Pharmacokinetics of Coadministered Guanfacine Extended Release and Lisdexamfetamine Dimesylate

Abstract

BackgroundIn clinical practice, α2-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug–drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.ObjectiveThe primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.Study DesignThis was an open-label, randomized, three-period crossover, DDI study.SettingThe study was conducted in a single clinical research center.ParticipantsForty-two healthy adults were randomized in this study.InterventionsSubjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.Main Outcome MeasuresBlood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90 % confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80–1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).ResultsForty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0–∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90 % CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90 % CI exceeded the standard range for bioequivalence by 7 %. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9 % of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3 %) and headache (7.5, 4.9, and 7.3 %) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.ConclusionsIn healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.

Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder

“…Moreover, no unique TEAE emerged from GXR adjunctive to a long-acting psychostimulant. 26,50 This is consistent with findings from studies conducted in healthy adults showing that no unique TEAEs were observed with coadministration of GXR and MPH 47 or lisdexamfetamine 48 compared with either treatment alone.…”

“…45 In addition, when guanfacine and valproic acid are administered simultaneously, plasma valproate levels may rise significantly. 46 However, two small openlabel studies conducted with healthy adults revealed that coadministration of GXR and MPH 47 or lisdexamfetamine 48 did not result in significant pharmacokinetic drug-drug interactions.…”

Method validation and determination of lisdexamfetamine and amphetamine in oral fluid, plasma and urine by LC–MS/MS

“…The method developed for the three matrices was validated and was also successfully applied to assess real samples, showing for the first time the detection of LDX in oral fluid. ; Roesch et al, 2013;Rowley et al, 2012). Therefore, the aim of this study is to describe the development and validation of an LC-MS/MS method for the simultaneous quantification of LDX and its main biotransformation product AMPH in human oral fluid, plasma and urine.…”

Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder

“… 45 In addition, when guanfacine and valproic acid are administered simultaneously, plasma valproate levels may rise significantly. 46 However, two small open-label studies conducted with healthy adults revealed that coadministration of GXR and MPH 47 or lisdexamfetamine 48 did not result in significant pharmacokinetic drug–drug interactions.…”