<b>Utility of PBPK Modeling in Predicting and Characterizing Clinical Drug Interactions</b>

Foti, Robert S.

doi:10.1124/dmd.123.001384

Cited by 6 publications

(1 citation statement)

References 156 publications

(189 reference statements)

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“…Physiologically based pharmacokinetics (PBPK) modeling is utilized in drug development and during clinical candidate selection to predict human pharmacokinetics (PK) and to assess drug-drug interaction (DDI) risks. 1, 2 PBPK has the potential to accelerate compound progression during the lead optimization phases, providing a platform to integrate in vitro and in vivo pre-clinical data towards human dose optimization, thereby reducing reliance on pre-clinical experiments. Early use of PBPK to support structure-activity relationships (SAR) has been explored by several investigators; despite the promising results, widespread adoption at this stage remains limited.…”

Section: Introductionmentioning

confidence: 99%

Estimating Organ-to-Plasma Ratios in physiologically based PK modeling: a simplified approach for early drug discovery

Broccatelli,

Ramakrishnan

2024

Preprint

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Physiologically based pharmacokinetics (PBPK) modeling is a valuable tool in drug development and candidate selection. However, its widespread adoption in early stages of drug discovery remains limited. This study proposes a novel simplified approach to estimate organ-to-plasma ratio (Kp) values based on measured or estimated volume of distribution (VDss) to eliminate the reliance on additional in vitro data such as blood to plasma partition, LogP and pKa, which may not be available for newly synthesized molecules. The study includes 11 simulations across 4 compounds and 5 species. When simulations were based on ideal VDss and clearance (CL) values determined through non-compartmental analysis (NCA), the observed average absolute fold error (AAFE) aligned with experimental variability in the in vivo experiments (AAFE=1.3). However, when in vitro to in vivo correlation approaches were used to predict VDss and CL starting from in vitro intrinsic CL, plasma protein binding and microsomal binding, the AAFE increased to 1.7, reflecting the additional error introduced by the use of in vitro data to determine PK properties. Overall, this work provides a starting point for the facile implementation of PBPK models to meet the needs of early drug discovery projects.

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Section: Introductionmentioning

confidence: 99%

Estimating Organ-to-Plasma Ratios in physiologically based PK modeling: a simplified approach for early drug discovery

Broccatelli,

Ramakrishnan

2024

Preprint

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Dose Optimization Informed by PBPK Modeling: State‐of‐the Art and Future

Rowland Yeo,

Gil Berglund,

Chen

2024

Clin Pharma and Therapeutics

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Model‐informed drug development (MIDD) is a powerful quantitative approach that plays an integral role in drug development and regulatory review. While applied throughout the life cycle of the development of new drugs, a key application of MIDD is to inform clinical trial design including dose selection and optimization. To date, physiologically‐based pharmacokinetic (PBPK) modeling, an established component of the MIDD toolkit, has mainly been used for assessment of drug–drug interactions (DDIs) and consequential dose adjustments in regulatory submissions. As a result of recent scientific advances and growing confidence in the utility of the approach, PBPK models are being increasingly applied to provide dose recommendations for subjects with differing ages, genetics, and disease states. In this review, we present our perspective on the current landscape of regulatory acceptance of PBPK applications supported by relevant case studies. We also discuss the recent progress and future challenges associated with expanding the utility of PBPK models into emerging areas for regulatory decision making, especially dose optimization in highly vulnerable and understudied populations and facilitating diversity in clinical trials.

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Pharmacokinetics–Pharmacodynamics Modeling for Evaluating Drug–Drug Interactions in Polypharmacy: Development and Challenges

Zhao,

Huang,

et al. 2024

Clin Pharmacokinet

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Utility of PBPK Modeling in Predicting and Characterizing Clinical Drug Interactions

Cited by 6 publications

References 156 publications

Estimating Organ-to-Plasma Ratios in physiologically based PK modeling: a simplified approach for early drug discovery

Estimating Organ-to-Plasma Ratios in physiologically based PK modeling: a simplified approach for early drug discovery

Dose Optimization Informed by PBPK Modeling: State‐of‐the Art and Future

Pharmacokinetics–Pharmacodynamics Modeling for Evaluating Drug–Drug Interactions in Polypharmacy: Development and Challenges

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