Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy?: a pharmacokinetic study with two oral formulations (Luminal® vet, Phenoleptil®) in dogs

BMC Veterinary Research

Wolfgang Löscher²  Jens P Bankstahl¹  Marion Bankstahl² 

[1] Present address: Preclinical Molecular Imaging, Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany;Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, and Center for Systems Neuroscience, Hannover 30559, Germany

关键词: Brand name vs. generic formulation;    Antiepileptic drugs;    Seizures;    Epilepsy;   

Others  :  1119436
DOI  :  10.1186/1746-6148-9-202

 received in 2013-05-23, accepted in 2013-10-03,  发布年份 2013

【 摘 要 】

Background

In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal® or the veterinary products Luminal® vet and the generic formulation Phenoleptil®. Luminal® and Luminal® vet are identical 100 mg tablet formulations, while Phenoleptil® is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil® for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal® (human tablets) to Phenoleptil® in epileptic dogs, which were controlled by treatment with Luminal®, induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal® vet vs. Phenoleptil® with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average.

Results

Peak plasma concentrations (C_max) following Luminal® vet vs. Phenoleptil® were about the same in most dogs (10.9 ± 0.92 vs. 10.5 ± 0.77 μg/ml), and only one dog showed noticeable lower concentrations after Phenoleptil® vs. Luminal® vet. Elimination half-life was about 50 h (50.3 ± 3.1 vs. 52.9 ± 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil® vs. Luminal® vet.) was 0.98 ± 0.031, indicating that both formulations resulted in about the same bioavailability.

Conclusions

Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to recurrence of seizures are obviously not related to a generally lower bioavailability of the generic formulation, although single dogs may exhibit lower plasma levels after the generic formulation that could be clinically meaningful.

【 授权许可】

   
2013 Bankstahl et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Löscher W, Schwartz-Porsche D, Frey H-H, Schmidt D: Evaluation of epileptic dogs as an animal model of human epilepsy. Arzneim -Forsch (Drug Res ) 1985, 35:82-87.
• [2]Podell M: Seizures in dogs. Vet Clin North Am Small Anim Pract 1996, 26:779-809.
• [3]Chandler K: Canine epilepsy: what can we learn from human seizure disorders? Vet J 2006, 172:207-217.
• [4]Berendt M, Gredal H, Ersboll AK, Alving J: Premature death, risk factors, and life patterns in dogs with epilepsy. J Vet Intern Med 2007, 21:754-759.
• [5]Schwartz-Porsche D, Löscher W, Frey H-H: Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. J Vet Pharmacol Ther 1985, 8:113-119.
• [6]Podell M: Antiepileptic drug therapy. Clin Tech Small Anim Pract 1998, 13:185-192.
• [7]Boothe DM, Dewey C, Carpenter DM: Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. J Am Vet Med Assoc 2012, 240:1073-1083.
• [8]Yasiry Z, Shorvon SD: How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia 2012, 53(Suppl 8):26-39.
• [9]Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, et al.: Antiepileptic drugs–best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE commission on therapeutic strategies. Epilepsia 2008, 49:1239-1276.
• [10]Hansen RN, Campbell JD, Sullivan SD: Association between antiepileptic drug switching and epilepsy-related events. Epilepsy Behav 2009, 15:481-485.
• [11]Bialer M, Midha KK: Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. Epilepsia 2010, 51:941-950.
• [12]Shaw SJ, Hartman AL: The controversy over generic antiepileptic drugs. J Pediatr Pharmacol Ther 2010, 15:81-93.
• [13]Krauss GL, Caffo B, Chang YT, Hendrix CW, Chuang K: Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol 2011, 70:221-228.
• [14]Privitera MD: Generic antiepileptic drugs: current controversies and future directions. Epilepsy Curr 2008, 8:113-117.
• [15]Brandt C, Nozadze M, Heuchert N, Rattka M, Löscher W: Disease-modifying effects of phenobarbital and the NKCC1 inhibitor bumetanide in the pilocarpine model of temporal lobe epilepsy. J Neurosci 2010, 30:8602-8612.
• [16]Frey H-H, Göbel W, Löscher W: Pharmacokinetics of primidone and its active metabolites in the dog. Arch Int Pharmacodyn Ther 1979, 242:14-30.
• [17]Al Tahan F, Frey HH: Absorption kinetics and bioavailability of phenobarbital after oral administration to dogs. J Vet Pharmacol Ther 1985, 8:205-207.
• [18]Margolese HC, Wolf Y, Desmarais JE, Beauclair L: Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol 2010, 25:180-182.
• [19]Erickson SC, Le L, Ramsey SD, Solow BK, Zakharyan A, Stockl KM, et al.: Clinical and pharmacy utilization outcomes with brand to generic antiepileptic switches in patients with epilepsy. Epilepsia 2011, 52:1365-1371.
• [20]Frey H-H: Anticonvulsant drugs used in the treatment of epilepsy. Problems Vet Med 1989, 1:558-577.
• [21]Löscher W, Schmidt D: Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia 2006, 47:1253-1284.
• [22]Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW: Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology 2007, 68:1249-1250.