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ABSTRACT: Carisbamate's effect (200 mg twice-daily [study 1], 600 mg twice-daily [study 2]) on warfarin's (25 mg single dose) pharmacokinetics and pharmacodynamics (international normalized ratio) was assessed during 2 open-label studies in healthy participants. Coadministration of either carisbamate regimen produced small changes on the mean maximum plasma concentration (C(max)) and mean area under the plasma concentration-time curve to the last measurable time point (AUC(last)) of (S)- and (R)-warfarin, which are unlikely to be clinically significant. For (S)-warfarin, the ratios (with carisbamate/without carisbamate) of geometric means for C(max) were 105.44 (study 1) and 98.48 (study 2) and for AUC(last) were 109.33 (study 1) and 114.43 (study 2); the corresponding 90% confidence intervals were within the bioequivalence limits of 80% to 125%. Results were similar for (R)-warfarin. Carisbamate at 600 mg (but not 200 mg) twice-daily prolonged the elimination half-life of (S)- and (R)-warfarin by ~10 hours (25% and 32% increase, respectively). Prothrombin time was unaltered by either carisbamate dose. Adverse events with the highest incidence were dizziness (50%) and headache (50%) in study 1 and somnolence (56%) in study 2. Warfarin exposure and international normalized ratio were unaffected by coadministration of carisbamate 200 mg or 600 mg twice-daily. Carisbamate was well tolerated.
The Journal of Clinical Pharmacology 10/2011; 52(9):1420-9. · 2.91 Impact Factor
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ABSTRACT: This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose. A modest increase in mean area under the plasma concentration-time curve from 0 to infinity (AUC(∞)) was observed for the mild impairment group compared with the normal group (ratio of geometric means ~116%), while mean maximum plasma concentration (C(max)) values were similar (ratio of geometric means ~94%). The AUC(∞) value for the moderate hepatic-impaired group was approximately 207% that of the normal group, while there was a smaller increase in C(max) (~118%) compared with the normal group. Mean half-life (t(1/2)) values were prolonged in the moderate impairment group (21 hours) relative to the normal group (11 hours). There was a decrease in apparent clearance (CL/F) and an increase in AUC(∞u) (AUC(∞) × % drug unbound). The percentage of carisbamate unbound to proteins did not change across the groups, suggesting the increases in AUC(∞) were due to decreased intrinsic hepatic clearance. Carisbamate 200 mg was well tolerated.
The Journal of Clinical Pharmacology 05/2011; 52(5):738-46. · 2.91 Impact Factor
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ABSTRACT: A once-daily extended-release galantamine(GAL-ER) formulation has been designed to improve tolerability compared with twice-daily immediate-release galantamine (GAL-IR).
The aim of this study was to conduct a post hoc analysis of the clinical presentation of nausea and vomiting with GAL-ER compared with GAL-IR in subjects with mild to moderate Alzheimer's disease (AD).
This is the report of a post hoc analysis of a large, randomized, double-blind, placebo-controlled, multicenter trial of GAL-ER with GAL-IR as the active control in subjects with mild to moderate AD. Galantamine dose was titrated every 4 weeks by increments of 8 mg/d to a daily dose of 16 or 24 mg, based on tolerability. Daily rates of nausea and vomiting were compared for the GAL-ER and GAL-IR groups. AUCs of the daily percentage of subjects reporting nausea/vomiting during dose titration were calculated. Antiemetic use for nausea/vomiting was compared between GAL-ER and GAL-IR groups.
Demographic characteristics were similar between the GAL-ER, GAL-IR, and placebo groups. Nausea was reported by 16.9% (54/319) of GAL-ER, 13.8% (45/326) of GAL-IR, and 5.0% (16/320) of placebo patients; vomiting was reported for 6.6% (21/319) of GAL-ER, 8.6% (28/326) of GAL-IR, and 2.2% (7/320) of placebo patients. The mean (SD) daily rate of nausea in the total population was 3.1 (13.43%) in the GAL-ER group and 5.2% (22.07%) in the GAL-IR group (P = NS); the mean (SD) daily rate of vomiting for the total population was 0.6% (4.14%) in the GAL-ER group and 1.6% (14.50%) in the GAL-IR group (P = NS). The mean (SD) daily rate of nausea or vomiting in the total population was 1.2 (8.46) and 0.4 (5.44) in the placebo group, respectively. For subjects reporting nausea, the mean (SD, SE) percentage of days with nausea was lower with GAL-ER than with GAL-IR (18.4% [28.22%, 5.31%] vs 38.0% [48.23%, 6.04%]; P = 0.014). AUC of the daily percentage of subjects reporting nausea/vomiting during dose titration was significantly higher in the GAL-IR group compared with the placebo group (320.9 vs 102.9; P = 0.01); there was no statistical difference between the GAL-ER group and placebo (171.1 vs 102.9; P = NS). Antiemetic use by subjects reporting nausea or vomiting was significantly lower in the GAL-ER group than the GAL-IR group (33.3% vs 53.4%; P = 0.028).
