1, 2, 4, 5, 6, 8, 10, 12, 16, 18, 24, 48, 72, and 96 hours after each dose. Samples were maintained on wet ice until being centrifuged in preparation for plasma separation. Within 30 to 60 minutes after each sample collection, Vacutainer tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey) were centrifuged at 4°C at 3000 rpm for 10 minutes. The separated plasma was divided and placed into 2 tubes (primary tube and backup tube, each containing 1-1.5 mL of plasma). All plasma samples were stored in refrigerated storage units at -20°C until shipment. Plasma samples were shipped to the laboratory (Shire Laboratories Inc., Rockville, Maryland) on dry ice in an insulated container according to the regulations of the International Air Transport Association. The primary and backup samples were shipped at different times. Bioanalyltic analyses of guanfacine concentrations were determined using a validated liquid chromatographic mass spectrometric (LC/MS/MS) method. The upper and lower parameters of guanfacine concentrations in ethylenediaminetetraacetic-acid plasma were 0.05 and 25.0 ng/mL, respectively. The in-study accuracy and precision of the clinical samples were moni620
tored by simultaneous assays of quality-control (QC) and clinical samples. Mean accuracy rates of calibration standards for clinical and QC samples were between 98.0% and 101.8% and 100.5% and 107.6%, respectively, with precision rates of 1.8% to 3.8% and 4.6% to 5.6%, respectively. Pharmacokinetic analyses were performed by Kramer Consulting, Potomac, Maryland. Clinical laboratory analyses were performed by MDS Pharma Services, Phoenix, Arizona. ECG data were interpreted at a central facility (eResearch Technology, Philadelphia, Pennsylvania).
Tolerability Tolerability was assessed through analysis of AE data obtained from laboratory reports, including standard serology testing with complete blood-cell count and serum chemistry panel; screening for the HIV virus and hepatitis-B antibodies and surface antigens; urinalysis with screening for tetrahydrocannabinol, cocaine, phencyclidine, opiates, amphetamines, barbiturates, benzodiazepines, and alcohol; serum 13-human chorionic gonadotropin pregnancy testing for female subjects immediately before and after the study or on early withdrawal; ECG data; and the findings of a physical examination, including height and weight measurements and monitoring of vital signs. Drawing of all blood samples was performed at the testing center. To collect data on new-onset adverse effects (AEs) and other treatment-related concerns, the clinical staff contacted subjects by telephone -30 days after subjects received their final dose of GXR.
Statistical Methods C. . . . T . . . . AUC0_t, AUC0_~, terminal elimination rate constant ()~z),tl/2, apparent oral clearance (CLpo), and apparent volume of distribution (VffF) were calculated using noncompartmental analysis. Values for C. . . . AUC0_t, and AUC0~ , were normalized according to the amount (mg) of GXR given to subjects. Summary statistics were calculated for the GXR plasma concentration-time data. Data for the pharmacokinetic parameters of GXR 1-, 2-, and 4-mg tablets were statistically analyzed to assess linearity between doses. An analysis of variance was constructed on the logarithmic-scaled, dose-normalized pharmacokinetic data to test the effect of sequence, subject within sequence, dose, and tablet manufacturer on dose proportionality. Point estimates and 90% CIs were obtained for mean plasma concentration-time Volume 29 Number 4
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ratios. It was determined that the linearity of pharmacokinetic data could be concluded if the 90% CIs obtained for the mean geometric ratios of C . . . . AUC0_t, and AUC0~ were within the range of 0.80 to 1.25. Power analysis was based on a previous study of guanfacine in which it was found that the coefficient of variation in C . . . . AUC0_t, and AUC0~ values was -29%. Given that mean values for the pharmacokinetic parameters of a manufactured product are within the 93.5% region of another product, a sample size of 42 subjects would have 80% power to reject the null hypotheses at 1-sided significance levels of 5% in favor of the alternative hypothesis, which is that the products are bioequivalent. It was anticipated that 2 patients per period would withdraw or be discontinued prematurely from the study. To account for this, 52 subjects were recruited. RES U LTS The study enrolled 28 (53.8%) male and 24 (46.2%) female subjects. Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-55 years) and mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120 kg) (Table I). There were no marked differences in baseline demographic characteristics of subjects within or between sequence groups. Overall, baseline assessments, including laboratory values and the findings of physical examinations were within the reference range for male and female subjects. Forty-nine subjects completed the study. Three subjects were discontinued by study investigators (1 tested positive for amphetamines, 1 did not comply with all study procedures, and 1 simultaneously participated in 2 clinical research studies); data for these subjects were included in the pharmacokinetic analyses. All subjects who completed the study were compliant with treatment. Phamacokinetic Results Values for mean (SD) guanfacine plasma concentrations were for GXR 1, 2, or 4 rag, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for Cmax; 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL • h -1 for AUC0_t; and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL • h -1 for AUC0_~. Mean (SD) tl/2 was 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 rag, respectively. April 2007
Table I. Baseline demographic and clinical characteristics of randomized subjects receiving guanracine extended-release 1-, 2-, and 4-mg tablets (N = 52). Characteristic Race, no. (%) Hispanic White Black Sex, no. (%) Male Female Age, y Mean (SD) Median, range Weight, kg Mean (SD) Median, range Height, cm Mean (SD) Median, range
Value 40 (76.9) 7 (13.5) 5 (9.6) 28 (53.8) 24 (46.2) 32.9 (10.3) 29.0 (18-54) 73.4 (15.7) 69.1 (49.6-120) 167.9 (11.18) 167.1 (149.9-188)
D o s e Proportionality The pharmacokinetic parameters of GXR 1, 2, and 4 mg exhibited a generally linear statistical relationship. Mean increases in plasma concentrations of guanfacine were proportional to the amount (rag) of GXR given to subjects (Figure). Increases in mean C . . . . AUC0_t, and AUC0~ , particularly between GXR 2 and 4 rag, were generally proportional to dose (Table II). Although, there was an -2.5-fold variation in mean body weight among study subjects, when body weight was normalized to 70 kg per individual, the pharmacokinetic parameters of GXR were similarly dose proportional (Table III). The 90% CIs obtained for the geometric mean ratios of dosenormalized C . . . . AUC0_t, and AUC0_~ between GXR 1 and 4 mg and between GXR 2 and 4 mg were within the region of 1.0, with the exception of the increase in mean CmaX between GXR 1 and 2 mg (Table IV). Consistent with the comparisons of dose-normalized data, the lower limits of the 90% CIs for the geometric mean ratios with GXR 1:2 mg were >1.0, indicating a slight lack of proportionality at the lowest dose (ie, plasma levels did not increase proportionally as the dose was increased from 1 to 2 rag). 621
Clinical Therapeutics
4-
,~2
I
I m g (n = 52) 2 m g ( n = I00) 4 m g (n = 98)
3-
rg
E~ R-._ v
~u
2-
q~
1
0
2
4
6
8
10
12
14
16
18
I
I
I
20
22
24
Time After Study Drug Administration (h)
Figure. Mean plasma concentrations after oral administration ofguanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults (N = 49).
