Skip links

Role of In Vitro / In Vivo Metabolism Studies in 505(b)(2) Drug Development of Metabolite Products

At Premier Consulting, we believe that the 505(b)(2) drug development pathway is best used when we can improve the safety and/or efficacy of an existing drug product. We see many opportunities to improve clinical effectiveness, but before trying to prove this in a clinical setting – which is time-consuming and costly, we try to examine the hypothesis using other means. This blog post discusses in vitro/in vivo metabolism studies that we use to assist sponsors to reduce cost, time, and the risk of failure in the clinic.

Prodrugs that are extensively metabolized to their active forms in vivo often display variability in their clinical response. In order to mitigate some of this variability, drug developers often develop intermediate or active metabolite products. Two benefits of developing metabolite drug products are to reduce variability in clinical response and to bypass drug-drug interactions.

A critical component in the drug development program for a metabolite product is the preliminary analysis of the metabolic pathway of the metabolite as compared to the parent compound. Similarity in metabolic profiles between the metabolite product and the parent compound may allow a more abbreviated, streamlined program through the 505(b)(2) regulatory pathway.

The in vitro/in vivo metabolism studies are recommended early on in the drug development program, as they provide reassurance to the Agency that there is minimal uncertainty in regard to the safety of the proposed metabolite product. If these initial studies determine different metabolic characteristics than the parent compound, the proposed drug product may be considered a new chemical entity, with full requirements for nonclinical and clinical studies.

Three types of studies that are helpful in evaluating the metabolism of the metabolite product as compared to the parent compound include:

  • In vitro hepatocyte study
  • In vivo absorption, distribution, metabolism, and excretion (ADME) study
  • In vitro intestinal microsome study

In vitro hepatocyte studies are one way to evaluate and compare the metabolism of the proposed metabolite product to that of the parent compound. An in vitro hepatocyte study examines the metabolism of a drug product across various species, including humans. The in vitro study assesses both phase 1 (cytochrome [CYP] 450 isozymes) and phase 2 (glutathione and glucuronide conjugations) metabolic reactions. This study also provides information pertaining to the correct selection of animal species for further evaluation in an in vivo absorption, distribution, metabolism, and excretion (ADME) study if this information was not provided in the original approval of the parent compound.

The in vivo ADME study will complete the picture of the metabolism of the metabolite drug product to the parent compound and help establish an adequate bridge in order to rely on the Agency’s findings of safety and efficacy for the parent compound.

For metabolite products that have never been dosed orally (metabolites normally generated from the parent compound in the liver), intestinal microsome studies provide valuable information regarding the metabolism of the metabolite product at the gut wall during the absorption process.

The development of a metabolite product may provide the ability to bypass clinically significant drug-drug interactions of the parent compound. In vitro CYP inhibition studies are often recommended to evaluate the potential of the proposed metabolite product to inhibit the human liver microsomal CYP enzymes as compared to the parent product. The data generated from the CYP inhibition studies will provide scientific support for the expected improvement in clinical drug interactions with administration of the metabolite compared to the parent compound.