Presented at the 14th ISSX International Meeting, September 2025
Oliver Hatley, Olha Shuklinova, Anna Murphy, Roz Southall, Eman El-Khateeb, Jingjing Yu, Isabelle
Ragueneau-Majlessi, and Iain Gardner
The application of Physiologically Based Pharmacokinetic (PBPK) modelling in FDA NDAs was assessed across 2023 and 2024 approvals.
Background/objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug-drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam).
Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites.
Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes.
Discussion and conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions.
Purpose
This analysis aimed to provide mechanistic understanding and clinical relevance of pharmacokinetic drug-drug interactions (DDIs) associated with drugs approved by the Food and Drug Administration in 2022.
Methods
Drug metabolism, transport, and DDI data available in New Drug Applications (NDAs) of small molecular drugs approved (n = 22) was analyzed. The mechanism and clinical magnitude of these interactions were characterized based on in vitro, in silico, and clinical data.
Findings
As victims, 10 drugs were identified as clinical substrates. Of these, 7 drugs were substrates of CYP3A, including the sensitive substrates daridorexant and mitapivat. As perpetrators, 3 drugs (adagrasib, lenacapavir, and vonoprazan) were clinical inhibitors of CYP enzymes, and 2 drugs (mavacamten and mitapivat) showed induction. Regarding transporter data, abrocitinib and deucravacitinib were found to be substrates of OAT3 and P-gp/BCRP, respectively, and 4 drugs (abrocitinib, adagrasib, lenacapavir, and oteseconazole) were found to inhibit P-gp and/or BCRP. As expected, all clinical DDIs with AUC changes ≥ 2-fold triggered label recommendations. Over half of DDIs with an AUC change < 2 also had label recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Overall, CYP3A played a major role in the drug disposition of the drugs approved in 2022, mediating all strong drug interactions.
Implications
The mechanistic information obtained from studying these new therapeutics with marker compounds can be extrapolated to common concomitant medications sharing the same pharmacokinetic properties, enhancing the safe and effective administration of these products in situations of polytherapy.
Presented at the 14th ISSX International Meeting, September 2025
Jingjing Yu, Sophie Argon, Katie Owens, Yan Wang, and Isabelle Ragueneau-Majlessi
In the present work, drug metabolism, drug transport, and drug interaction in vitro, in silico, and clinical data for small molecular drugs approved by the U.S. Food and Drug Administration in 2024 (N = 34) were analyzed using Certara Drug Interaction Database (DIDB®; https://www.druginteractionsolutions.org/). The mechanism(s) and clinical relevance of these pharmacokinetic interactions were characterized based on information available in the new drug application reviews.
In September, we added 116 citations in DIDB, including 51 in vitro (with 25 articles published in September 2025) and 65 in vivo articles (with 45 articles published in September 2025).
3 NDAs approved in September 2025, including Brensocatib (BRINSUPRI), Sebetralstat (EKTERLY), and Aceclidine (VIZZ) were also curated in DIDB.
You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.
As always, feel free to contact us if you have any questions or comments.
Drs. Jingjing Yu and Sophie Argon will be attending the upcoming ISSX 2025 meeting in Chicago, where they will present a poster titled “Pharmacokinetic Drug Interactions with Drugs Approved by the US Food and Drug Administration in 2024: A Review of Clinical Data Available in New Drug Application Reviews”.
The poster, numbered 70, will be presented in Poster Session 2 on Tuesday, September 23, from 1:30 to 2:30 p.m. in the poster hall. Dr. Jingjing Yu will be presenting.
If you’re interested in exploring the new features of the DIDB, particularly the new tool, the Concomitant Meds Navigator, please contact them (didbase@certara.com) or stop by the Certara booth (#315) to arrange a demo during the meeting.
In Aug, we added 124 citations in DIDB, including 69 in vitro (with 23 articles published in August 2025) and 55 in vivo articles (with 29 articles published in August 2025).
3 NDAs approved in July 2025, including delgocitinib (ANZUPGO), sunvozertinib (ZEGFROVY), and sepiapterin (SEPHIENCE) were also curated in DIDB.
You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.
As always, feel free to contact us if you have any questions or comments.
In July, we added 86 citations in DIDB, including 53 in vitro (with 17 articles published in July 2025) and 33 in vivo articles (with 32 articles published in July 2025).
3 NDA/BLAs approved in June 2025, including clesrovimab (ENFLONSIA), garadacimab (ANDEMBRY), and taletrectinib (IBTROZI) were also curated in DIDB.
You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.
As always, feel free to contact us if you have any questions or comments.
In June, we added 110 citations in DIDB, including 51 in vitro (with 22 articles published in June 2025) and 59 in vivo articles (with 28 articles published in June 2025).
3 NDA/BLAs approved in May 2025, including avutometinib and defactinib (AVMAPKI FAKZYNJA CO-PACK), acoltremon (TRYPTYR), and telisotuzumab vedotin (EMRELIS) were also curated in DIDB.
You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.
As always, feel free to contact us if you have any questions or comments.
In May, we added 122 citations in DIDB, including 62 in vitro (with 19 articles published in May 2025) and 60 in vivo articles (with 35 articles published in May 2025).
3 NDA/BLAs approved in 2025, including atrasentan (VANRAFIA), fitusiran (QFITLIA), and nipocalimab (IMAAVY) were also curated in DIDB.
You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.
As always, feel free to contact us if you have any questions or comments.