Table II. Single-dose pharmacokinetic properties o f guanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults. All values are mean (SD) unless otherwise indicated (N = 49).* Dose o f GXR
Parameter C . . . . ng/mL AUC0 t, ng/mL" h if AUC 0 ~, ng/mL" h if Tmax, median, hf Xz, h if tl/2, hf
1 mg (n = 52)
2 mg (n = 100)
4 mg (n = 98)
0.98 (0.26) 29.3 (8.8) 32.4 (8.8) 6.0 0.0416 (0.009) 17.5 (3.8)
1.57 (0.51) 54.5 (17.7) 58.0 (18.9) 6.0 0.0436 (0.008) 16.6 (3.8)
3.58 (1.39) 119.1 (42.3) 124.1 (45.1) 5.5 0.0441 (0.009) 16.7 (4.9)
560 (194) 7.75 (2.22)
642 (229) 8.91 (3.3)
619 (278) 8.52 (3.3)
823 (249)
891 (285)
860 (346)
1 1.4 (3.0)
1 2.4 (3.8)
1 2.0 (4.5)
CL/F, kgf mL/min mL/min" h 1 Vz/Ff L
L/kg
Z,z = terminal elimination rate constant; CL/F = apparent oral clearance; V/F = apparent volume of distribution. *No. of plasma concentration-time measurements, with -2 per subject for GXR 2 and 4 mg: fn = 43, 96, and 98 for GXR 1, 2, and 4 mg, respectively.
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Table III. Single-dose pharmacokinetic parameters (normalized to a body weight of 70 kg per subject) ofguanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults (N = 49). All values are mean (SD).
Dose of GXR 1 mg (n = 52)
Parameter ng/mk AUC0t, n g / m L ' h 1~ AUC0 ~ , n g / m L ' h 1~ CL/F, mL/min ~ Vz/F, k~ C....
0.99 (0.38) 29.7 (11.6) 32.9 (11.8) 543 (156) 798 (212)
2 mg (n =100) 1.60 55.8 59.3 623 867
4 mg (n = 98)
(0.70) (24.3) (25.9) (212) (268)
3.67 (1.86) 122.0 (56.0) 127.1 (59.0) 596 (231) 837 (318)
n = number of plasma concentration-time measurements, with -2 per subject for GXR 2 and 4 mg; CL/F = apparent oral clearance; VJF = apparent volume of distribution. +~n= 43, 96, and 98, for GXR 1, 2, and 4 rag, respectively.
Table IV. Results of analysis of variance (logarithmic-scaled, dose-proportional) of the single-dose pharmacoki-
netic parameters ofguanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults (N = 49). Values are mean (SD) unless otherwise indicated. Estimated Geometric Mean Ratios Between Doses of GXR (90% CI)
Dose of GXR
Parameter
1 mg
2 mg
4 mg
1:2 mg
1:4 mg
2:4 mg
C. . . .
0.940
0.747
0.845
1.258 (1.169-1.354)
1.112 (1.033-1.197)
0.884 (0.836-0.934)
AUC0 t, ng/mL" h 1
27.825
25.806
27.860
1.078 (1.008-1.153)
0.999 (0.934-1.069)
0.926 (0.880-0.975)
AUC0 ~, ng/mL" h 1
29.605
27.289
28.993
1.085 (1.009-1.166)
1.021 (0.950-1.097)
0.941 (0.894-0.991)
ng/mL
Tolerability A total of 172 AEs were reported by 40 (76.9%) of 52 subjects. Most AEs (170) were assessed by the study investigators or subjects as mild; 2 were assessed as moderate, and none were assessed as severe or serious. Of the 172 reported AEs, 143 were determined by the study investigators to be probably or possibly related to the study drug. None of the subjects withdrew from the study or were discontinued by the investigators because of AEs. Although 5 subjects reported mild chest discomfort or chest pain, analysis of laboratory results, April 2007
vital-sign and ECG data, and physical examination findings indicated no clinically significant cardiovascular abnormalities. AEs affecting the nervous system, including somnolence, dizziness, headache, and loss of consciousness (reported by 1 subject as "faintness" after blood was drawn and resolved without treatment <10 minutes) were the most common, occurring in 37 (71.2%) subjects. Somnolence, headache, dizziness, dry mouth, and fatigue occurred in 33 (63.5%), 19 (36.5%), 6 (11.5%), (11.5%), and 5 (9.6%) of subjects, respectively (Table V). 623
Clinical Therapeutics
DISCUSSION Stimulant drugs have been reported to be efficacious in controlling symptoms in -70% of patients with ADHD7; however, -30% of patients receiving these medications either do not respond to treatment or cannot tolerate this type of medication. 8 Early clinical findings have suggested that immediate-release guanfacine may provide therapeutic efficacy for symptoms of ADHD. 16-19 Extended-release formulations offer 3 potential improvements over immediate-release formulations. First, therapeutic concentrations could potentially be sustained over longer periods with less fluctuation in plasma drug concentrations of these drugs. Second, incidence of AEs might potentially be reduced, since initial plasma concentrations of these drugs would not be expected to be as great. With some immediaterelease preparations, the active drug may reach Cmax quickly; thus, AEs can emerge unexpectedly. For example, hypotension has been reported to occur in some patients receiving immediate-release nifedipine for hypertension.21 Sudden reductions in blood pressure and other significant hemodynamic changes associated with high initial serum concentrations of some immediate-release formulations may be avoided with extended-release formulations. Third, because fewer daily doses may be required with extended-release products, treatment compliance might be improved. For example, in an event-monitoring study in newly treated and long-term epilepsy patients, study investigators found an inverse correlation between dosing frequency and treatment compliance.22 In that study, the averaged compliance rates with medications administered 1, 2, 3, or 4 times daily were 87%, 81%, 77%, and 39%, respectively. Thus, improved treatment compliance may be associated with once-daily formulations. Although published clinical trials have examined the efficacy of immediate-release guanfacine administered 2 to 4 times daily in adults and children with symptoms of ADHD, 16-19 the efficacy of GXR of single-dose tablets is still under investigation. Study Limitations Because this was a single-dose study, long-term AEs could not be assessed. Somnolence, characterized as mild to moderate, was the most frequently reported AE. However, in the trial of immediate-release guanfacine in children with ADHD and comorbid tic disorders, is 6 subjects complained of mild sedation that 624
