80–1.25 (Cmax GMR 0.957, 90 % CI 0.907–1.01; AUC∞ GMR 1.001, 90 % CI 0.958–1.046), demonstrating the

bioequivalence of MPH alone and with GXR. Fig. 2 Mean plasma dexmethylphenidate (d-MPH) concentrations over time following administration of methylphenidate hydrochloride (MPH) alone and in combination with guanfacine extended release (GXR). A time shift has been applied to the figure; values have been Compound Library purchase slightly staggered on the x-axis for clarity, as some values were Inhibitor Library manufacturer similar between the two treatment regimens 3.2 Safety Results Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache (5.4, 10.5, and 8.1 % following GXR, MPH, and GXR and MPH combined, respectively), dizziness (2.7, 5.3, and 2.7 %, respectively), and postural dizziness (8.1, 0.0 and 0.0 %, respectively). The TEAEs observed were consistent with the known effects of GXR and MPH administered alone. One event (orthostatic syncope) was considered serious but was mild in severity and did not lead to study discontinuation. The subject was a 22-year-old male who had no selleck compound relevant history, no history of syncope, and no recent illness. The event occurred 2 h after he received his first treatment,

which was a single oral dose of GXR 4 mg alone. The event lasted less than 1 minute, and the subject recovered spontaneously and completed the study. No subject had a severe AE or an AE leading to withdrawal. The majority of TEAEs were mild, and no differences in the types, incidences, or severity of TEAEs were reported across treatments. No clinically meaningful differences in biochemistry, hematology, or urinalysis results across treatment groups were noted. The

effects of monotherapy with GXR or MPH on vital signs, including SBP, DBP, and supine pulse rate, were as expected. Figure 3 shows the mean supine pulse rates over the course of 12 h following administration of GXR, MPH, and GXR and MPH. Following administration of GXR, there was a modest decrease in the mean pulse rate, which started returning to baseline levels L-gulonolactone oxidase 6 h postdose. In contrast, a modest increase in the mean supine pulse rate was seen with MPH. Fig. 3 Mean (±standard deviation) supine pulse rate over hours 1 to 12 following study drug administration (observed values). GXR guanfacine extended release, MPH methylphenidate hydrochloride Changes in supine SBP (Fig. 4a) and DBP (Fig. 4b) were also noted after administration of GXR and MPH alone. Modest decreases in blood pressure (BP) were seen with GXR, and small increases in BP were reported with MPH. Fig. 4 a Mean [±standard deviation (SD)] supine systolic blood pressure (SBP) and b mean (±SD) supine diastolic blood pressure (DBP) over hours 1 to 12 following drug administration (observed values). GXR guanfacine extended release, MPH methylphenidate hydrochloride As shown in Figs.