Best Practices in PBPK: The Case of Efavirenz

Lisa Almond

According to the FDA’s Guidance for Industry on Drug-drug interactions (DDIs), assessment of a new drug’s DDI liability has three major objectives: determining whether any interactions necessitate dosing adjustment, informing the extent of therapeutic monitoring that may be required and identifying any potential contraindications to concomitant use when lesser measures cannot mitigate risk Physiologically-based pharmacokinetic […]

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Topics: PBPK Modeling & Simulation

Prediction of Drug-drug Interactions Arising From CYP3A Induction Using a Physiologically-based Dynamic Model

Using physiologically-based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine […]

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Development of a Multicompartment Permeability-limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs

Achieving sufficient concentrations of antituberculosis (TB) drugs in pulmonary tissue at the optimum time is still a challenge in developing therapeutic regimens for TB. A physiologically based pharmacokinetic model incorporating a multi-compartment permeability-limited lung model was developed and used to simulate plasma and pulmonary concentrations of seven drugs. Passive permeability of drugs within the lung was predicted using an in vitro-in vivo extrapolation approach. Simulated epithelial lining fluid (ELF):plasma concentration ratios showed reasonable […]

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A Physiologically-based Pharmacokinetic Modeling Approach to Predict Disease-drug Interactions: Suppression of CYP3A by IL-6

Elevated cytokine levels are known to downregulate expression and suppress activity of cytochrome P450 enzymes (CYPs). Cytokine-modulating therapeutic proteins (TPs) used in the treatment of inflammation or infection could reverse suppression, manifesting as TP-drug-drug interactions (TP-DDIs). A physiologically based pharmacokinetic model was used to quantitatively predict the impact of interleukin-6 (IL-6) on sensitive CYP3A4 substrates. […]

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Pharmacokinetic and Pharmacodynamic Analysis of Efavirenz Dose Reduction Using an In Vitro-In Vivo Extrapolation Model

The pharmacokinetics (PK) of efavirenz (EFV) is characterized by marked inter-patient variability that correlates with its pharmacodynamics (PD). In vitro-in vivo extrapolation (IVIVE) is a “bottom-up” approach that combines drug data with system information to predict PK and PD. The aim of this study was to simulate EFV PK and PD after dose reductions. At […]

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