Table V. Treatment-emergent adverse events reported in _>10% of healthy adults receiving single oral doses of guanfacine extended-release 1-, 2-, and 4-mg tablets (N = 52). Adverse Event
No. (%) of Subjects
Somnolence
33 (63.5)
Headache
19 (36.5)
Dizziness
6 (11.5)
Dry mouth
6 (11.5)
Fatigue
5
(9.6)
resolved in time with continued treatment or decrease in dose. Although c~2-adrenoceptor agonists have been associated with sleepiness and lowered blood pressure, 17a8 theoretically, extended-release formulations might help ameliorate these effects. The present study findings suggest a statistically linear between-dose relationship in the pharmacokinetic parameters of GXR 1-, 2-, and 4-rag tablets; thus, GXR might potentially offer improved tolerability. CONCLUSIONS In this small population of healthy adults, the singledose pharmacokinetic parameters of GXR 1-, 2-, and 4-rag tablets were generally linear statistically. Increases in mean C . . . . AUC0_t, and AUC0~ of guanfacine were proportional to dose, with the exception of the increase in mean Cmax between GXR 1 and 2 nag. All 3 doses appeared to be well tolerated, with no serious AEs or related withdrawals or discontinuation from study participation due to AEs. ACKNOWLEDGM ENTS The authors thank NeoHealth Inc., Hasbrouck Heights, New Jersey, for assistance with the writing and editing of this manuscript. REFERENCES 1. Centers for Disease Control and Prevention (CDC). Mental health in the United States. Prevalence of-diagnosis and medication treatment for attention-deficit/ hyperactivity disorder-United States, 2003. MMWR Morb Mortal Wkly Re/). 2005;54:842-847.
2. Cincinnati Children's Hospital Medical Center. Evidence based clinical practice guidelines: Outpatient evaluation and management of attention deficit/hyperactivitydisorVolume 29 Number 4
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der. Cincinnati, Ohio: Cincinnati Children's Hospital Medical Center; April 30, 2004.
3. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000. 4. American Academy of Pediatrics Subcommittee on Attention-Deficit/ Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: Treatment of the school-aged child with attention-deficit~hyperactivity disorder. Pediatrics. 2001 ;108:1033-1044. 5. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attentiondeficit~hyperactivity disorder. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry.
1999;56:1073-1086. 6. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-Month outcomes of treatment strategies for attentiondeficit/hyperactivity disorder. Pediatrics. 2004;113:754-761. 7. Olfson M. New options in the pharmacological management of attentiondeficit~hyperactivity disorder. Am J Manag Care. 2004;10(Suppl 4): 5117-5124. 8. WaxmonskyJG. Nonstimulant therapies for attention-deficit hyperactivity disorder ( A D H D ) i n children and adults. Essent Psychopharmacol. 2005; 6:262-276. 9. US Food and Drug Administration. Drugs of abuse. Chapter 5 Stimulants, http://www, u sdoj.gov/dea/ pu bs/abuse/5-stim.htl. Accessed April 9, 2005. 10. Arnsten AF, Li BM. Neurobiolo~ of executive functions: Catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377-1384. 11. Pliszka SR. The neuropsychopharmacology of attention-deficit/ hyperactivity disorder. Biol Psychiatry. 2005;57:1385-1390. April 2 0 0 7
12. FranowiczJS, Kessler LE, Borja CM, et al. Mutation of the 0~2-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine.J Neurosci. 2002;22:8771-8777. 13. Arnsten AF, SteereJC, Hunt RD. The contribution of 0~2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry.
1996;53:448-455. 14. Kuczenski R, Segal DS. Exposure of adolescent rats to oral methylphenidate prefrontal effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci. 2002;22:7264-7271. 15. Arnsten AFT, Dudley AG. Methylphenidate improves prefrontal cortical cognitive function through 0~-adrenoreceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in attention deficit hyperactivity disorder. Behav Brain Funct. 2005;1:2. 16. HorriganJP, Barnhill.J. Guanfacine for treatment of attention-deficit hyperactivity disorder in boys. J Child Adolesc Psychopharmacol. 1995;5:215-223.
17. Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder.JAm Acad ChildAdolesc Psychiatry. 1995;34:50-54. 18. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study ofguanracine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001 ;158:1067-1074. 19. Taylor FB, Russo J. Comparing guanfacine and dextroamphetamine for the treatment of adult attentiondeficit~hyperactivity disorder. J Clin Psychopharmacol. 2001 ;21:223-228. 20. Chappell PB, Riddle MA, Scahill L, et al. Guanfacine treatment ofcomorbid attention-deficit hyperactivity disorder and Tourette's syndrome: Preliminary clinical experience. J Am Acad Child Adolesc Psychiatry. 1995;34: 1140-1146. 21. Opie LH, Messerli FH. Nifedipine and mortality. Grave defects in the dossier.
Circulation. 1995;92:1068-1073. 22. CramerJA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique [published correction appears in JAMA. 1989;262:1472].
JAMA. 1989;261:3273-3277.
