This short essay summarizes some information on drug-drug interactions focusing on CYP enzymes based on FDA guidance. (Available :https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers )

Drug-drug interaction

In vitro

Clinical index drugs

According to FDA guidance on Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (Available : https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions )

This classification information helps to determine whether other drugs that have not been investigated in a DDI study have clinically significant DDIs with the investigational drug and therefore need to be mentioned in labeling. For example, if an investigational drug is a strong CYP3A inhibitor, its potential to interact with drugs that have clinically significant interactions with other strong CYP3A inhibitors should be considered, and the sponsor should add appropriate language regarding these additional interactions to the investigational drug’s labeling.

To test whether the investigational drug is a perpetrator, sponsors should use index substrates, which have defined changes in systemic exposure when administered with a strong inhibitor for a specific drug elimination pathway. A list of currently recommended index drugs for specific CYP pathways (either as substrates, inhibitors, or inducers) is maintained on the FDA’s Web site for Drug Development and Drug Interactions. (Available :https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table2 ).

Sensitive index substrates are index drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies.

The above table is prepared to provide examples of clinical sensitive or moderate sensitive index substrates and is not intended to be an exhaustive list. Index substrates listed in this table were selected considering their sensitivity, specificity, safety profiles, and adequate number of reported clinical DDI studies with different in vivo inhibitors (≥ 3 for CYP3A or ≥ 2 for CYP1A2, 2C8, 2C9, 2C19, and 2D6).

Index inhibitors predictably inhibit metabolism via a given pathway and are commonly used in prospective clinical DDI studies.

This table is prepared to provide examples of clinical index inhibitors and is not intended to be an exhaustive list. Index inhibitors listed in this table were selected based on potency and selectivity of inhibition, safety profiles, and adequate number of reported clinical DDI studies with different in vivo substrates [≥ 3 for CYP3A, ≥ 2 for CYP1A2, 2C9, 2C19, and 2D6, or ≥ 1 for CYP2C8 (strong inhibitors)].

Index inducers predictably induce metabolism via a given pathway and are commonly used in prospective clinical DDI studies.

This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list. Index inducers listed in this table were selected based on potency of induction, safety profiles, and number of reported clinical DDI studies with different in vivo substrates (≥ 2 substrates).

Examples of clinical substrates, inhibitors, and inducers

Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies.

The above table is prepared to provide examples of clinical substrates and not intended to be an exhaustive list

Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, respectively.

This table is prepared to provide examples of clinical inhibitors and is not intended to be an exhaustive list.

Strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates of a given metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively.

This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list.