Certara’s Best of Blogs 2016

A selection of short essays from our blog, written to empower our customers with modeling and simulation (M&S) and regulatory writing solutions in order to help them solve the toughest drug development problems. Certara staff contributions range in topic from pharmacometrics to systems biology to the growing importance of regulatory writing and sharing clinical trial results.

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Using PBPK Models to Optimize Antiviral Dosing at the Point of Care

Manoranjenni Chetty

The use of physiologically-based pharmacokinetic (PBPK) modeling for drug development is well-established and is now routinely used by the pharmaceutical industry, regulators, and researchers. In this blog post, I’ll discuss a novel application that combined PBPK and Bayesian modeling to help clinicians optimize dosing at the point of patient care. This application was used to […]

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Topics: PBPK Modeling & Simulation

Potential Sources of Inter-subject Variability in Monoclonal Antibody Pharmacokinetics

Understanding inter-subject variability in drug pharmacokinetics and pharmacodynamics is important to ensure that all patients attain suitable drug exposure to achieve efficacy and avoid toxicity. Inter-subject variability in the pharmacokinetics of therapeutic monoclonal antibodies (mAbs) is generally moderate to high; however, the factors responsible for the high inter-subject variability have not been comprehensively reviewed. In […]

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Getting at the HAART of Precision Dosing: Using PBPK Models to Optimize Dosing of an Antiviral

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. It is primarily metabolized by CY2B6. A standard dose of efavirenz has been associated with serious adverse reactions in poor metabolizers (PMs) of CYP2B6, necessitating a reduction […]

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Are Physiologically-based Pharmacokinetic Models Reporting the Right Cmax? Central Venous Versus Peripheral Sampling Site

Physiologically based pharmacokinetic (PBPK) models can over-predict maximum plasma concentrations (Cmax) following intravenous administration. A proposed explanation is that invariably PBPK models report the concentration in the central venous compartment, rather than the site where the samples are drawn. The purpose of this study was to identify and validate potential corrective models based on anatomy and physiology governing the blood supply at the site of sampling and incorporate them into a PBPK platform. Four models were […]

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Prediction of the Pharmacokinetics, Pharmacodynamics, and Efficacy of a Monoclonal Antibody, Using a Physiologically-based Pharmacokinetic FcRn Model

Although advantages of physiologically based pharmacokinetic models (PBPK) are now well established, PBPK models that are linked to pharmacodynamic (PD) models to predict pharmacokinetics (PK), PD, and efficacy of monoclonal antibodies (mAbs) in humans are uncommon. The aim of this study was to develop a PD model that could be linked to a physiologically based mechanistic FcRn model to predict PK, PD, and efficacy of efalizumab. The mechanistic FcRn model for mAbs with target-mediated drug disposition within […]

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Applications of Linking PBPK and PD Models to Predict the Impact of Genotypic Variability, Formulation Differences, Differences in Target Binding Capacity and Target Site Drug Concentrations on Drug Responses and Variability

This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared […]

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Application of a Physiologically-based Pharmacokinetic Model to Predict OATP1B1-related Variability in Pharmacodynamics of Rosuvastatin

Typically, pharmacokinetic-pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake […]

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