Address correspondence to: Dennis Swearingen, MD, MDS Pharma Services,
4747 East Beautiful Lane, Phoenix, AZ 85044. E-maih dennis.swearingen@ mdsps.com 625
A Phase I, Randomized, Open-Label, Crossover Study of the Single-Dose Pharmacokinetic Properties of Guanfacine Extended-Release 1-, 2-, and 4-mg Tablets in Healthy Adults Dennis Swearingen, MD1; Michael Pennick, BSc2; Amir Shojaei, PhD3; Andrew Lyne, MSc, Cstat2; and Kimberly Fiske, BS3 1MDS Pharma Services, Phoenix,Arizona; 2Shire PharmaceuticalDevelopment Ltd., Chineham, United Kingdom; and 3Shire DevelopmentInc., Wayne, Pennsylvania ABSTRACT
Background: Guanfacine is an %-adrenoreceptor agonist used to treat children and adults with attention-deficit/ hyperactivity disorder. An extended-release formulation of guanfacine is currently under development. Objective: The objective of this study was to assess the single-dose pharmacokinetic properties and dose proportionality of guanfacine extended-rdease (GXR) tablets after oral administration in healthy adults. Methods: This was a Phase I, randomized, openlabel, single-dose, crossover trial of GXR 1-, 2-, and 4-mg tablets in healthy adults. In the lead-in period (period 1), subjects received a single GXR 1-mg tablet, and then were randomized to receive single GXR 2- or 4-mg tablets during 4 separate weekly visits. Vital signs were monitored, blood samples were obtained, and subjects underwent electrocardiography (ECG) before dose administration and at regular intervals over 96 hours. The pharmacokinetic parameters of C.... AUC0_t, and AUC0_~ were determined after each dose of GXR in all subjects. Summary statistics for the concentration-time data were analyzed to assess between-dose linearity. An analysis-of-variance model was constructed to test the concentration-time data for dose proportionality. Tolerability was assessed at each visit through the analysis of standard serology tests; urinalysis/drug screen reports; and physical examination, including height and weight measurements; vital-sign data; and ECG findings. Results: The total study enrollment was 52 subjects, including 28 men (53.8%) and 24 (46.2%) women. The subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-54 years) and a mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120.0 kg). Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Three subjects were discontinued by the study investigators because of noncompliance with study procedures or use of concomitant medicaApril 2007
tions. Forty-nine subjects completed the study. Mean (SD) values for guanfacine plasma concentrations with GXR 1, 2, and 4 mg, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for Cmax; 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL • h -1 for AUC0_t; and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL • h -1 for AUC0~. Mean (SD) tl/2 values were 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 mg, respectively. The geometric mean ratios for C . . . . AUC0_t, and AUC0_~ were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in Cmax between GXR 1 and 2 mg. All treatment-emergent adverse events (AEs) were assessed as mild or moderate and resolved without treatment with the exception of headache in 3 subjects and 1 case of lower back discomfort, which resolved with therapy. Left rib pain was reported in 1 subject, but it is unknown if it had resolved, since the subject was lost to followup. No subjects withdrew from participation or were discontinued by the study investigators as a result of AEs. The most common treatment-emergent AE, somnolence, occurred in 33 (63.5%) of 52 subjects. All mean vital-sign measurements and mean ECG parameters remained within normal limits after dosing and no marked changes from baseline measurements were noted. Mean values for all test results of hematology and serum chemistry panels were within
The article was presented as an abstract at the 35th Annual Meeting of- the American College of- Clinical Pharmacy, October 26-29, 2006, St. Louis, Missouri.
Accepted for publicationJanuary 23, 200Z doi:l 0.1016/].clinthera.2007.04.016 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2007 Excerpta Medica, Inc.
61 7
Clinical Therapeutics
the reference range at completion of the study, with no significant changes from baseline. Conclusions: In these 49 healthy adult subjects, the single-dose pharmacokinetic properties of GXR 1-, 2-, and 4-mg tablets appeared to be statistically linear; that is, increases in mean C. . . . AUC0_t, and AUC0~ of guanfacine were proportional to dose, with the exception of the increase in mean Cmax between GXR 1 and 2 mg. All doses appeared to be well tolerated, with no serious AEs or withdrawal or discontinuation from study participation due to AEs reported. (Clin Ther. 2007;29:617-625). Copyright © 2007 Excerpta Medica, Inc. Key words: guanfacine, SPD503, attention-deficit/ hyperactivity disorder, ADHD, pharmacokinetics, stimulant, 0~2-adrenoceptor agonist.
INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders affecting children. Prevalence estimates vary, but according to data from the National Survey of Children's Health, -8% of US children were diagnosed with ADHD in 2003, and -56% of these children were treated with medication. 1 Prevalence appears to be higher in boys, with ADHD affecting an estimated 9% and 3% of elementary-school-aged boys and girls, respectively.2 Three subtypes of ADHD are recognized by health care professionals. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), 3 patients with ADHD may have symptoms that are of the predominantly hyperactive-impulsive type, predominantly inattentive type, or the combined type. Psychostimulant medications are the mainstay of therapy for patients with ADHD. 4-6 Although >80% of these patients receive stimulant drugs, <40% are reported to exhibit fully normal behavior with treatment. 4 Additionally, -30% of patients either do not respond to or cannot tolerate long-term therapy with these agents. 7,s An additional concern is that stimulants are classified by the US Drug Enforcement Administration as Schedule II controlled substances, which require a written prescription, in triplicate in some states, with every new prescription and refill. 9 Although stimulant drugs have been reported to be efficacious in controlling some symptoms of ADHD in -70% of patients, 7 concerns about the potential effects 618
of their long-term use, such as substance abuse and the slowing of growth in height and weight, have prompted investigators to examine the use of nonstimulant therapies. 7 Several classes of nonstimulant drugs appear to be efficacious in patients with ADHD, 7 including tricyclic antidepressants (eg, imipramine, desipramine), bupropion, and the 0~2-adrenoceptor agonists clonidine and guanfacine. 7 Norepinephrine has been reported to regulate prefrontal cortex functioning (PCF) through %-adrenoceptors, apparently modulating arousal and sensory sensitivity, as well as the processing of analytic thinking and reasoning. 1° Thus, the noradrenergic effects of psychostimulants, especially amphetamines, may be important for effective treatment of ADHD. The major effect of the stimulant methylphenidate, for instance, is increased synaptic concentration of dopamine through the blocking of presynaptic dopamine reuptake. Amphetamines work similarly, while also increasing the release of dopamine and norepinephrine. 11 The nonstimulant 0~2-adrenoceptor agonist guanfacine has been reported to enhance PCF in rats, monkeys, and humans; in patients with ADHD, guanfacine may ameliorate prefrontal cortical deficits. 12 Specifically, guanfacine appears to act primarily on the 0~2-adrenoceptors in the prefrontal cortex, enhancing working memory, cognitive function, and attentiveness. 13 Although the dopaminergic effects of amphetamines may be essential for attention, the noradrenergic effects of these drugs and of nonstimulant therapies targeting 0~2-adrenoceptors may increase attention and enhance executive function and working memory.1° Biochemical evidence from studies in rats has indicated that low oral doses of methylphenidate, which produce plasma concentrations in rats comparable to those in patients with ADHD, may have a greater effect on norepinephrine than on dopamine in subcortical structures. 14 Recent research suggests that low oral doses of methylphenidate may improve performance of PCF tasks in rats and mice due, in part, to 0~2adrenoceptor stimulation. 15 Consistent with this view, clinical trials have found that the 0~2-adrenoceptor guanfacine was associated with improvement in symptom scores and performance of PCF-regulated tasks in children 16-1s and adults 19 with ADHD as measured by the Connors' Continuous Performance Test (Par Inc., Lutz, Florida). These findings suggest that guanfacine may have a role in the treatment of ADHDrelated symptoms. Volume 29 Number 4
