Topiramate: An in Vitro and in Vivo Comparison between the Pharmacokinetic Properties of a Generic (Sincronil) and the Reference (Topamax) Formulation

Marco Prosdocimi, Fethi Trabelsi, Flavio Moroni

Department of Pharmacology, University of Firenze, Florence, Italy.
Fidia Farmaceutici, Abano Terme, Italy.
Pharmanet, Montreal, Canada.

DOI: 10.4236/pp.2012.32019                

Abstract

The use of generic formulation of therapeutic agents may allow a significant reduction of costs for patients and the National Health Services. This is particularly true for drugs used in prolonged therapies such as topiramate which is effective in the treatment of epilepsy, migraine, alcohol abuse and psychiatric conditions. The purposes of this study were: 1) evaluate Topiramate (50 mg) release in vitro from a generic (Sincronil) and the reference formulation (Topamax); 2) compare the above mentioned generic and reference formulations in bioavailability studies in healthy volunteers. Dissolution tests in vitro showed that more than 95% of the active principle was released within 15 minutes both from the reference and the generic formulation. No difference in release kinetics was found between the two topiramate preparations. In vivo pharmacokinetic data were obtained by administering 1 tablet containing 50 mg of topiramate of each of the two formulations to 28 healthy volunteers under fasting conditions, using a randomized, single-dose, open-label, 2-way crossover design. The treatment phases were separated by a washout period of 21 days. The maximum concentration reached in plasma (C_max) for the reference and the generic formulation, were 946 ± 308 and 849 ± 247 (ng/mL) and the area under the curve (AUC_0-t) were 35,900 ± 7800 and 34,300 ± 8100 (ng·h/mL) respectively. The data indicate that the rate and extent of absorption of the reference or generic 50 mg topiramate formulation are not significantly different and suggest that the therapeutic effects of the two preparations do not significantly differ.

