Pharmacokinetics and Safety of Levetiracetam Extended-Release Tablets and Relative Bioavailability Compared with Immediate-Release Tablets in Healthy Chinese Subjects

• Published in: European journal of drug metabolism and pharmacokinetics 2018-08, Vol.43 (4), p.405-413
• Main Authors: Wang, Meng, Wang, Mengmeng, Zhang, Quanying, Zong, Shunlin, Lv, Chengzhe
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anticonvulsants - adverse effects; Anticonvulsants - pharmacokinetics; Biological Availability; Biomedical and Life Sciences; Biomedicine; Cross-Over Studies; Delayed-Action Preparations; Fasting; Food-Drug Interactions; Healthy Volunteers; Human Physiology; Humans; Male; Medical Biochemistry; Middle Aged; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Piracetam - administration & dosage; Piracetam - adverse effects; Piracetam - analogs & derivatives; Piracetam - pharmacokinetics; Tablets; Young Adult
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-018-0461-2

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 ( C max ) and a 33.6% lower minimum steady-state plasma concentration ( C ss min ) than IR tablet intake, while the median time to C max ( t max ) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC 0– t ), AUC from zero to infinity (AUC 0– ∞ ), AUC at steady state (AUC ss , τ  = 24 h), C max at steady state ( C ss max ) and average concentration at steady state ( C ss av ) were contained within the 80–125% range of bioequivalence. The C max and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher C max . The 90% confidence interval (CIs) of the fed/fasted ratios for C max and AUC were entirely contained within the 80–125% range of bioequivalence acceptance, except the t max was delayed ( P