Mingzhen Xu1, Yang Ni1, Ying Zhou1, Xiaomeng He1, Huqun Li1, Hui Chen2, Weiyong Li3. 1. Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. 2. Department of Infectious Disease, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. shining_119@163.com. 3. Institute of Clinical Pharmacy, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. liweiyong2015@126.com.
Abstract
BACKGROUND:Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptic medications for add-on treatment of seizures in the setting of Lennox-Gastaut syndrome in patients from the age of 4 years. OBJECTIVE: The purpose of this study was to determine the pharmacokinetic and safety profile of single and multiple doses of rufinamide in healthy Chinese subjects. The effects of food and gender on the pharmacokinetic properties of rufinamide were also evaluated. METHODS: In the single-dose study, volunteers were randomly assigned to 4 dose groups and received a single dose of 200, 400, 800, 1200 mg rufinamide tablets under fasting condition. Ten subjects in the 200-mg dose group were randomly assigned to either a high-fat or non-high-fat breakfast group in each study period. The drug administration was separated by a washout period of 7 calendar days. In the multiple-dose study, 10 subjects were administered on an empty stomach rufinamide 200 mg twice daily for 6 consecutive days. Liquid chromatography tandem mass spectrometry (LC-MS/MS) method was applied to determine plasma concentration of rufinamide. Pharmacokinetic parameters, including the maximum plasma concentration (C max), the time to peak concentration (t max), the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUC0-t ) and from time 0 to infinity (AUC0-∞), terminal elimination half-life (t 1/2), apparent volume of distribution (V d), apparent clearance (CL), average residence time (MRT), area under the plasma concentration versus time curve from time 0 to the last measurable concentration at steady state (AUCss), peak concentration (C max,ss) and trough level concentration (C min,ss) at steady state were calculated using non-compartmental models. Tolerability was assessed based on investigator inquiries, spontaneous reports and clinical evaluations. RESULTS:Rufinamide displayed a dose-dependent, but sub-proportional increase in exposure following single-dose and repeated dose administration. After administration of single dose of 200, 400, 800 and 1200 mg, without food, the rufinamide mean C max (standard deviation, SD) was 1806.5 (526.4), 2490 (564.8), 3719 (976.1) and 4166 (1187.1) μg/L, respectively. Mean AUC0-t (SD) was 34,571 (9484), 56,246 (18,077), 89,022 (23,379) and 107,316 (34,766) μg·h/L, respectively. While in fed condition at the dosage of 200 mg, mean C max (SD) and mean AUC0-t (SD) were 2363 (582) μg/L and 40,593 (10,516) μg·h/L, respectively. After administration of multiple doses, arithmetic mean (SD) values of C max and AUC0-t were 3566 (873) μg/L and 62,803 (19,873) μg·h/L, respectively. The steady state was achieved by day 3 of multiple dosing after 2 daily doses (twice a day), the corresponding accumulation factor (AUCss/AUC0-t) was 0.9057. Although there were no substantial effects on exposure resulting from gender differences, a notable food effect was observed, with AUC and C max increased by 17.4 and 30.8 %, respectively. Single- and multiple-dose phases were generally safe and well tolerated. CONCLUSION: Overall, 15 % (6/40) of subjects experienced a mild indisposition with no serious adverse events. On single and multiple dosing, rufinamide exhibited nonlinear pharmacokinetics and was well tolerated in healthy Chinese subjects.
RCT Entities:
BACKGROUND:Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptic medications for add-on treatment of seizures in the setting of Lennox-Gastaut syndrome in patients from the age of 4 years. OBJECTIVE: The purpose of this study was to determine the pharmacokinetic and safety profile of single and multiple doses of rufinamide in healthy Chinese subjects. The effects of food and gender on the pharmacokinetic properties of rufinamide were also evaluated. METHODS: In the single-dose study, volunteers were randomly assigned to 4 dose groups and received a single dose of 200, 400, 800, 1200 mg rufinamide tablets under fasting condition. Ten subjects in the 200-mg dose group were randomly assigned to either a high-fat or non-high-fat breakfast group in each study period. The drug administration was separated by a washout period of 7 calendar days. In the multiple-dose study, 10 subjects were administered on an empty stomach rufinamide 200 mg twice daily for 6 consecutive days. Liquid chromatography tandem mass spectrometry (LC-MS/MS) method was applied to determine plasma concentration of rufinamide. Pharmacokinetic parameters, including the maximum plasma concentration (C max), the time to peak concentration (t max), the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUC0-t ) and from time 0 to infinity (AUC0-∞), terminal elimination half-life (t 1/2), apparent volume of distribution (V d), apparent clearance (CL), average residence time (MRT), area under the plasma concentration versus time curve from time 0 to the last measurable concentration at steady state (AUCss), peak concentration (C max,ss) and trough level concentration (C min,ss) at steady state were calculated using non-compartmental models. Tolerability was assessed based on investigator inquiries, spontaneous reports and clinical evaluations. RESULTS:Rufinamide displayed a dose-dependent, but sub-proportional increase in exposure following single-dose and repeated dose administration. After administration of single dose of 200, 400, 800 and 1200 mg, without food, the rufinamide mean C max (standard deviation, SD) was 1806.5 (526.4), 2490 (564.8), 3719 (976.1) and 4166 (1187.1) μg/L, respectively. Mean AUC0-t (SD) was 34,571 (9484), 56,246 (18,077), 89,022 (23,379) and 107,316 (34,766) μg·h/L, respectively. While in fed condition at the dosage of 200 mg, mean C max (SD) and mean AUC0-t (SD) were 2363 (582) μg/L and 40,593 (10,516) μg·h/L, respectively. After administration of multiple doses, arithmetic mean (SD) values of C max and AUC0-t were 3566 (873) μg/L and 62,803 (19,873) μg·h/L, respectively. The steady state was achieved by day 3 of multiple dosing after 2 daily doses (twice a day), the corresponding accumulation factor (AUCss/AUC0-t) was 0.9057. Although there were no substantial effects on exposure resulting from gender differences, a notable food effect was observed, with AUC and C max increased by 17.4 and 30.8 %, respectively. Single- and multiple-dose phases were generally safe and well tolerated. CONCLUSION: Overall, 15 % (6/40) of subjects experienced a mild indisposition with no serious adverse events. On single and multiple dosing, rufinamide exhibited nonlinear pharmacokinetics and was well tolerated in healthy Chinese subjects.
Authors: Martin J Brodie; William E Rosenfeld; Blanca Vazquez; Rajesh Sachdeo; Carlos Perdomo; Allison Mann; Santiago Arroyo Journal: Epilepsia Date: 2009-06-01 Impact factor: 5.864