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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.
Clin Ther. 2007 Apr; 29(4):617-25.CT

Abstract

BACKGROUND

Guanfacine is an alpha(2)-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-release (GXR) tablets after oral administration in healthy adults.

METHODS

This was a Phase I, randomized, open-label, 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 CmaX, AUC(0-t), and AUC(0-infinity) 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 medications. 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 C(max); 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL . h(-1) for AUC(0-t); and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL . h(-1) for AUC(0-infinity) . Mean (SD) t((1/2)) 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(max), AUC(0-t), and AUC(0-infinity) were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in C(max) 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 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(max), AUC(0-t), and AUC(0-infinity) of guanfacine were proportional to dose, with the exception of the increase in mean C(max) 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.

Authors+Show Affiliations

MDS Pharma Services, Phoenix, Arizona 85044, USA. dennis.swearingen@mdsps.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

17617285

Citation

Swearingen, Dennis, et al. "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, vol. 29, no. 4, 2007, pp. 617-25.
Swearingen D, Pennick M, Shojaei A, et al. 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. Clin Ther. 2007;29(4):617-25.
Swearingen, D., Pennick, M., Shojaei, A., Lyne, A., & Fiske, K. (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. Clinical Therapeutics, 29(4), 617-25.
Swearingen D, et al. 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. Clin Ther. 2007;29(4):617-25. PubMed PMID: 17617285.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Swearingen,Dennis, AU - Pennick,Michael, AU - Shojaei,Amir, AU - Lyne,Andrew, AU - Fiske,Kimberly, PY - 2007/01/23/accepted PY - 2007/7/10/pubmed PY - 2007/8/8/medline PY - 2007/7/10/entrez SP - 617 EP - 25 JF - Clinical therapeutics JO - Clin Ther VL - 29 IS - 4 N2 - BACKGROUND: Guanfacine is an alpha(2)-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-release (GXR) tablets after oral administration in healthy adults. METHODS: This was a Phase I, randomized, open-label, 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 CmaX, AUC(0-t), and AUC(0-infinity) 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 medications. 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 C(max); 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL . h(-1) for AUC(0-t); and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL . h(-1) for AUC(0-infinity) . Mean (SD) t((1/2)) 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(max), AUC(0-t), and AUC(0-infinity) were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in C(max) 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 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(max), AUC(0-t), and AUC(0-infinity) of guanfacine were proportional to dose, with the exception of the increase in mean C(max) 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. SN - 0149-2918 UR - https://www.unboundmedicine.com/medline/citation/17617285/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(07)00116-6 DB - PRIME DP - Unbound Medicine ER -