In these subjects with AD, the daily percentage of subjects reporting nausea and vomiting, and the percentage of days with vomiting among subjects reporting vomiting, did not significantly differ between the GAL-ER and GAL-IR groups. However, GAL-ER was associated with a significantly lower percentage of days with nausea than GAL-IR among subjects reporting nausea. AUC of the daily percentage of subjects with nausea or vomiting during dose titration did not differ significantly between the GAL-ER and placebo groups but was significantly higher in the GAL-IR group than placebo. Subjects with nausea or vomiting who received GAL-ER reported significantly less antiemetic use than those treated with GAL-IR. These results suggest the need for additional studies to explore the potential differences in the tolerability of these formulations.
Clinical Therapeutics 04/2006; 28(3):365-72. · 2.32 Impact Factor
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ABSTRACT: To assess the steady-state galantamine (GAL) bioavailability of the extended-release 24-mg qd capsule (GAL-ER) with and without food and to evaluate the relative bioavailability of GAL-ER with the immediate-release 12-mg bid tablet (GAL-IR) at steady state.
This was a single-center, open-label, randomized, 3-way crossover study in 24 healthy volunteers (12 males and 12 females) aged 18 to 45 years. After 7 days of GAL-ER 8 mg qd each morning and 7 days of GAL-ER 16 mg qd each morning, subjects received the following treatments in randomized, crossover order (7 days each): GAL-ER 24 mg qd each morning (fasted before Day 7 morning dose), GAL-ER 24 mg qd each morning (fed before Day 7 morning dose), and GAL-IR 12 mg bid (fasted before Day 7). Pharmacokinetic parameters of GAL at steady state were determined after morning intake on Day 7 of each treatment week. Safety evaluations included adverse event (AE) reporting, physical examination, clinical laboratory tests, vital signs, and electrocardiography.
The treatment ratios of area under the plasma concentration-time curve of GAL from time 0-24 h post-dosing (AUC24 h), peak plasma concentration (Cmax), and pre-dose plasma concentration (Cmin) for GAL-ER fed/fasting were 105%, 112%, and 103%, respectively. The treatment ratios and 90% confidence intervals for all above mentioned pharmacokinetic parameters demonstrated bioequivalence (with the range of 80-125%), indicating that food had no effect on GAL-ER bioavailability. As anticipated, GAL-ER (fasting) had mean AUC24 h similar to GAL-IR (fasting), with lower Cmax (63 ng/mL vs 84 ng/mL) and longer time to reach Cmax (4.4 h vs 1.2 h). The treatment ratios and 90% confidence intervals for both AUC24 h and Cmin demonstrated bioequivalence (within the range of 80-125%). The treatment ratio for Cmax was 75.7%, indicating a 24% lower Cmax for GAL-ER than for GAL-IR. In this study, GAL-ER was safe and well tolerated with or without food and was comparable to the GAL-IR formulation.
Food had no effect on the GAL bioavailability of GAL-ER at steady state. GAL-ER was bioequivalent to GAL-IR with respect to AUC24 h and Cmin.
Current Medical Research and Opinion 11/2005; 21(10):1547-54. · 2.38 Impact Factor
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ABSTRACT: To demonstrate using pharmacokinetic (PK) modeling and simulation, that the PK that the PK parameters for drug exposure with galantamine parameters for drug exposure with galantamine immediate-release (IR) tablet and galantamine extended-release (ER) capsule are comparable in patients with Alzheimer's disease (AD) during in patients with Alzheimer's disease (AD) during the switch from twice-daily IR tablet at steady state to the new once-daily ER capsule, and to support a recommendation that patients receiving the IR tablet at steady state can be successfully switched to the ER capsule at the same daily dosage with no titration period.
Simulations were performed using a population PK model developed from clinical studies with IR galantamine in the target AD population, in combination with IR and ER absorption parameters obtained from a PK study in healthy volunteers which showed similar results. PK simulations were performed for the switch from IR tablet 8 mg b.i.d. to ER capsule 16 mg q.d. and from IR tablet 12 mg b.i.d. to ER capsule 24 mg q.d.
This simulation predicted that patients switched from the IR tablet to the ER capsule, the PK parameters for drug exposure on the first day of ER treatment would be similar to those of IR treatment at steady state. After steady state was achieved with ER galantamine, values for peak concentration and trough concentration were slightly lower (5% and 18%, respectively) than those seen at steady state for IR galantamine; this finding is considered to have no clinical implications. Area under the curve (AUC) with ER galantamine was similar to that seen at steady state with IR galantamine.
These results suggest that no titration period is required in patients receiving stable doses of twice-daily IR galantamine who are switched to once-daily ER galantamine. The once-daily dosage regimen of ER galantamine without a titration period should prove convenient for AD patients and their caregivers and should increase treatment compliance.
Current Medical Research and Opinion 05/2005; 21(4):483-8. · 2.38 Impact Factor
