Defining Narrow vs. Wide Therapeutic Index
A therapeutic index of 2 is the standard cutoff value used to distinguish narrow therapeutic index (NTI) drugs from wide therapeutic index drugs—drugs with a ratio below 2 between the upper and lower limits of the therapeutic range are classified as NTI drugs. 1
The Standard Definition
Narrow therapeutic index drugs are defined as those where the therapeutic index (ratio between upper and lower therapeutic range limits) is less than 2. 1
The FDA further characterizes NTI drugs as those 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. 2
This classification means that for NTI drugs, the toxic dose is less than twice the effective dose, leaving minimal margin for dosing error. 1
Clinical Implications of the Threshold
Drugs classified as NTI require individualized dose optimization when they exhibit wide between-subject variability, are dosed near maximum tolerated dose, or have known exposure-response/exposure-safety relationships. 3
For drugs with wide therapeutic indices (ratio >2) and minimal toxicity profiles, fixed adult dosing is typically adequate without intensive monitoring. 3
NTI drugs require more precise dosing approaches including therapeutic drug monitoring (TDM), as they fulfill traditional TDM criteria: long-term therapy, significant inter-individual pharmacokinetic variability, narrow therapeutic index, and well-defined exposure-response relationships. 3
Examples and Practical Application
Phenytoin has been definitively shown to have a therapeutic index of 2, placing it at the exact threshold for NTI classification. 4
Phenobarbital and valproate have therapeutic indices exceeding 2, classifying them as non-NTI drugs despite being antiepileptic agents requiring monitoring. 4
Warfarin is classified as an NTI drug, where small changes in systemic concentration can lead to significant pharmacodynamic changes resulting in either subtherapeutic anticoagulation or dangerous overanticoagulation. 5
Monitoring Requirements Based on Classification
For NTI drugs, doses are typically not rounded or are rounded only to the nearest one-tenth of a milliliter to maintain safety margins. 3
The FDA proposes that bioequivalence of NTI drugs be determined using stricter criteria (90.00%-111.11% limits) compared to standard drugs, reflecting the critical importance of maintaining consistent drug exposure. 2
Therapeutic drug monitoring is strongly recommended for NTI drugs, particularly in vulnerable populations (children, elderly, pregnant women) and critically ill patients where pharmacokinetic variability is unpredictable. 3