D. Swearingen et al.
Clinical trials have found immediate-release guanfacine to be well tolerated and effective in controlling symptoms of ADHD in adults and children. 16-19 In an open-label, controlled, 1-month trial in 13 children with ADHD (mean age, 11.1 years), children receiving immediaterelease guanfacine as monotherapy (titration range, 0.54 mg/d) had significantly greater improvement in symptom severity scores for hyperactivity and inattention than those receiving placebo (P < 0.01). lr In an g-week, placebo-controlled trial of guanfacine in children with ADHD and comorbid tic disorders (mean age, 10.4 years; range, 7-14 years), scores for commission and omission errors on the Connors' Continuous Performance Test decreased by 22% and 17%, respectively, in children receiving immediate-release guanfacine 1.5 mg compared with increases of 29% and 31%, respectively, in scores for placebo recipients (P = 0.01 and P = 0.04, respectively), is The children receiving guanfacine also had a 31% reduction in total tic scores on the Yale Global Tic Severity Scale compared with 0% improvement in the placebo group (P < 0.001). is In a 6-week, double-blind, placebocontrolled, crossover trial in 17 adults with ADHD, patients receiving immediate-release guanfacine (mean [SD] dose, 1.10 [0.60] mg) had improvements in symptom scores similar to those of patients receiving dextroamphetamine (mean [SD] dose, 10.2 [7.4] mg). 19 Mean (SD) total scores on the DSM-IV symptom checklist for the dextroamphetamine and guanfacine groups versus placebo group were 24.2 (12.0) and 22.3 (8.2), respectively, versus 30.4 (10.6) (P < 0.05). Compared with placebo recipients, both treatment groups had significantly greater improvement in Stroop Color subscale scores, however, only the guanfacine group had a significantly greater improvement in Stroop Color-Word task scores (P < 0.01). Based on the need for nonstimulant treatment options and initial positive reports of the efficacy and tolerability of immediate-release guanfacine for the treatment of ADHD symptoms, a once-daily formulation-guanfacine extended-release ([GXR] Shire Pharmaceutical Development code, SPD503)--is currently in development. Extended-release formulations offer greater dosing convenience than immediate-release formulations because they permit once-daily dosing; thus, there is the potential for improved treatment compliance with GXR. Tolerability and treatment effect may be improved because of fewer fluctuations in peak-to-trough plasma concentrations of guanfacine. Moreover, GXR could potentially provide effective symptom control throughout the day. April 2007
In the present study, the single-dose pharmacokinetic parameters, tolerability profile, and bioequivalence of GXR tablets manufactured at 2 different sites were examined in healthy adults (Pharmaceutics International Inc., Hunt Valley, Maryland and Shire US Manufacturing Inc., Owings Mills, Maryland). For the purpose of this article, the pharmacokinetic data for GXR tablets from each of these 2 manufacturers were pooled for analysis of dose proportionality. However, a discussion of the bioequivalence of GXR tablets from 2 different manufacturers is not within the scope of this article. SUBJECTS AND METHODS This was a Phase I, randomized, open-label, crossover study examining the single-dose pharmacokinetic parameters of GXR 1-, 2-, and 4-mg tablets. Institutional review board (IRB) approval (MDS Pharma Services IRB, Lincoln, Nebraska) was received to conduct the study, and written informed consent was obtained from all subjects.
Subjects Healthy men and women aged 18 to 55 years were recruited by the MDS facility in Phoenix, Arizona, through IRB-approved advertisements. Fifty-two volunteers were identified for study participation with -12 additional volunteers identified as backup subjects. A total of 52 subjects were enrolled. Subjects with any specific cardiac condition (including systolic/ diastolic blood pressure >140/>90 mm Hg or abnormal electrocardiographic [ECG] findings) or a family history of cardiac abnormalities were excluded from the study. Pregnant women and subjects using concomitant medications or illicit drugs also were excluded. Additional exclusion criteria were use of any investigational drug <30 days before study entry; donation of >500 mL blood or plasma <30 days before the first dose of the study drug; any plasma donation <7 days before the first dose of the study drug; treatment with any drug affecting the hepatic cytochrome P450 enzyme system <30 days before the first dose; hemoglobin level <12.0%; abnormal thyroid function; or clinical abnormality deemed significant in the opinion of the physician investigator. Subjects fasted overnight before receiving each dose of the study drug in all periods of all sequences. The study began with a lead-in period in which all subjects were administered a single GXR 1-mg tablet 619
Clinical Therapeutics with 240 mL of water. Subjects were then randomly assigned to 1 of 4 dosing sequences, each consisting of 4 treatment periods separated by a 7-day washout period. In periods 2 and 3, subjects were administered GXR 2-mg tablets; GXR 4-mg tablets were administered in periods 4 and 5. Thirteen subjects were randomized to each treatment sequence. Subjects who completed the study received all 3 doses of GXR. Subjects were given doses in a confined research facility that was supervised by clinical staff. Subjects arrived at the research facility 12 to 18 hours before each scheduled dose and remained for 48 hours until the first collection of blood samples. Subjects returned to the facility for the 72- and 96-hour collections. Subjects received a total sum compensation for all visits.
