Brief Summary: Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro

Name of Guidance

Brief Summary: Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro

Status of Guidance

Final Guidance

Date of Guidance

April 1997

Released by

Center for Drug Evaluation and Research/Center for Biologics Evaluation and Research

Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072104.pdf

Target audience

Developers of drugs or biologics

Laws and Regulations

No laws or regulations were referenced in this guidance.

Definitions

Genetic polymorphism: A genetic variation that results in different forms or types of individuals among the members of a single species.

Excretion: The removal of a waste product of metabolism.

Metabolite: Any product of metabolism.

Prodrug: A substance that becomes a pharmacologically active after being chemically converted through metabolic processes.

Background

Drugs entering the body are eventually removed from the body. This can happen in one of two ways. One way is through the outright elimination of the drug through the process of excretion. The other way is through metabolism in which the drug is modified into one or more active or inactive metabolites. In addition, a drug can also interact with other drugs or foods a patient may be taking concurrently, causing the drug’s effect to be decreased (inhibited) or increased (induced), or causing the other drug’s effect to be inhibited or induced.

Summary

This guidance advocates investigating whether a drug is excreted unchanged or metabolized (and by what metabolic pathways) as early as possible (eg, before phase 2 testing) to determine how the drug is affected once it is in the body, including potential drug-drug interactions. This guidance pertains to drug molecules with a molecular weight <10 kD.

Rationale

It is important for a drug developer to know how a drug is removed from the body (by excretion or metabolism) because the process can significantly determine the safety and efficacy of a drug and, thereby, determine how it should be used. When a drug is metabolized, it may go through one or more metabolic (enzymatic) pathways, producing a modified form of the drug, called a metabolite.

If a drug is metabolized, it is necessary to know which metabolic route/routes are involved because genetic variations (aka genetic polymorphisms) from one person to the next can influence the rate of metabolism and potentially cause large differences in the concentrations of the drug and its metabolite in the blood. These differences can mean the difference between a safe drug concentration within the designated therapeutic window, a low concentration in which the drug will not have a therapeutic effect, or a high concentration in which the drug level will be toxic. Knowledge of a drug’s route(s) of metabolism can help a drug developer determine proper doses and necessary dose adjustments to ensure safe and efficacious use of the drug. It is also necessary to know about the nature of the metabolites produced by the metabolic process.

Resulting Recommendations

The FDA recommends drug developers to consider the following approaches to in vitro studies of drug metabolism and drug interactions:

1). Investigate metabolic processes (including route[s] of metabolism) and drug-drug interactions as early as possible in the drug development process, ideally prior to phase 2 studies (eg, as early as pharmacokinetic/phase 1 studies). The data produced will enhance the design of subsequent studies regarding clinical dose/response, interaction, and special populations.

2. Allow more concomitant drug use during studies early in the development process.

3. Identify significant metabolites and prodrugs and their pharmacological properties.

4. Identify metabolic differences in patient groups based on genetic polymorphisms, or other demographic factors (eg, age, race, gender). Doing so will assist in determining proper dosing in different patient populations, and, ultimately, dose adjustments.

5. Use the information gained from early identification of metabolic routes of elimination and metabolites in in vitro studies to guide the design of preclinical studies in animals to compare drug and metabolite exposure in humans and animals. Also conduct these studies in animals early in the course of drug development, as the information obtained can be used to help plan and interpret later clinical studies.

6. Give precedence to results from in vivo studies over results from in vitro studies. However, if in vitro studies determine that certain metabolic pathways are not involved in the elimination of a drug, in vivo testing may be unnecessary.

7. Conduct in vitro studies of drug at concentrations that will be relevant in vivo to identify if other substances inhibit or induce the effect of the drug.

8. Label for class effects for various metabolic enzymes. Use the data gained in in vitro studies about metabolic pathways to draw generalizations about what substances the drug may interact with and include this in the product labeling. For example, knowing that the drug is metabolized by CYP450 enzymes, certain inhibition and/or induction interactions can be expected, and dose adjustments may be necessary. Fully disclose on the labeling if generalizations are being made from in vitro studies.

Impact

Compliance with this guidance should help drug/biologic developers plan efficient, cost-saving drug testing plans, allowing them to gain an understanding of metabolic pathways and potential drug interactions early on in a drug’s development (eg, in the in vitro stage). Gaining this knowledge early in a drug’s development will help eliminate unnecessary subsequent testing that would be costly and inefficient at a later stage (eg, clinical) of development.