Model-based Drug Development in Oncology: What’s Next?

Model-based estimates of tumor growth inhibition (TGI) metrics have the potential to enhance learning in early (phase II) clinical studies. They can be used as end points and biomarkers to predict treatment effect on clinical outcome measures—e.g., overall survival (OS)—and support phase II study design, end-of-phase II decisions, and phase III planning and execution. Efforts … Continued

Systems Pharmacology for Drug Discovery and Development: Paradigm Shift or Flash in the Pan?

Systems pharmacology is an emerging approach that sets out to use quantitative concepts rooted in the synergy between modeling and simulation on one hand and large-scale data collection and analysis on the other to investigate biological systems and design therapeutic interventions. Interest in this field has recently increased substantially, but so have perceived challenges and … Continued

Simulations Using a Drug-disease Modeling Framework and Phase 2 Data Predict Phase 3 Survival Outcome in First-line Non-small Cell Lung Cancer

Simulations were performed for carboplatin/paclitaxel (C/P) plus motesanib or bevacizumab vs. C/P as first-line treatment for advanced non small-cell lung cancer (NSCLC) using a published drug disease model. With 700 patients in each arm, simulated hazard ratios for motesanib (0.87; 95% confidence interval [CI], 0.71-1.1) and bevacizumab (0.89; 95% CI, 0.73-1.1) agreed with results from … Continued

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 … Continued

Physiologically-based Pharmacokinetics Joined with In Vitro-In Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology

Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent “system” information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity … Continued

Model-based Meta-analysis for Comparative Efficacy and Safety: Application in Drug Development and Beyond

High development cost, low development success, cost-disciplined health-care policies, and intense competition demand an efficient drug development process. New compounds need to bring value to patients by being safe, efficacious, and cost-effective as compared with existing treatment options. Model-based meta-analysis (MBMA) facilitates integration and utilization of summary-level efficacy and safety data, providing a quantitative framework … Continued

Therapeutic Index of Anticoagulants for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose-response Meta-analysis

Information on the comparative effectiveness of drugs is crucial for drug development decisions, in addition to being needed by regulators, prescribers, and payers. We have carried out a dose-response meta-analysis of three end points each for efficacy and bleeding for various anticoagulants evaluated for the prevention of venous thromboembolism (VTE) following orthopedic surgery to assess … Continued

A Dose-response Meta-analysis for Quantifying Relative Efficacy of Biologics in Rheumatoid Arthritis

We present a dose-response meta-analysis to quantify relative efficacy of biologic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). There is a strong rationale for this analysis because, although multiple biologics are available, information on head-to-head comparisons is limited. Data on the percentage of patients attaining American College of Rheumatology (ACR) 20, 50, … Continued

Applications of Physiologically-based Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug … Continued

Clinical Trial Simulations in Pediatric Patients Using Realistic Covariates: Application to Teduglutide, a Glucagon-like Peptide-2 Analog in Neonates and Infants with Short-bowel Syndrome

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn’s disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal … Continued

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