Bioequivalence Evaluation of 2 Tablet Formulations of Entecavir in Healthy Chinese Volunteers: A Single-Dose, Randomized-Sequence, Open-Label Crossover Study

Abstract

A randomized, 2-way crossover study was conducted in healthy Chinese male volunteers to evaluate the bioequivalence of a new generic formulation of entecavir (CAS 142217-69-4) tablets (test) and the available branded formulation (reference) to meet the requirements for marketing the test product in China. Test and reference tablets were administered as a single dose on 2 treatment days separated by a 2-week washout period. Blood samples were collected for a period of 24 h following drug administration. Plasma concentration of entecavir was determined by a liquid chromatography-tandem mass spectrometry (LC/MS/MS) method. Pharmacokinetic parameters were calculated using a noncompartmental model. Bioequivalence was determined by calculating 90% CIs for the ratios of C_max, AUC_0–t and AUC_0–∞ values for the test and reference products. Tolerability was assessed by monitoring vital signs, laboratory tests and interviews with the volunteers before administration and every 2 h during the study. The 90% CIs of entecavir for C_max, AUC_0–t and AUC_0–∞ were 95.2–106.9%, 98.4–104.6% and 97.3–104.4%, respectively, which fell within the interval of 80–125%. No clinically important adverse effects were reported. These results suggested that the test formulation of entecavir tablets met the regulatory criterion for bioequivalence to the reference formulation.

Key words

bioequivalence - pharmacokinetics - entecavir - CAS 142217-69-4 - LC-MS/MS - healthy volunteers

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^*  Co-first authors

• References

• 1 McClune AC, Tong MJ. Chronic hepatitis B and hepatocellular carcinoma. Clin Liver Dis 2010; 14: 461-476
• 2 Zoulim F. Hepatitis: Treatment failure in chronic hepatitis B. Nat Rev Gastroenterol Hepatol 2011; 8: 366-367
• 3 Te HS, Jensen DM. Epidemiology of hepatitis B and C viruses: a global overview. Clin Liver Dis 2010; 14: 1-21 vii
• 4 Matthews SJ. Entecavir for the treatment of chronic hepatitis B virus infection. Clin Ther 2006; 28: 184-203
• 5 Honkoop P, De Man RA. Entecavir: a potent new antiviral drug for hepatitis B. Expert Opin Investig Drugs 2003; 12: 683-688
• 6 Langley DR, Walsh AW, Baldick CJ et al. Inhibition of hepatitis B virus polymerase by entecavir. J Virol 2007; 81: 3992-4001
• 7 Rivkin A. Entecavir: a new nucleoside analogue for the treatment of chronic hepatitis B. Drugs Today. Barc; 2007. 43. 201-220
• 8 Cheng PN, Chang TT. Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients. Expert Rev Anti Infect Ther 2008; 6: 569-579
• 9 Yan JH, Bifano M, Olsen S et al. Entecavir pharmacokinetics, safety, and tolerability after multiple ascending doses in healthy subjects. J Clin Pharmacol 2006; 46: 1250-1258