Presented at the 127th ASCPT International Meeting, March 2026
Jingjing Yu, Ichiko Petrie, Sophie Argon, Katie Owens, and Isabelle Ragueneau-Majlessi
The objective of the present work was to review recent PMRs and PMCs related to CYP3A, the enzyme most often evaluated in post-marketing studies, to characterize the nature of the requests.
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.
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.
Presented at the 26th North American ISSX and JSSX Meeting, September 2024
Jingjing Yu, Sophie Argon, Yan Wang, and Isabelle Ragueneau-Majlessi
The mechanistic evaluation of enzyme- and transporter-based drug-drug interactions (DDIs) is an integral part of the drug development process and supports the safe and effective clinical use of new therapies. In the present work, DDI data for small molecular drugs approved by the U.S. Food and Drug Administration in 2023 (N = 38) were analyzed using the Certara Drug Interaction Database. The mechanism(s) and clinical magnitude of the observed interactions were characterized based on information available in the new drug application reviews.
Presented at the 25th North American ISSX Meeting, September 2023
Jingjing Yu, Sophie Argon, Katie Owens, Ichiko Petrie, and Isabelle Ragueneau-Majlessi
Kinase inhibitors (KIs) are among the most represented therapeutic areas for novel drugs approved in recent years. In the present analysis, drug metabolism data for all KIs approved in the US since 2011 were reviewed. Mechanistic clinical drug interaction studies with CYP3A perpetrators were fully analyzed using Certara’s Drug Interaction Database (DIDB®). The mechanism(s) and clinical relevance of these interactions were characterized based on information available in the new drug application reviews.
Presented at the 25th North American ISSX Meeting, September 2023
Jingjing Yu, Yan Wang, and Isabelle Ragueneau-Majlessi
Understanding the ADME processes involved in pharmacokinetic-based drug-drug interactions (DDIs) is critical to facilitate an optimal management of DDIs in the clinic. In the present work, drug metabolism and transport in vitro and in vivo data for small molecular drugs approved by the U.S. Food and Drug Administration in 2022 (N=22) were analyzed using the Certara Drug Interaction Database. The mechanism(s) and clinical relevance of these interactions were characterized based on information available in the new drug application (NDA) reviews.
This analysis aimed to identify all strong drug-drug interactions (DDIs) associated with drugs approved by the US Food and Drug Administration (FDA) in 2021.
Presented at the ISSX/MDO Meeting, September 2022
Jingjing Yu, Yan Wang, and Isabelle Ragueneau-Majlessi
The mechanistic evaluation of enzyme- and transporter-based drug-drug interactions (DDIs) during drug development is critical to support management strategies in the clinic.
The objectives of the study were to review pharmacokinetic-based clinical DDI data available in the new drug application (NDA) reviews for drugs approved by the FDA in 2021, and to understand the main mechanisms that mediate interactions resulting in label recommendations.
Food effect (FE) and gastric pH-dependent drug-drug interactions (DDIs) are both absorption-related. Here, we evaluated if Biopharmaceutics Classification System (BCS) classes may be correlated with FE or pH-dependent DDIs. Trends in FE data were investigated for 170 drugs with clinical FE studies from the literature and new drugs approved from 2013 to 2019 by US Food and Drug Administration. A subset of 38 drugs was also evaluated to determine whether FE results can inform the need for a gastric pH-dependent DDI study. The results of FE studies were defined as no effect (AUC ratio 0.80-1.25), increased exposure (AUC ratio ≥1.25), or decreased exposure (AUC ratio ≤0.8). Drugs with significantly increased exposure FE (AUC ratio ≥2.0; N=14) were BCS Class 2 or 4, while drugs with significantly decreased exposure FE (AUC ratio ≤0.5; N=2) were BCS Class 1/3 or 3. The lack of FE was aligned with the lack of a pH-dependent DDI for all 7 BCS Class 1 or 3 drugs as expected. For the 13 BCS Class 2 or 4 weak base drugs with an increased exposure FE, 6 had a pH-dependent DDI (AUC ratio ≤0.8). Among the 16 BCS Class 2 or 4 weak base drugs with no FE, 6 had a pH-dependent DDI (AUC ratio ≤0.8). FE appears to have limited correlation with BCS classes except for BCS Class 1 drugs, confirming that multiple physiological mechanisms can impact FE. Lack of FE does not indicate absence of pH-dependent DDI for BCS Class 2 or 4 drugs.