Blood Sample Collection Vital signs were monitored, blood samples were obtained, and ECG data were collected before dose administration for all subjects in all treatment periods and sequence groups. Monitoring of vital signs was repeated at 6, 7, 8, 9, 10, 24, 48, 72, and 96 hours after dose administration; ECG data were collected at 6, 7, 8, 9, 10, and 96 hours after doses were dispensed; and blood samples were obtained at 1, 2, 4, 5, 6, 8, 10, 12, 16, 18, 24, 48, 72, and 96 hours after each dose. Samples were maintained on wet ice until being centrifuged in preparation for plasma separation. Within 30 to 60 minutes after each sample collection, Vacutainer tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey) were centrifuged at 4°C at 3000 rpm for 10 minutes. The separated plasma was divided and placed into 2 tubes (primary tube and backup tube, each containing 1-1.5 mL of plasma). All plasma samples were stored in refrigerated storage units at -20°C until shipment. Plasma samples were shipped to the laboratory (Shire Laboratories Inc., Rockville, Maryland) on dry ice in an insulated container according to the regulations of the International Air Transport Association. The primary and backup samples were shipped at different times. Bioanalyltic analyses of guanfacine concentrations were determined using a validated liquid chromatographic mass spectrometric (LC/MS/MS) method. The upper and lower parameters of guanfacine concentrations in ethylenediaminetetraacetic-acid plasma were 0.05 and 25.0 ng/mL, respectively. The in-study accuracy and precision of the clinical samples were moni620
tored by simultaneous assays of quality-control (QC) and clinical samples. Mean accuracy rates of calibration standards for clinical and QC samples were between 98.0% and 101.8% and 100.5% and 107.6%, respectively, with precision rates of 1.8% to 3.8% and 4.6% to 5.6%, respectively. Pharmacokinetic analyses were performed by Kramer Consulting, Potomac, Maryland. Clinical laboratory analyses were performed by MDS Pharma Services, Phoenix, Arizona. ECG data were interpreted at a central facility (eResearch Technology, Philadelphia, Pennsylvania).
Tolerability Tolerability was assessed through analysis of AE data obtained from laboratory reports, including standard serology testing with complete blood-cell count and serum chemistry panel; screening for the HIV virus and hepatitis-B antibodies and surface antigens; urinalysis with screening for tetrahydrocannabinol, cocaine, phencyclidine, opiates, amphetamines, barbiturates, benzodiazepines, and alcohol; serum 13-human chorionic gonadotropin pregnancy testing for female subjects immediately before and after the study or on early withdrawal; ECG data; and the findings of a physical examination, including height and weight measurements and monitoring of vital signs. Drawing of all blood samples was performed at the testing center. To collect data on new-onset adverse effects (AEs) and other treatment-related concerns, the clinical staff contacted subjects by telephone -30 days after subjects received their final dose of GXR.
Statistical Methods C. . . . T . . . . AUC0_t, AUC0_~, terminal elimination rate constant ()~z),tl/2, apparent oral clearance (CLpo), and apparent volume of distribution (VffF) were calculated using noncompartmental analysis. Values for C. . . . AUC0_t, and AUC0~ , were normalized according to the amount (mg) of GXR given to subjects. Summary statistics were calculated for the GXR plasma concentration-time data. Data for the pharmacokinetic parameters of GXR 1-, 2-, and 4-mg tablets were statistically analyzed to assess linearity between doses. An analysis of variance was constructed on the logarithmic-scaled, dose-normalized pharmacokinetic data to test the effect of sequence, subject within sequence, dose, and tablet manufacturer on dose proportionality. Point estimates and 90% CIs were obtained for mean plasma concentration-time Volume 29 Number 4
D. Swearingen et al.
ratios. It was determined that the linearity of pharmacokinetic data could be concluded if the 90% CIs obtained for the mean geometric ratios of C . . . . AUC0_t, and AUC0~ were within the range of 0.80 to 1.25. Power analysis was based on a previous study of guanfacine in which it was found that the coefficient of variation in C . . . . AUC0_t, and AUC0~ values was -29%. Given that mean values for the pharmacokinetic parameters of a manufactured product are within the 93.5% region of another product, a sample size of 42 subjects would have 80% power to reject the null hypotheses at 1-sided significance levels of 5% in favor of the alternative hypothesis, which is that the products are bioequivalent. It was anticipated that 2 patients per period would withdraw or be discontinued prematurely from the study. To account for this, 52 subjects were recruited. RES U LTS The study enrolled 28 (53.8%) male and 24 (46.2%) female subjects. Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-55 years) and mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120 kg) (Table I). There were no marked differences in baseline demographic characteristics of subjects within or between sequence groups. Overall, baseline assessments, including laboratory values and the findings of physical examinations were within the reference range for male and female subjects. Forty-nine subjects completed the study. Three subjects were discontinued by study investigators (1 tested positive for amphetamines, 1 did not comply with all study procedures, and 1 simultaneously participated in 2 clinical research studies); data for these subjects were included in the pharmacokinetic analyses. All subjects who completed the study were compliant with treatment. Phamacokinetic Results Values for mean (SD) guanfacine plasma concentrations were for GXR 1, 2, or 4 rag, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for Cmax; 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL • h -1 for AUC0_t; and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL • h -1 for AUC0_~. Mean (SD) tl/2 was 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 rag, respectively. April 2007
Table I. Baseline demographic and clinical characteristics of randomized subjects receiving guanracine extended-release 1-, 2-, and 4-mg tablets (N = 52). Characteristic Race, no. (%) Hispanic White Black Sex, no. (%) Male Female Age, y Mean (SD) Median, range Weight, kg Mean (SD) Median, range Height, cm Mean (SD) Median, range
Value 40 (76.9) 7 (13.5) 5 (9.6) 28 (53.8) 24 (46.2) 32.9 (10.3) 29.0 (18-54) 73.4 (15.7) 69.1 (49.6-120) 167.9 (11.18) 167.1 (149.9-188)
D o s e Proportionality The pharmacokinetic parameters of GXR 1, 2, and 4 mg exhibited a generally linear statistical relationship. Mean increases in plasma concentrations of guanfacine were proportional to the amount (rag) of GXR given to subjects (Figure). Increases in mean C . . . . AUC0_t, and AUC0~ , particularly between GXR 2 and 4 rag, were generally proportional to dose (Table II). Although, there was an -2.5-fold variation in mean body weight among study subjects, when body weight was normalized to 70 kg per individual, the pharmacokinetic parameters of GXR were similarly dose proportional (Table III). The 90% CIs obtained for the geometric mean ratios of dosenormalized C . . . . AUC0_t, and AUC0_~ between GXR 1 and 4 mg and between GXR 2 and 4 mg were within the region of 1.0, with the exception of the increase in mean CmaX between GXR 1 and 2 mg (Table IV). Consistent with the comparisons of dose-normalized data, the lower limits of the 90% CIs for the geometric mean ratios with GXR 1:2 mg were >1.0, indicating a slight lack of proportionality at the lowest dose (ie, plasma levels did not increase proportionally as the dose was increased from 1 to 2 rag). 621
Clinical Therapeutics
4-
,~2
I
I m g (n = 52) 2 m g ( n = I00) 4 m g (n = 98)
3-
rg
E~ R-._ v
~u
2-
q~
1
0
2
4
6
8
10
12
14
16
18
I
I
I
20
22
24
Time After Study Drug Administration (h)
Figure. Mean plasma concentrations after oral administration ofguanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults (N = 49).
