What is the meaning of a narrow therapeutic index (NTI) is a topic explained by author Roy G Beran, in a mini review .
NTI drugs are drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. Drugs are considered to have an NTI when comparison of the 50% median effective dose (ED50) and 50% median lethal dose (LD50) is ≤2 . The European Medicines Agency (EMA) requires bioequivalence of 90%–111%  for NTI drugs, but even this represents >23% variation.
The US Food and Drug Administration (FDA) accepts bioequivalence if the ratio of AUCgeneric to AUCbranded and Cmax generic to Cmax branded, for the average of the sample of participants lies between 0.80%–1.25% of the originator medication, at the 90% confidence level for AUC and Cmax [4, 5]. Despite this acceptable variation of between 80%–125%, some investigators confirmed a true variation of as much as ~70%–140% (namely 74%–142%), amounting to halving or doubling the true comparison [6, 7].
While the active ingredients, in the generic compound, may equate to that within the originator formulation, it may be reconstituted in a different format (referred to, by FDA, as pharmaceutical alternatives . It may contain a different salt or ester of the active moiety or alternatively different dosages or strengths, e.g. the amlodipine salt may be besylate or camsylate, ferrous sulphate or gluconate . This may result in different bioavailability with altered absorption or solubility characteristics directly modifying efficacy and safety .
Bioequivalent studies do not compare batch-to-batch variability nor country-to-country variations. In complex diseases, such as Parkinson’s disease, patients may absorb the medication more slowly, because of delayed gastric motility and possible co-medications, such as dopamine agonists, anticholinergic, monoamine oxidase inhibitors and antipsychotics, which may affect medication availability . In addition, drug interactions, in conjunction with co-medications, may also not have been adequately addressed by simple bioequivalence studies in healthy volunteers .
Conflict of interest
The author of the research paper  declared that there was no conflict of interest.
Abstracted by Professor Roy G Beran, Neurology Department, Liverpool Hospital, Liverpool, Australia.
GaBI Journal Citation Impact
2.2 – CiteScore 2021 (calculated on 5 May 2022)
2.3 – CiteScoreTracker 2021 (Last updated on 6 June 2022)
Submit a manuscript to GaBI Journal
What is meant by a generic medication and generic equivalence?
Consequences of generics being favoured by healthcare providers
The cost of developing drugs and use of generics
Re-evaluation of the use of generics, especially when treating conditions such as epilepsy
LATIN AMERICAN FORUM
The new section of the ‘Latin American Forum’ on GaBI has been launched. The objective of this new section is to provide you with all the latest news and updates on developments of generic and biosimilar medicines in Latin America in Spanish.
View this week’s headline article: Nomenclature of biologicals and biosimilars in Peru
Browse the news in the Latin American Forum!
Register to receive the GaBI Latin American Forum newsletter. Inform colleagues and friends of this new initiative.
LATIN AMERICAN FORUM
Se ha lanzado la nueva sección del ‘Foro Latinoamericano’ sobre GaBI. El objetivo de esta nueva sección es brindarle las últimas noticias y actualizaciones sobre desarrollos de medicamentos genéricos y biosimilares en América Latina en español.
Vea el artículo principal de esta semana: Nomenclature of biologicals and biosimilars in Peru
!Explore las noticias en el Foro Latinoamericano!
Regístrese para recibir el boletín informativo GaBI Foro Latinoamericano. Informe a colegas y amigos sobre esta nueva iniciativa.
1. Beran RG. Generic substitution in patients whose illness has a narrow therapeutic index, such as epilepsy. APHE. 2020;1(2):1-5.
2. Crawford P, Feely M, Guberman A, et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006;15(3):165-76.
3. European Medicines Agency. Guideline on the investigation of bioequivalence. Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** 20 January 2010 [homepage on the Internet]. [cited 2022 May 20]. Available from: www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf
4. Hill AM, Barber MJ, Gotham D. Estimated costs of production and potential prices for the WHO Essential Medicines List. BMJ Glob Health 2018;3(1):e000571.
5. Yu LX, Jiang W, Zhang X, et al. Novel bioequivalence approach for narrow therapeutic index drugs. Clin Pharmacol Ther. 2015;97(3):286-91.
6. American Academy of Neurology. Assessment: generic substitution for antiepileptic medication. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1990;40(11):1641-3.
7. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand name psychoactive drugs. Clin Ther. 2003;25(6):1578-92.
8. Go CL, Rosales RL, Schmidt P, et al. Generic versus branded pharmacotherapy in Parkinson’s disease: does it matter? A review. Parkinsonism Relat Disord. 2011;17(5):308-12.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Copyright – Unless otherwise stated all contents of this website are © 2022 Pro Pharma Communications International. All Rights Reserved.
Post your comment