High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach
IntroductionThe cytochrome P450 enzyme 3A4 (CYP3A4) mediates numerous drug-drug interactions (DDIs) by inducing the metabolism of co-administered drugs, which can result in reduced therapeutic efficacy or increased toxicity. This study developed and validated a Physiologically Based Pharmacokinetic...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1521068/full |
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| author | Cheng-Guang Yang Tao Chen Wen-Teng Si An-Hai Wang Hong-Can Ren Li Wang |
| author_facet | Cheng-Guang Yang Tao Chen Wen-Teng Si An-Hai Wang Hong-Can Ren Li Wang |
| author_sort | Cheng-Guang Yang |
| collection | DOAJ |
| description | IntroductionThe cytochrome P450 enzyme 3A4 (CYP3A4) mediates numerous drug-drug interactions (DDIs) by inducing the metabolism of co-administered drugs, which can result in reduced therapeutic efficacy or increased toxicity. This study developed and validated a Physiologically Based Pharmacokinetic (PBPK) model to predict CYP3A4 induction-mediated DDIs, focusing on the early stages of clinical drug development.MethodsThe PBPK model for rifampicin, a potent CYP3A4 inducer, was developed and validated using human pharmacokinetic data. Subsequently, PBPK models for ‘victim’ drugs were constructed and validated. The PBPK-DDI model’s predictive performance was assessed by comparing predicted area under the curve (AUC) and maximum concentration (Cmax) ratioswith empirical data, using both the 0.5 to 2-fold criterion and theGuest criteria.ResultsThe rifampicin PBPK model accurately simulated human pharmacokinetic profiles. The PBPK-DDI model demonstrated high predictive accuracy for AUC ratios, with 89% of predictions within the 0.5 to 2-fold criterion and 79% meeting the Guest criteria. For Cmax ratios, an impressive 93% of predictions were within the acceptable range. The model significantly outperformed the static model, particularly in estimating DDI risks associated with CYP3A4 induction.DiscussionThe PBPK-DDI model is a reliable tool for predicting CYP3A4 induction-mediated DDIs. Its high predictive accuracy, confirmed by adherence to evaluation standards, affirms its reliability for drug development and clinical pharmacology. Future refinements may further enhance its predictive value. |
| format | Article |
| id | doaj-art-2e49a3cda54f4d3ea502ffbf48b116da |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-2e49a3cda54f4d3ea502ffbf48b116da2025-08-20T03:11:22ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-02-011610.3389/fphar.2025.15210681521068High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approachCheng-Guang Yang0Tao Chen1Wen-Teng Si2An-Hai Wang3Hong-Can Ren4Li Wang5Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai PharmoGo Co., Ltd., Shanghai, ChinaDepartment of Joint Surgery, Zhengzhou Orthopaedic Hospital, Zhengzhou, ChinaNeurology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaDepartment of Drug Discovery and Development, GenFleet Therapeutics (Shanghai) Inc., Shanghai, ChinaDepartment of Drug Discovery and Development, GenFleet Therapeutics (Shanghai) Inc., Shanghai, ChinaIntroductionThe cytochrome P450 enzyme 3A4 (CYP3A4) mediates numerous drug-drug interactions (DDIs) by inducing the metabolism of co-administered drugs, which can result in reduced therapeutic efficacy or increased toxicity. This study developed and validated a Physiologically Based Pharmacokinetic (PBPK) model to predict CYP3A4 induction-mediated DDIs, focusing on the early stages of clinical drug development.MethodsThe PBPK model for rifampicin, a potent CYP3A4 inducer, was developed and validated using human pharmacokinetic data. Subsequently, PBPK models for ‘victim’ drugs were constructed and validated. The PBPK-DDI model’s predictive performance was assessed by comparing predicted area under the curve (AUC) and maximum concentration (Cmax) ratioswith empirical data, using both the 0.5 to 2-fold criterion and theGuest criteria.ResultsThe rifampicin PBPK model accurately simulated human pharmacokinetic profiles. The PBPK-DDI model demonstrated high predictive accuracy for AUC ratios, with 89% of predictions within the 0.5 to 2-fold criterion and 79% meeting the Guest criteria. For Cmax ratios, an impressive 93% of predictions were within the acceptable range. The model significantly outperformed the static model, particularly in estimating DDI risks associated with CYP3A4 induction.DiscussionThe PBPK-DDI model is a reliable tool for predicting CYP3A4 induction-mediated DDIs. Its high predictive accuracy, confirmed by adherence to evaluation standards, affirms its reliability for drug development and clinical pharmacology. Future refinements may further enhance its predictive value.https://www.frontiersin.org/articles/10.3389/fphar.2025.1521068/fulldrug interactionsrifampicinCYP3A enzymePBPKpharmacokinetics |
| spellingShingle | Cheng-Guang Yang Tao Chen Wen-Teng Si An-Hai Wang Hong-Can Ren Li Wang High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach Frontiers in Pharmacology drug interactions rifampicin CYP3A enzyme PBPK pharmacokinetics |
| title | High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach |
| title_full | High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach |
| title_fullStr | High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach |
| title_full_unstemmed | High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach |
| title_short | High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach |
| title_sort | high performance pbpk model for predicting cyp3a4 induction mediated drug interactions a refined and validated approach |
| topic | drug interactions rifampicin CYP3A enzyme PBPK pharmacokinetics |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1521068/full |
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