Table II. Single-dose pharmacokinetic properties o f guanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults. All values are mean (SD) unless otherwise indicated (N = 49).* Dose o f GXR
Parameter C . . . . ng/mL AUC0 t, ng/mL" h if AUC 0 ~, ng/mL" h if Tmax, median, hf Xz, h if tl/2, hf
1 mg (n = 52)
2 mg (n = 100)
4 mg (n = 98)
0.98 (0.26) 29.3 (8.8) 32.4 (8.8) 6.0 0.0416 (0.009) 17.5 (3.8)
1.57 (0.51) 54.5 (17.7) 58.0 (18.9) 6.0 0.0436 (0.008) 16.6 (3.8)
3.58 (1.39) 119.1 (42.3) 124.1 (45.1) 5.5 0.0441 (0.009) 16.7 (4.9)
560 (194) 7.75 (2.22)
642 (229) 8.91 (3.3)
619 (278) 8.52 (3.3)
823 (249)
891 (285)
860 (346)
1 1.4 (3.0)
1 2.4 (3.8)
1 2.0 (4.5)
CL/F, kgf mL/min mL/min" h 1 Vz/Ff L
L/kg
Z,z = terminal elimination rate constant; CL/F = apparent oral clearance; V/F = apparent volume of distribution. *No. of plasma concentration-time measurements, with -2 per subject for GXR 2 and 4 mg: fn = 43, 96, and 98 for GXR 1, 2, and 4 mg, respectively.
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Table III. Single-dose pharmacokinetic parameters (normalized to a body weight of 70 kg per subject) ofguanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults (N = 49). All values are mean (SD).
Dose of GXR 1 mg (n = 52)
Parameter ng/mk AUC0t, n g / m L ' h 1~ AUC0 ~ , n g / m L ' h 1~ CL/F, mL/min ~ Vz/F, k~ C....
0.99 (0.38) 29.7 (11.6) 32.9 (11.8) 543 (156) 798 (212)
2 mg (n =100) 1.60 55.8 59.3 623 867
4 mg (n = 98)
(0.70) (24.3) (25.9) (212) (268)
3.67 (1.86) 122.0 (56.0) 127.1 (59.0) 596 (231) 837 (318)
n = number of plasma concentration-time measurements, with -2 per subject for GXR 2 and 4 mg; CL/F = apparent oral clearance; VJF = apparent volume of distribution. +~n= 43, 96, and 98, for GXR 1, 2, and 4 rag, respectively.
Table IV. Results of analysis of variance (logarithmic-scaled, dose-proportional) of the single-dose pharmacoki-
netic parameters ofguanfacine extended-release (GXR) 1-, 2-, and 4-mg tablets in healthy adults (N = 49). Values are mean (SD) unless otherwise indicated. Estimated Geometric Mean Ratios Between Doses of GXR (90% CI)
Dose of GXR
Parameter
1 mg
2 mg
4 mg
1:2 mg
1:4 mg
2:4 mg
C. . . .
0.940
0.747
0.845
1.258 (1.169-1.354)
1.112 (1.033-1.197)
0.884 (0.836-0.934)
AUC0 t, ng/mL" h 1
27.825
25.806
27.860
1.078 (1.008-1.153)
0.999 (0.934-1.069)
0.926 (0.880-0.975)
AUC0 ~, ng/mL" h 1
29.605
27.289
28.993
1.085 (1.009-1.166)
1.021 (0.950-1.097)
0.941 (0.894-0.991)
ng/mL
Tolerability A total of 172 AEs were reported by 40 (76.9%) of 52 subjects. Most AEs (170) were assessed by the study investigators or subjects as mild; 2 were assessed as moderate, and none were assessed as severe or serious. Of the 172 reported AEs, 143 were determined by the study investigators to be probably or possibly related to the study drug. None of the subjects withdrew from the study or were discontinued by the investigators because of AEs. Although 5 subjects reported mild chest discomfort or chest pain, analysis of laboratory results, April 2007
vital-sign and ECG data, and physical examination findings indicated no clinically significant cardiovascular abnormalities. AEs affecting the nervous system, including somnolence, dizziness, headache, and loss of consciousness (reported by 1 subject as "faintness" after blood was drawn and resolved without treatment <10 minutes) were the most common, occurring in 37 (71.2%) subjects. Somnolence, headache, dizziness, dry mouth, and fatigue occurred in 33 (63.5%), 19 (36.5%), 6 (11.5%), (11.5%), and 5 (9.6%) of subjects, respectively (Table V). 623
Clinical Therapeutics
DISCUSSION Stimulant drugs have been reported to be efficacious in controlling symptoms in -70% of patients with ADHD7; however, -30% of patients receiving these medications either do not respond to treatment or cannot tolerate this type of medication. 8 Early clinical findings have suggested that immediate-release guanfacine may provide therapeutic efficacy for symptoms of ADHD. 16-19 Extended-release formulations offer 3 potential improvements over immediate-release formulations. First, therapeutic concentrations could potentially be sustained over longer periods with less fluctuation in plasma drug concentrations of these drugs. Second, incidence of AEs might potentially be reduced, since initial plasma concentrations of these drugs would not be expected to be as great. With some immediaterelease preparations, the active drug may reach Cmax quickly; thus, AEs can emerge unexpectedly. For example, hypotension has been reported to occur in some patients receiving immediate-release nifedipine for hypertension.21 Sudden reductions in blood pressure and other significant hemodynamic changes associated with high initial serum concentrations of some immediate-release formulations may be avoided with extended-release formulations. Third, because fewer daily doses may be required with extended-release products, treatment compliance might be improved. For example, in an event-monitoring study in newly treated and long-term epilepsy patients, study investigators found an inverse correlation between dosing frequency and treatment compliance.22 In that study, the averaged compliance rates with medications administered 1, 2, 3, or 4 times daily were 87%, 81%, 77%, and 39%, respectively. Thus, improved treatment compliance may be associated with once-daily formulations. Although published clinical trials have examined the efficacy of immediate-release guanfacine administered 2 to 4 times daily in adults and children with symptoms of ADHD, 16-19 the efficacy of GXR of single-dose tablets is still under investigation. Study Limitations Because this was a single-dose study, long-term AEs could not be assessed. Somnolence, characterized as mild to moderate, was the most frequently reported AE. However, in the trial of immediate-release guanfacine in children with ADHD and comorbid tic disorders, is 6 subjects complained of mild sedation that 624
