Comparative bioavailability study of phenytoin in healthy Nepalese volunteers
Our study aimed to assess and compare the bioavailability of Eptoin 100 mg and Epileptin 100mg tablets in Nepalese healthy volunteers. A randomized, two-treatment cross-over study with two weeks’ wash-out period was conducted in 12 healthy non-smoker and non-alcoholic Nepalese male volunteers over a period of 6 months in the department of Clinical Pharmacology and Therapeutic at B. P. Koirala Institute of Health Sciences, Dharan, Nepal after approval from the Institutional Review Committee. The participants were randomized using sealed envelope system and received a single 100 mg oral tablet of either of the formulations with a two week washout period. Blood samples were collected predose and at regular intervals postdose upto 72 hours. Plasma phenytoin levels were estimated by reverse phase high performance liquid chromatography. The analytical method was validated prior to the start of study. Cmax (Peak Plasma Concentration), Tmax (Time to achieve maximum Plasma Concentration), AUC0-72 (Area under plasma concentration time curve 0 to 72 hours), AUC0-∞ (Area under plasma concentration time curve 0 to ∞) and T½ (Elimination half-life) and Kel (Elimination rate constant) were calculated and 80-120% margin (90% confidence interval) was used to assess bioequivalence. ANOVA test was used to analyze the data at P-value of 0.05. All volunteers completed the study. The log-transformed values of Cmax, Tmax, AUC0-t, and AUC0-∞ of the both formulations were within the specified limits and were bioequivalent according to the regulatory definition of bioequivalence based on the rate and extent of absorption. Both products can be considered equally effective in medical practice.
Keywords: Bioavailability, Bioequivalence, healthy volunteer, Nepal, phenytoin sodium.
2. Shakya G, Malla S, Shakya KN, Shrestha R. Therapeutic Drug Monitoring of Antiepileptic Drugs. J Nepal Med Assoc, 2008; 47(17): 94-97.
3. Chen SS, Allen J, Oxley J, Richens A. Comparative bioavailability of phenytoin from generic formulations in the united kingdom. Epilepsia, 1982; 23(2):149-152.
4. Gidal BE, Tomson T. Debate: Substitution of generic drugs in epilepsy: Is there cause for concern? Epilepsia, 2008; 49 (Suppl 9):56-62.
5. Mikati M, Bassett N, Schachter S. Double-blind randomized study comparing brand-name and generic phenytoin monotherapy. Epilepsia, 1992; 33(2):359-365
6. Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology, 2008; 71(7):525-530.
7. Approved Drug Products With Therapeutic Equivalence Evaluations. 14th ed. Rockville MD: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research; 1994.
8. Rockville MD. FDA Guidance on statistical procedures for bioequivalence studies using a standard two-treatment crossover designs. Division of Bioequivalence, office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration; 1992.
9. FDA. Guidance for industry, Bioavailability and bioequivalence studies for orally administered drug products-General considerations. March 2003.
10. Galgatte UC, Jamdade VR1, Aute PP1, Chaudhari PD. Study on requirements of bioequivalence for registration of pharmaceutical products in USA, Europe and Canada. Saudi Pharm J, 2014; 22(5):391-402.
11. Westlake WJ. Use of confidence intervals in analysis of comparative bioavailability trials. J Pharm Sci, 1972; 61(8):1340-1341.
12. Barrett JS, Batra V, Chow A, Cook J, Gould AL, Heller AH et al. PhRMA perspective on population and individual bioequivalence. J Clin Pharmacol, 2000; 40(6):561-570.
13. Bois FY, Tozer TN, Hauck WW, Chen ML, Patnaik R, Williams RL. Bioequivalence: performance of several measures of rate of absorption. Pharm Res, 1994; 11(7):966-974.
14. Chen ML. An alternative approach for assessment of rate of absorption in bioequivalence studies. Pharm Res, 1992; 9(11):1380-1385.
15. Endrenyi L, Yan W. Variation of Cmax and Cmax/AUC in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol, 1993; 31(4):184-189.
16. Gibberd FB, Spencer KM, Webley M, Berry D. A comparison of the bioavailability of two brands of phenytoin. Br J Clin Pharmacol, 1982; 13(3):455-456.
17. Meyer MC, Straughn AB, Mhatre RM, Shah VP, Chen ML, Williams RL et al. Variability in the bioavailability of phenytoin capsules in males and females. Pharm Res, 2001; 18(3):394-397.
18. Gogtay NJ, Dalvi SS, Mhatre RB, Kirodian BG, Gupta AH, Jadhav SP et al. A randomized, crossover, assessor-blind study of the bioequivalence of a single oral dose of 200 mg of four formulations of phenytoin sodium in healthy, normal Indian volunteers. Ther Drug Monit, 2003; 25(2):215-220.
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