134: Lack of Consistency in Pharmacokinetic Drug-Drug Interaction Management With CYP3A Substrates in Phase II/III Clinical Trials: A Call for Regulatory Guidance

Statement of Purpose, Innovation or Hypothesis: In contrast to licensed medications, pharmacokinetic drug-drug interaction (DDI) management with investigational medicinal products (IMPs) is not covered in clinical decision support (CDS) systems. Study protocols generally include directions for DDI management, including a list of prohibited medications. In our experience, this information is highly variable, often outdated and/or incomplete. To our knowledge this problem has not yet been investigated in a systematic manner.
Description of Methods and Materials:Between January 1, 2022 and March 1, 2023, we reviewed phase II/III study protocols of ongoing clinical trials with small molecule IMPs, supported by the Pharmacy at Radboud Univ Medical Ctr, Nijmegen, the Netherlands. IMPs that were already licensed for other indications were excluded. For each IMP, we recorded the clinical development phase, the DDI profile of the IMP known at the time of writing the protocol (substrate/inhibitor/inducer), the list of prohibited medications, and the relevant sources that were mentioned. IMP name/number and sponsor were not recorded. In order to facilitate the analysis and interpretation of the data, we decided to focus on IMPs with CYP3A-related DDI management (n=12).
Data and

Results: The IMPs were equally divided between clinical development phase 2/3. All were multinational studies. These included 9 CYP3A substrates, 3 CYP3A inhibitors and 2 CYP3A inducers. The number of CYP3A inducers that were listed as prohibited co-medication in case the IMP was a CYP3A substrate varied between 0-26 agents, with the highest reference to rifampicin (n=6), carbamazepine (n=6) and St. John’s Wort (n=5). For CYP3A inhibitors this varied between 0-18 agents with the highest reference to clarithromycin, ketoconazole and telithromycin (all n=4). Remarkably, some agents that are withdrawn from the market (e.g. boceprevir, telaprevir, nelfinavir) were still listed as prohibited CYP3A inhibitors. The number of prohibited CYP3A substrates in case the IMP was a CYP3A inhibitor or inducer varied between 0-74 agents. In one study protocol, reference to the FDA website with CYP3A substrates/inhibitor/inducers was made. One study protocol warned that “sensitive CYP3A substrates with narrow therapeutic index” were not allowed without further specification. In two study protocols a reference was made to documents in the Investigator Site File which were not present in the Pharmacy. The clinical development phase did not appear to be related to the (in)completeness of DDI management instructions.
Interpretation, Conclusion or Significance: Although DDI management during clinical development of a drug can be challenging, the lack of (any) consistency that we observed in the study protocols is worrisome, and potentially harmful to study participants. We also acknowledge that the expected therapeutic range of the IMP may dictate how many inhibitors or inducers should be contra-indicated. Still, with suboptimal DDI management, study subjects may suffer from preventable adverse events of therapeutic failure caused by a missed DDI signal. Reference to specific CYP3A substrates, inhibitors or inducers appears to be highly variable and/or accidental. Study physicians have significant responsibility for adequate DDI management but they may not be sufficiently trained. We call for regulatory guidance to optimize DDI management in clinical drug development.
Disclosures: DB is co-founder of Global DDI Solutions.