Predicting the effect of cytochrome P450 inhibitors on substrate drugs: Analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration
Abstract
Background and objective The US Food and Drug Administration (FDA) has seen a recent increase in the application of physiologically based pharmacokinetic (PBPK) modeling towards assessing the potential of drug-drug interactions (DDI) in clinically relevant scenarios. To continue our assessment of such approaches, we evaluated the predictive performance of PBPK modeling in predicting cytochrome P450 (CYP)-mediated DDI.Methods This evaluation was based on 15 substrate PBPK models submitted by nine sponsors between 2009 and 2013. For these 15 models, a total of 26 DDI studies (cases) with various CYP inhibitors were available. Sponsors developed the PBPK models, reportedly without considering clinical DDI data. Inhibitor models were either developed by sponsors or provided by PBPK software developers and applied with minimal or no modification. The metric for assessing predictive performance of the sponsors' PBPK approach was the R predicted/observed value (R predicted/observed = [predicted mean exposure ratio]/[observed mean exposure ratio], with the exposure ratio defined as [C max (maximum plasma concentration) or AUC (area under the plasma concentration-time curve) in the presence of CYP inhibition]/[C max or AUC in the absence of CYP inhibition]).Results In 81 % (21/26) and 77 % (20/26) of cases, respectively, the R predicted/observed values for AUC and C max ratios were within a pre-defined threshold of 1.25-fold of the observed data. For all cases, the R predicted/observed values for AUC and C max were within a 2-fold range.Conclusion These results suggest that, based on the submissions to the FDA to date, there is a high degree of concordance between PBPK-predicted and observed effects of CYP inhibition, especially CYP3A-based, on the exposure of drug substrates.
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The net effect on a victim depends on the location of the affected transporter (absorption versus elimination) and cannot be predicted from in vitro inhibitory potency alone.
“The interaction illustrates an important principle: the net effect on a victim depends on the location of the affected transporter (absorption versus elimination) and cannot be predicted from in vitro inhibitory potency alone [64,65].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [64]
Because P-glycoprotein and CYP3A4 are frequently colocalized in the enterocyte and share substrates, simultaneous inhibition of both can have a multiplicative effect on bioavailability.
“Because P-gp and CYP3A4 are frequently colocalized in the enterocyte and share substrates, simultaneous inhibition of both can have a multiplicative effect on bioavailability [58,64].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [64]
An important part of the mechanistic evidence comes from in vitro and preclinical studies, in which berberine concentrations may exceed human systemic exposure; the clinical transferability of these data must therefore be interpreted with caution.
“An important part of the mechanistic evidence comes from in vitro and preclinical studies, in which berberine concentrations may exceed human systemic exposure [48,68]; the clinical transferability of these data must therefore be interpreted with caution [64,68].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [64]
The translational gap is constitutive of the field: in vitro concentrations that produce inhibition exceed human plasma concentrations by two to four orders of magnitude; local concentrations that would bridge the gap have been calculated but not measured in humans; PBPK models that would connect the two have not been validated against clinical data for berberine; and the human endpoints available
“The in vitro concentrations that produce inhibition exceed human plasma concentrations by two to four orders of magnitude, as Section 2.1 sets out; the local concentrations that would bridge the gap have been calculated but not measured in humans; the PBPK models that would connect the two have not been validated against clinical data for berberine; and the human endpoints available are surrogates”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [64]
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References 11 · Cited by 148
- Authors
- Wagner, C., Pan, Y., Hsu, V., Grillo, J. A., Zhang, L., Reynolds, K. S., Sinha, V., & Zhao, P.
- Affiliations
- United States Food and Drug Administration (US)
- Corresponding author
- Zhao, Ping
- Venue
- Clinical Pharmacokinetics
- Published
- 2014-09-27
- Volume
- 54
- Issue
- 1
- Pages
- 117-127
- ISSN
- 0312-5963 (ISSN-L)
- 1179-1926
- OpenAlex
- W1984755508
- Cited by
- 148
- References
- 11
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 17 · 2023: 11 · 2022: 10 · 2021: 17 · 2020: 10 · 2019: 11 · 2018: 19 · 2017: 12 · 2016: 17 · 2015: 9
- FWCI
- 14.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Clinical Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy
- Oak Ridge Institute for Science and Education
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- cytochrome P450 inhibitors, drug-drug interactions, physiologically based pharmacokinetic modeling, CYP3A, predictive performance, exposure ratio, cytochrome P450 inhibition
- MeSH terms
- Computer Simulation, Cytochrome P-450 Enzyme System, Drug Interactions, Humans, Models, Biological, Pharmacokinetics, United States, United States Food and Drug Administration, Cytochrome P-450 Enzyme Inhibitors
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