Model-Based Drug Development: The Road to Quantitative Pharmacology

Abstract

High development costs and low success rates in bringing new medicines to the market demand more efficient and effective approaches. Identified by the FDA as a valuable prognostic tool for fulfilling such a demand, model-based drug development is a mathematical and statistical approach that constructs, validates, and utilizes disease models, drug exposure-response models, and pharmacometric models to facilitate drug development. Quantitative pharmacology is a discipline that learns and confirms the key characteristics of new molecular entities in a quantitative manner, with goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans and enabling critical decision making. Model-based drug development serves as an integral part of quantitative pharmacology. This work reviews the general concept, basic elements, and evolving role of model-based drug development in quantitative pharmacology. Two case studies are presented to illustrate how the model-based drug development approach can facilitate knowledge management and decision making during drug development. The case studies also highlight the organizational learning that comes through implementation of quantitative pharmacology as a discipline. Finally, the prospects of quantitative pharmacology as an emerging discipline are discussed. Advances in this discipline will require continued collaboration between academia, industry and regulatory agencies.

From in vitro-in vivo relationship (IVIVR) towards in vitro-in vivo extrapolation (IVIVE): A case study of pulmonary delivery systems

“…Moreover, as anti-Xa factor activity is no direct measurement of heparin concentration, the above results confirm usability of RIVIVR for nonclassical PK data for the in vivo part of IVIVR. The results of the current study correspond well to the recent advancements in model-based drug development (6,7). In general, the in vitro-in vivo extrapolation relates to either PK or PD effects scaling from in vitromeasured ADME (absorption, distribution, metabolism and excretion) parameters or compound activity data for PK and PD, respectively, to the in vivo situation (8,9).…”

Getting Innovative Therapies Faster to Patients at the Right Dose: Impact of Quantitative Pharmacology Towards First Registration and Expanding Therapeutic Use

“…Quantitative pharmacology (QP) discovers and confirms the key drug characteristics to provide clear, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision‐making, and eventually bringing safe and effective medicines to patients 1. These modeling approaches include empirical, semimechanistic, or quantitative systems pharmacology modeling techniques with the aim to integrate current knowledge regarding the drug, disease, and mechanism, and then to predict (interpolate or extrapolate) outcomes under new conditions such as untested doses and regimens, populations, or diseases 2.…”

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

“…Following i.v. administration, gemcitabine has a short t 1/2 (ϳ8 -20 minutes) because of rapid deamination to dFdU [46], which has a long t 1/2 (ϳ50 hours) and is largely excreted in the urine [47]. dFdCTP peak concentrations were obtained within 30 minutes of the end of the infusion, and dFdCTP elimination was linear at low concentrations, and became biphasic at high concentrations in leukemic and blood mononuclear cells [46,48,49].…”