Food effect on the pharmacokinetics of entecavir from dispersible tablets following oral administration in healthy Chinese volunteers

Abstract

Objective:

The aim of the present study was to assess the effect of food on the pharmacokinetics of entecavir (CAS 142217-69-4) from dispersible tablets.

Methods:

In an open-label, two-way crossover study, 12 healthy Chinese volunteers randomly received a single oral dose of 1 mg entecavir dispersible tablets under fasted and fed conditions. Blood samples were collected and determined for pharmacokinetic analyses. A solid phase extraction for sample preparation and a LC/MS method were developed and validated for determination of entecavir in human plasma.

Results:

The absorption of entecavir from dispersible tablets was altered significantly with food intake, as evidenced by a decrease in C_max of 63%, a decrease in AUC_0–t of 22%, and a delay in T_max of 1.5 h. The calibration curve was linear from 0.2 to 25 ng/mL, with a lower limit of quantitation (LLOQ) of 0.2 ng/mL.

Conclusion:

Food intake has an obvious effect on the absorption of entecavir from dispersible tablets. It is better to take entecavir dispersible tablets on an empty stomach.

Key words

Antiviral agents - CAS 142217-69-4 - Entecavir, dispersible tablets, food effects, pharmacokinetics

• References

• 1 Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009; 373: 582-92
• 2 Liang XF, Chen YS, Wang XJ, He X, Chen LJ, Wang J et al. A study on the seroepidemiology of hepatitis B in Chinese population aged over 3-years old: the report from Chinese Center for Disease Control and Prevention. Chin J Epidemiol. 2005; 26: 655-8
• 3 Lu FM, Zhuang H. Management of hepatitis B in China. Chin Med J. 2009; 122: 3-4
• 4 Data on 2006 seroepidemiological survey on HBV infection in China. Available from: http://www.moh.gov.cn
• 5 Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR et al. Antiviral therapy for adults with chronic hepatitis B: A systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med. 2009; 150: 111-24
• 6 Baraclude™ (entecavir) package insert. Princeton (NJ):Bristol-Myers Squibb Company. March 2005.
• 7 Santantonio T, Fasano M. Resistance profile of entecavir in patients with chronic hepatitis B. Dig Liver Dis. 2008; (02) 11-5
• 8 Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF et al. Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology. 2006; 44: 1656-65
• 9 Yao GB, Zhou XQ, Xu DZ, Wang BE, Ren H, Liu J et al. Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China. Hepatol Int. 2007; 1: 373-81
• 10 Yuan Y, Iloeje U, Li H, Hay J, Yao GB. Economic implications of entecavir treatment in suppressing viral replication in chronic hepatitis B (CHB) patients in china from a perspective of the Chinese Social Security Program. Value Health. 2008; (Suppl) IIS11-22
• 11 Yang J. Liu XQ, Liu XD. Development of a bioavailability program package 2.0. Chin] Clin Pharmacol. 2003; 19: 125-7
• 12 Zhang DX, Fu YL, Gale JP, Aubry AF, Arnold ME. A sensitive method for the determination of entecavir at picogram per milliliter level in human plasma by solid phase extraction and high-pH LC-MS/MS. J Pharm Biomed Anal. 2008; 49 (4) 1027-33
• 13 Hivid (zalcitabine) Nutley, NJ: Hoffman-La Roche. 2002. Physician’s Desk Reference Electronic Library. 2004.
• 14 Gu CH, Li H, Levons J, Lentz K, Gandhi RB, Raghavan K et al. Predicting effect of food on extent of drug absorption based on physicochemical properties. Pharm Res. 2007; 24: 1118-30
• 15 Damle BD, Yan JH, Behr D, O’Mara E, Nichola P, Kaul S et al. Effect of food on the oral bioavailability of didanosine from encapsulated enteric-coated beads. J Clin Pharmacol. 2002; 42: 419-27
• 16 Fleisher D, Li C, Zhou YJ, Pao LH, Karim A. Drug, meal and formulation interactions influencing drug absorption after oral administration: clinical implications. Clin Pharmacokinet. 1999; 36: 233-54
• 17 Pao LH, Zhou SY, Cook C, Kararli T, Kirchhoff C, Truelove J et al. Reduced systemic availability of an antiarrhythmic drug, bidisomide, with meal co-administration: relationship with region-dependent intestinal absorption. Pharm Res. 1998; 15 (2) 221-7
• 18 Yan JH, Bifano M, Olsen S, Smith RA, Zhang DX, Grasela DM et al. Entecavir pharmacokinetics, safety, and toler-ability after multiple ascending doses in healthy subjects. J Clin Pharmacol. 2006; 46: 1250-8