European journal of drug metabolism and pharmacokinetics · 2018
Pharmacokinetics and Safety of Levetiracetam Extended-Release Tablets and Relative Bioavailability Compared with Immediate-Release Tablets in Healthy Chinese Subjects.
Клиническое исследованиеСравнительное исследованиеСтатьяНазвание и аннотация: Перевод в очереди
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Wang Meng, Wang Mengmeng, Zhang Quanying, Zong Shunlin, Lv Chengzhe
Аннотация
BACKGROUND AND OBJECTIVES: Levetiracetam is a second-generation antiepileptic drug and distributed ubiquitously in the central nervous system. The extended-release formulation of levetiracetam was developed to provide patients with the convenience of once-daily dosing, to improve drug compliance and tolerability. The objective of this study was to evaluate the pharmacokinetics and safety of levetiracetam extended-release (ER) tablets in healthy Chinese subjects following single and multiple doses.
METHODS: Two panels of 34 healthy subjects were enrolled. Trial 1 was a two-way crossover between levetiracetam ER tablets and immediate-release (IR) tablets under fasting conditions. Trial 2 was a four-way crossover single-dose study between levetiracetam ER fasted and ER with food.
RESULTS: Intake of single and multiple levetiracetam ER tablets resulted in a 42.3% lower maximum plasma concentration (Cmax) and a 33.6% lower minimum steady-state plasma concentration (Css min) than IR tablet intake, while the median time to Cmax (tmax) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC0-t), AUC from zero to infinity (AUC0-∞), AUC at steady state (AUCss, τ = 24 h), Cmax at steady state (Css max) and average concentration at steady state (Css av) were contained within the 80-125% range of bioequivalence. The Cmax and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher Cmax. The 90% confidence interval (CIs) of the fed/fasted ratios for Cmax and AUC were entirely contained within the 80-125% range of bioequivalence acceptance, except the tmax was delayed (P < 0.05). The most frequent treatment-emergent adverse events were somnolence, dizziness and thirst.
CONCLUSIONS: After single and multiple doses, the absorption of levetiracetam ER was equal to IR, the tmax was significantly delayed, and the Cmax and Css min were significantly decreased. Food did not affect the absorption of the levetiracetam ER tablet, but the Cmax increased and the tmax was delayed. The levetiracetam ER tablet was well tolerated and found to be dose proportional from 500 to 2000 mg in healthy Chinese subjects.
METHODS: Two panels of 34 healthy subjects were enrolled. Trial 1 was a two-way crossover between levetiracetam ER tablets and immediate-release (IR) tablets under fasting conditions. Trial 2 was a four-way crossover single-dose study between levetiracetam ER fasted and ER with food.
RESULTS: Intake of single and multiple levetiracetam ER tablets resulted in a 42.3% lower maximum plasma concentration (Cmax) and a 33.6% lower minimum steady-state plasma concentration (Css min) than IR tablet intake, while the median time to Cmax (tmax) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC0-t), AUC from zero to infinity (AUC0-∞), AUC at steady state (AUCss, τ = 24 h), Cmax at steady state (Css max) and average concentration at steady state (Css av) were contained within the 80-125% range of bioequivalence. The Cmax and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher Cmax. The 90% confidence interval (CIs) of the fed/fasted ratios for Cmax and AUC were entirely contained within the 80-125% range of bioequivalence acceptance, except the tmax was delayed (P < 0.05). The most frequent treatment-emergent adverse events were somnolence, dizziness and thirst.
CONCLUSIONS: After single and multiple doses, the absorption of levetiracetam ER was equal to IR, the tmax was significantly delayed, and the Cmax and Css min were significantly decreased. Food did not affect the absorption of the levetiracetam ER tablet, but the Cmax increased and the tmax was delayed. The levetiracetam ER tablet was well tolerated and found to be dose proportional from 500 to 2000 mg in healthy Chinese subjects.