16 research outputs found
A mathematical analysis of rebound in a target-mediated drug disposition model: I.Without feedback
Population Pharmacokinetic Model of the Pregabalin-Sildenafil Interaction in Rats: Application of Simulation to Preclinical PK-PD Study Design
On the Prediction of the Human Response: A Recycled Mechanistic Pharmacokinetic/Pharmacodynamic Approach
FTY720 is Neuroprotective and Improves Functional Outcomes After Intracerebral Hemorrhage in Mice
From Target Selection to the Minimum Acceptable Biological Effect Level for Human Study: Use of Mechanism-based PK/PD Modeling to Design Safe and Efficacious Biologics
In this paper, two applications of mechanism-based modeling are presented with their utility from candidate selection to first-in-human dosage selection. The first example is for a monoclonal antibody against a cytomegalovirus glycoprotein complex, which involves an antibody binding model and a viral load model. The model was used as part of a feasibility analysis prior to antibody generation, setting the specifications for the affinity needed to achieve a desired level of clinical efficacy. The second example is a pharmacokinetic–pharmacodynamic model based on a single-dose pharmacology study in cynomolgus monkey using data on pharmacokinetics, receptor occupancy, and the dynamics of target cell depletion and recovery. The model was used to estimate the MABEL, here defined as the minimum acceptable biological effect level against which a dose is selected for a first-in-human study. From these applications, we demonstrate that mechanism-based PK/PD binding models are useful for predicting human response to biologics compounds. Especially, such models have the ability to integrate preclinical and clinical, in vitro and in vivo information and facilitate rational decision making during various stages of drug discovery and translational research
Fingolimod for Multiple Sclerosis: Mechanism of Action, Clinical Outcomes, and Future Directions
Prediction of Exposure–Response Relationships to Support First-in-Human Study Design
In drug development, phase 1 first-in-human studies represent a major milestone as the drug moves from preclinical discovery to clinical development activities. The safety of human subjects is paramount to the conduct of these studies and regulatory considerations guide activities. Forces of evolution on the pharmaceutical industry are re-shaping the first-in-human dose selection strategy. Namely, high attrition rates in part due to lack of efficacy have led to the re-organization of research and development organizations around the umbrella of translational research. Translational research strives to bring basic research advances into the clinic and support the reverse transfer of information to enhance compound selection strategies. Pharmacokinetic/pharmacodynamic (PK/PD) modeling holds a unique position in translational research by attempting to integrate diverse sets of information. PK/PD modeling has demonstrated utility in dose selection and trial design for later stages of drug development and is now being employed with greater prevalence in the translational research setting to manage risk (i.e., oncology and inflammation/immunology). Moving from empirical Emax models to more mechanistic representations of the biological system, a higher fidelity of human predictions is expected. Strategies that have proven useful for PK predictions are being applied to PK/PD predictions. This review article examines examples of the application of PK/PD modeling in establishing target concentrations for supporting first-in-human study design