Model-based Drug Development

Abstract

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.

Direct Oral Anticoagulants Vs. Enoxaparin for Prevention of Venous Thromboembolism Following Orthopedic Surgery: A Dose–Response Meta‐analysis

“…As part of a model‐informed drug development strategy,23, 24 a model‐based meta‐analysis was carried out to evaluate the dose–response relationships for efficacy end points (major VTE and total VTE) and safety end points (major, clinically relevant, and total bleeding) of anticoagulants used for the prevention of VTE following THR and TKR surgery. A similar analysis was previously used to compare the various classes of anticoagulants and demonstrated that the therapeutic index relative to enoxaparin was greater for direct FXa inhibitors than for other classes of anticoagulants 21.…”

“…As a key component of knowledge management,23, 24 these models can be used in conjunction with emerging data from investigational agents to help inform dose selection and study design, which will ensure efficient clinical development and adequate differentiation from current therapy.…”

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…The underlying causes for these additional complexities in the exposure-response relationships can be diverse and related to factors such as active or inhibitory metabolites, indirect response characteristics, a transient time delay between concentration and effect, or an equilibration delay in the distribution of drug to the biophase compartment (5,12,14,16,17,(22)(23)(24)(26)(27)(28). Additionally, target-mediated PK models (21,29) and bi-or tri-molecular interaction PK-PD models (4,30) that describe antibody PK, the interactions between antigen(s) and antibody, and the elimination of free antigen(s) are highly informative tools used for prediction of safe and effective dosing strategies (13,31).…”

Agent-Based Modeling in Systems Pharmacology

“…There has been a near constant flow of new terms introduced into the literature1 in an attempt to capture this phenomenon: “MBDD,”2 “model‐facilitated” or “model‐informed drug development,”3 “Quantitative and Systems Pharmacology,”4 and “pharmacometrics.” Large pharmaceutical companies have begun to review, quantify, and report the successes derived from the adoption of a model‐based strategy, providing a thorough description of its implementation and impact 5, 6, 7. The US Food and Drug Administration (FDA) recently utilized mechanistic model‐based methodologies to design a postmarketing clinical trial8; serving as a clear demonstration of the increasing confidence in and adoption of model‐based techniques in pharmacology.…”