Narrow therapeutic index drugs

Benet and Goyan [34] have presented a clear exposition on bioequivalence and narrow therapeutic index drugs. Among other papers of relevance to this topic are those by Tsang and coworkers [35], el-Tahtawy and associates [36], and Midha and collaborators [37],... 

M. Burns, Management of narrow therapeutic index drugs, J. Thromb. Thrombolysis, 7, 137 (1999). 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Waiver of in vivo bioequivalence studies for major post approval manufacturing changes for the BCS Class I (Biopharmaceutics Classification System highly soluble, highly permeable and rapidly dissolving) solid oral products is NOT recommended for narrow therapeutic index drugs (17). 

If formulations with three or more release rates are used to develop the IVrVC model, no further evaluation beyond this initial estimation of prediction error may be necessary for non-narrow therapeutic index drugs (Category 2 a and b apphcations, see page 12). However, depending on the results of this internal prediction error calculation, determination of prediction error externally may be appropriate. 

Estimation of Prediction Error Externally. The second aspect relates to how well the model predicts data when one or more additional test data sets are used that differ from those used to define the correlation. This is appropriate in some situations, parhcularly when only two formulations with different release rates are used to develop the IVlVC model, when calculation of prediction error internally is inconclusive, or when a narrow therapeutic index drug is studied. 

Narrow Therapeutic Index Drugs. If an IVIVC model is to be used in estimating the in vivo performance of formulations of narrow therapeutic index drugs, the model s predictability should be tested further with a data set that differs from those data sets used to define the correlation. In other words, the external predictability of the correlation should be evaluated. 

Note—If the classification of a drug as a narrow therapeutic index drug is uncertain, appropriate review staff in CDER should be consulted. 

With the exception of narrow therapeutic index drugs, the external predictability step in the IVIVC evaluation process may be omitted if the evaluation of internal predictability indicates acceptable % PE. However, when the evaluation of internal predictability is inconclusive, evaluation of external predictability is recommended. 

Category 2 Biowaivers Using an IVIVC Non-Narrow Therapeutic Index Drugs... 

Narrow Therapeutic Index Drugs Drugs having, for example, less than a two-fold difference in the minimum toxic concentrations and the minimum effective concentrations (21 CFR 320.33 (c)). 

This guidance uses the term narrow therapeutic range instead of narrow therapeutic index drug, although the latter is more commonly used. 

All barbiturates currently available cause a continuum of depression of body function, from sleepiness to shutting down of necessary functions. The amount of depression or weakening is increased by many factors, the most obvious being dose. The more barbiturates a person takes, the greater depression will occur. Barbiturates are considered narrow therapeutic index drugs. This means there is a very small difference between an effective and a lethal dose of barbiturates. 

Benet LZ, Goyan JE. Bioequivalence and narrow therapeutic index drugs. Pharmacotherapy 1995 15 433 140. 

Williams RL. FDA position on product selection for narrow therapeutic index drugs. Am J Health Syst Pharm 1997 54 1630-1632. 

Benet, L.Z. Goyan, J.E. Bioequivalence and Narrow Therapeutic Index Drugs. Pharmacotherapy 1995, 75 (4), 433-440. 

For establishing external predictability, the exposure parameters for a new formulation are predicted using its in vitro dissolution profile and the IVIVC model, and the predicted parameters are compared with the observed parameters. The PEs are computed as for the internal validation. For Cmax and AUC, the PE for the external validation formulation should not exceed 10%. A PE of 10-20% indicates inconclusive predictability and illustrates the need for further study using additional data sets. For drugs with a narrow therapeutic index, external validation is required despite acceptable internal validation, whereas internal validation is usually sufficient with non-narrow therapeutic index drugs. 

If the IVIVC for a non-narrow therapeutic index drug was developed with formulations with three or more release rates, the evaluation of the internal predictability would be sufficient to determine its appropriateness. 

The drug is considered to be a narrow therapeutic index drug. 

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