Table V. Treatment-emergent adverse events reported in _>10% of healthy adults receiving single oral doses of guanfacine extended-release 1-, 2-, and 4-mg tablets (N = 52). Adverse Event
No. (%) of Subjects
Somnolence
33 (63.5)
Headache
19 (36.5)
Dizziness
6 (11.5)
Dry mouth
6 (11.5)
Fatigue
5
(9.6)
resolved in time with continued treatment or decrease in dose. Although c~2-adrenoceptor agonists have been associated with sleepiness and lowered blood pressure, 17a8 theoretically, extended-release formulations might help ameliorate these effects. The present study findings suggest a statistically linear between-dose relationship in the pharmacokinetic parameters of GXR 1-, 2-, and 4-rag tablets; thus, GXR might potentially offer improved tolerability. CONCLUSIONS In this small population of healthy adults, the singledose pharmacokinetic parameters of GXR 1-, 2-, and 4-rag tablets were generally linear statistically. Increases in mean C . . . . AUC0_t, and AUC0~ of guanfacine were proportional to dose, with the exception of the increase in mean Cmax between GXR 1 and 2 nag. All 3 doses appeared to be well tolerated, with no serious AEs or related withdrawals or discontinuation from study participation due to AEs. ACKNOWLEDGM ENTS The authors thank NeoHealth Inc., Hasbrouck Heights, New Jersey, for assistance with the writing and editing of this manuscript. REFERENCES 1. Centers for Disease Control and Prevention (CDC). Mental health in the United States. Prevalence of-diagnosis and medication treatment for attention-deficit/ hyperactivity disorder-United States, 2003. MMWR Morb Mortal Wkly Re/). 2005;54:842-847.
2. Cincinnati Children's Hospital Medical Center. Evidence based clinical practice guidelines: Outpatient evaluation and management of attention deficit/hyperactivitydisorVolume 29 Number 4
D. Swearingen et al.
der. Cincinnati, Ohio: Cincinnati Children's Hospital Medical Center; April 30, 2004.
3. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000. 4. American Academy of Pediatrics Subcommittee on Attention-Deficit/ Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: Treatment of the school-aged child with attention-deficit~hyperactivity disorder. Pediatrics. 2001 ;108:1033-1044. 5. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attentiondeficit~hyperactivity disorder. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry.
1999;56:1073-1086. 6. MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-Month outcomes of treatment strategies for attentiondeficit/hyperactivity disorder. Pediatrics. 2004;113:754-761. 7. Olfson M. New options in the pharmacological management of attentiondeficit~hyperactivity disorder. Am J Manag Care. 2004;10(Suppl 4): 5117-5124. 8. WaxmonskyJG. Nonstimulant therapies for attention-deficit hyperactivity disorder ( A D H D ) i n children and adults. Essent Psychopharmacol. 2005; 6:262-276. 9. US Food and Drug Administration. Drugs of abuse. Chapter 5 Stimulants, http://www, u sdoj.gov/dea/ pu bs/abuse/5-stim.htl. Accessed April 9, 2005. 10. Arnsten AF, Li BM. Neurobiolo~ of executive functions: Catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377-1384. 11. Pliszka SR. The neuropsychopharmacology of attention-deficit/ hyperactivity disorder. Biol Psychiatry. 2005;57:1385-1390. April 2 0 0 7
12. FranowiczJS, Kessler LE, Borja CM, et al. Mutation of the 0~2-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine.J Neurosci. 2002;22:8771-8777. 13. Arnsten AF, SteereJC, Hunt RD. The contribution of 0~2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry.
1996;53:448-455. 14. Kuczenski R, Segal DS. Exposure of adolescent rats to oral methylphenidate prefrontal effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci. 2002;22:7264-7271. 15. Arnsten AFT, Dudley AG. Methylphenidate improves prefrontal cortical cognitive function through 0~-adrenoreceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in attention deficit hyperactivity disorder. Behav Brain Funct. 2005;1:2. 16. HorriganJP, Barnhill.J. Guanfacine for treatment of attention-deficit hyperactivity disorder in boys. J Child Adolesc Psychopharmacol. 1995;5:215-223.
17. Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder.JAm Acad ChildAdolesc Psychiatry. 1995;34:50-54. 18. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study ofguanracine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001 ;158:1067-1074. 19. Taylor FB, Russo J. Comparing guanfacine and dextroamphetamine for the treatment of adult attentiondeficit~hyperactivity disorder. J Clin Psychopharmacol. 2001 ;21:223-228. 20. Chappell PB, Riddle MA, Scahill L, et al. Guanfacine treatment ofcomorbid attention-deficit hyperactivity disorder and Tourette's syndrome: Preliminary clinical experience. J Am Acad Child Adolesc Psychiatry. 1995;34: 1140-1146. 21. Opie LH, Messerli FH. Nifedipine and mortality. Grave defects in the dossier.
Circulation. 1995;92:1068-1073. 22. CramerJA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique [published correction appears in JAMA. 1989;262:1472].
JAMA. 1989;261:3273-3277.
Address correspondence to: Dennis Swearingen, MD, MDS Pharma Services,
4747 East Beautiful Lane, Phoenix, AZ 85044. E-maih dennis.swearingen@ mdsps.com 625