Certara’s Best of Blogs 2015

A selection of short essays from our blog, written to empower our customers with biosimulation 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.

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Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations

Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, “observed data” from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant […]

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1 Size Doesn’t Fit All: PBPK M&S for Individual Risk of Complex DDIs

Helen Humphries

Drug-drug interactions (DDIs) are a primary threat to the safety and efficacy of clinical practice. Clinically relevant drug interactions are primarily due to drug-induced alterations in the activity and quantity of metabolic enzymes and transporters. Indeed, DDIs that cause unmanageable, severe adverse effects have led to restrictions in clinical use and even, drug withdrawals from the market. There is a real need to be able to predict variability in the extent of DDI for individuals that could be missed in a clinical trial.

While there has been notable success in predicting potential DDIs caused by alterations in cytochrome P-450 (CYP) metabolism, there are still major challenges in assessing “Complex DDIs.” DDIs become more complex when they involve more than two drugs, multiple CYP, non-CYP and active transport processes and metabolites of any of the drugs involved. Moreover, the prediction of DDIs is further complicated by “Complex Patients”— patients with organ impairment, pediatrics, or other special populations where the conduct of clinical trials is either not ethical or feasible. In this blog post, I’ll discuss how mechanistic predictions using Physiologically-Based Pharmacokinetic (PBPK) modeling and simulation (M&S) are increasingly being used to address these complex scenarios. Ultimately, further refining these approaches will enable personalized assessment of DDI potential during drug development and also, potentially by clinicians at the point of care.

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Topics: Drug Safety, Model-based Drug Development, PBPK Modeling and Simulation
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