Narrow Therapeutic Index (NTI)

Definition

A narrow therapeutic index (NTI) is a characteristic of drugs where there is a small difference between therapeutic and toxic doses. This means that small changes in drug concentration can lead to either treatment failure or adverse effects. (Gozzo et al., 2022)

Quantitative Measures

Therapeutic Index (TI)

TI = TD50 / ED50

Where:

• TD50: Toxic dose for 50% of the population
• ED50: Effective dose for 50% of the population

A lower TI indicates a narrower therapeutic index. (Gozzo et al., 2022)

Therapeutic Window

The range between the minimum effective concentration and the minimum toxic concentration. For NTI drugs, this window is small. (Gozzo et al., 2022)

Characteristics of NTI Drugs

Sensitive to Small Variations

Small changes in plasma concentrations can result in:

• Insufficient therapeutic response
• Onset of adverse effects (Gozzo et al., 2022)

Require Individualized Dosing

Particularly important for:

• Older patients
• Patients with comorbidities
• Patients on multiple medications (Gozzo et al., 2022)

Need for Monitoring

Regular monitoring of drug levels and patient response is often necessary. (George, 1982)

Examples of NTI Drugs

Anticoagulants

• Vitamin K antagonists
• Heparin

Antiepileptic Drugs

• Valproic acid
• Phenobarbital
• Phenytoin
• Carbamazepine

Other Examples

• Digoxin
• Lithium carbonate
• Aminoglycosides
• Cyclosporine

(Gozzo et al., 2022)

Regulatory Considerations

Stricter Bioequivalence Criteria

For generic versions of NTI drugs:

• Standard bioequivalence range: 80-125%
• NTI drug bioequivalence range: 90-111%

(Gozzo et al., 2022)

Lack of Universal Definition

• No universally accepted list of NTI drugs
• Case-by-case determination based on clinical considerations
• Varies between regulatory agencies (Gozzo et al., 2022)

Clinical Implications

Careful Dose Titration

Doses are chosen to provide the highest benefit with the lowest risk, considering both potential negative effects and therapeutic effects. (Gozzo et al., 2022)

Generic Substitution Concerns

Some experts propose not applying substitution of generics for NTI drugs due to potential differences in bioavailability. (Gozzo et al., 2022)

Biocreep Phenomenon

Potential issue when switching between different generic versions of an NTI drug, as they may have different bioavailabilities while still meeting bioequivalence criteria. (Gozzo et al., 2022)

Importance in Drug Development

Challenges in Generic Development

Stricter bioequivalence criteria for NTI drugs can make generic development more difficult and costly. (Paixão et al., 2024)

Need for Advanced Formulations

Development of modified-release formulations or alternative delivery systems may help improve the safety and efficacy of NTI drugs. (Urquhart, 2003)