Keywords

Topiramate; Migraine; Pharmacokinetics

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	C. A. Jackevicius, M. M. Chou, J. S. Ross, N. D. Shah, and H. M. Krumholz, “Generic Atorvastatin and Health Care Costs,” New England Journal of Medicine, Vol. 366, No. 3, 2011, pp. 201-204. doi:10.1056/NEJMp1113112
[2]	C. Chu, E. Rudant, M. Bonvalet, H. Agostini, P. Cavalie, L. Bonhomme-Faivre, J. Frenkiel, J. Taillandier, A. Boissonnas, D. Vittecoq and B. Wyplosz, “Generic Drug Prescriptions Following Hospital Discharge: A Prospective Study in France,” European Journal of Internal Medicine, Vol. 22, No. 5, 2011, pp. e45-e49. doi:10.1016/j.ejim.2011.01.016
[3]	M. Yamada and T. E. Welty, “Generic Substitution of Antiepileptic Drugs: A Systematic Review of Prospective and Retrospective Studies,” The Annals of Pharmacotherapy, Vol. 45, No. 11, 2011, pp. 1406-1415. doi:10.1345/aph.1Q349
[4]	R. P. Shank and B. E. Maryanoff, “Molecular Pharmacodynamics, Clinical Therapeutics, and Pharmacokinetics of Topiramate,” CNS Neuroscience & Therapeutics, Vol. 14, No. 2, 2008, pp. 120-142. doi:10.1111/j.1527-3458.2008.00041.x
[5]	B. A. Johnson, N. Rosenthal, J. A. Capece, F. Wiegand, L. Mao, K. Beyers, A. McKay, N. Ait-Daoud, R. F. Anton, D. A. Ciraulo, H. R. Kranzler, K. Mann, S. S. O’Malley, and R. M. Swift, “Topiramate for Treating Alcohol Dependence: A Randomized Controlled Trial,” JAMA, Vol. 298, 2007, pp. 1641-1651. doi:10.1001/jama.298.14.1641
[6]	P. Crawford, M. Feely, A. Guberman and G. Kramer, “Are There Potential Problems with Generic Substitution of Antiepileptic Drugs? A Review of Issues,” Seizure, Vol. 15, No. 3, 2006, pp. 165-176. doi:10.1016/j.seizure.2005.12.010
[7]	J. E. Desmarais, L. Beauclair and H. C. Margolese, “Switching from Brand-Name to Generic Psychotropic Medications: A Literature Review,” CNS Neuroscience & Therapeutics, Vol. 17, No. 6, 2011, pp.750-760. doi:10.1111/j.1755-5949.2010.00210.x
[8]	A. S. Kes-selheim, M. R. Stedman, E. J. Bubrick, J. J. Gagne, A. S. Misono, J. L. Lee, M. A. Brookhart, J. Avorn and W. H. Shrank, “Seizure Outcomes Following the Use of Generic versus Brand-Name Antiepileptic Drugs: A Systematic Review and Meta-Analysis,” Drugs, Vol. 70, No. 6, 2010, pp. 605-621. doi:10.2165/10898530-000000000-00000
[9]	M. Maliepaard, N. Banishki, C. C. Gispende Wied, S. Teerenstra and A. J. Elferink, “Interchangeability of Generic Anti-Epileptic Drugs: A Quantitative Analysis of Topiramate and Gabapentin,” European Journal of Clinical Pharmacology, Vol. 67, No. 10, 2011, pp. 1007-1016. doi:10.1007/s00228-011-1041-4
[10]	L. Edvinsson and M. Linde, “New Drugs in Migraine Treatment and Prophylaxis: Telcagepant and Topiramate,” Lancet, Vol. 376, No. 9741, 2010, pp. 645-655. doi:10.1016/S0140-6736(10)60323-6
[11]	W. E. Rosenfeld, “Topiramate: A Review of Preclinical, Pharmacoki-netic, and Clinical Data,” Clinical Therapeutics, Vol. 19, No. 6, 1997, pp. 1294-1308. doi:10.1016/S0149-2918(97)80006-9
[12]	J. H. Park, Y. S. Park, M. H. Lee, S. Y. Rhim, J. C. Song, S. J. Lee, J. M. Kim, L. M. Shaw, and J. S. Kang, “Determination of Plasma Topiramate Concentration Using LC-MS/MS for Pharmacokinetic and Bioequivalence Studies in Healthy Korean Volunteers,” Biomedical Chromatography, Vol. 22, No. 8, 2008, pp. 822-829. doi:10.1002/bmc.995
[13]	A. Pineyro-Lopez, E. Piney-ro-Garza, M. Gomez-Silva, R. Reyes-Araiza, M. A. Flores-Diego, S. Borrego-Alvarado, M. E. Gamino-Pena, R. Vargas-Zapata and M. E. Salazar-Leal, “Bioequivalence of Single 100-mg Doses of Two Oral Formulations of Topiramate: An Open-Label, Randomized-Sequence, Two-Period Crossover Study in Healthy Adult Male Mexican Volunteers,” Clinical Therapeutics, Vol. 31, 2009, pp. 411-417. doi:10.1016/j.clinthera.2009.02.001
[14]	I. Saavedra, E. Tamayo, A. Gamboa, J. Sasso, N. Varela, I. Moreno, D. Marchant, D. Caceres and L. Quinones, “Relative Bioavailability Study with Two Oral Formulations of Topiramate Using a Validated UPLC-MS/MS Method,” International Journal of Clinical Pharmacology, Therapy, & Toxicology, Vol. 48, 2010, pp. 342-348.
[15]	E. Beghi, “Efficacy and Tolerability of the New Antiepileptic Drugs: Comparison of Two Recent Guidelines,” Lancet Neurology, Vol. 3, No. 10, 2004, pp. 618-621. doi:10.1016/S1474-4422(04)00882-8
[16]	A. May, M. Leone, J. Afra, M. Linde, P. S. Sandor, S. Evers and P. J. Goadsby, “EFNS Guidelines on the Treatment of Cluster Headache and Other Trigeminal- Autonomic Cephalal-gias,” European Journal of Neurology, Vol. 13, 2006, pp. 1066-1077. doi:10.1111/j.1468-1331.2006.01566.x
[17]	S. Evers, J. Afra, A. Frese, P. J. Goadsby, M. Linde, A. May and P. S. Sandor, “EFNS Guideline on the Drug Treatment of Migraine—Revised Report of an EFNS Task Force,” European Journal of Neurology, Vol. 16, 2009, pp. 968-981. doi:10.1111/j.1468-1331.2009.02748.x