Current Regulatory Considerations for Microbiome-Based Pharmacokinetics

Abstract

Recent progress in metagenome analysis has offered new insight into pharmacomicrobiomics. For example, the microbiota has been shown to be involved in the intestinal drug metabolism of more than 50 drugs. Although some regulatory points on pharmacomicrobiomics to be considered are mentioned in the guideline for drug-drug interactions（PSEHB/PED Notification No. 0723-4, July 2018）, a series of analyses for current regulatory considerations regarding pharmacomicrobiomics has never been reported. In this study, we reviewed the regulatory points associated with drug metabolism by the microbiota using reports on premarketing evaluations, interview forms, and package inserts of 618 new prescription drugs approved between April 2017 and March 2022. Fifty-five drugs are metabolized, secreted, and reabsorbed via the enterohepatic circulation, and 38 of these drugs are enzymatically converted into glucuronides through glucuronosyltransferases in the liver, possibly allowing them to be excreted in the intestines. Glucuronidases, gut-bacterial enzymes, can deconjugate glucuronides in the intestine, resulting in intestinal absorption of parental drugs. The influence of the microbiota on drug pharmacokinetics is mentioned in the regulatory documents for only 16 drugs. The microbiota compromises approximately 1,000 different microbial species, but in vitro culture systems have never been developed for most of them. The regulatory science for pharmacomicrobiomics continues to be delayed due the lack of effective platforms for studying microbiome-based pharmacokinetics.