What is the meaning of a narrow therapeutic index?

Generics/Research | Posted 17/06/2022 post-comment0 Post your comment

What is the meaning of a narrow therapeutic index (NTI) is a topic explained by author Roy G Beran, in a mini review [1].

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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 [2]. The European Medicines Agency (EMA) requires bioequivalence of 90%–111% [3] 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 [7]. 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 [7]. This may result in different bioavailability with altered absorption or solubility characteristics directly modifying efficacy and safety [7].

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 [8]. In addition, drug interactions, in conjunction with co-medications, may also not have been adequately addressed by simple bioequivalence studies in healthy volunteers [8].

Conflict of interest
The author of the research paper [1] declared that there was no conflict of interest.

Abstracted by Professor Roy G Beran, Neurology Department, Liverpool Hospital, Liverpool, Australia.

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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.

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