97 research outputs found
Use of Quantitative Pharmacology in the Development of HAE1, a High-Affinity Anti-IgE Monoclonal Antibody
HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (≤10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data
New insights into the synergism of nucleoside analogs with radiotherapy
Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells
In Vivo Methods to Study Uptake of Nanoparticles into the Brain
Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods
A Practitioner’s Guide to Performing a Holistic Evaluation of Technology-Enhanced Learning in Medical Education
Technology-enhanced learning (TEL) is now a common mode of educational delivery within medical education. Despite this upsurge, there remains a paucity in comprehensive evaluation of TEL efficacy. In order to make meaningful and evidence-informed decisions on ‘how’ and ‘when’ to utilise technology within a course, ‘useful knowledge’ is required to support faculty in these decision-making processes. In this monograph, a series of pragmatic and achievable approaches for conducting a holistic evaluation of a TEL resource intervention are detailed. These suggestions are based on an established TEL evaluation framework, as well as the author’s own experience and that of the broader literature. The approaches cover development of an appropriate research question that is based on the availability of existing TEL resources alongside the peer-reviewed literature; the development of an appropriate team as well as recommendations for navigating ethical approval; conducting small-scale quantitative and qualitative measure; and performing a large-scale mixed methods assessment to understand the holistic impact of the TEL resource
The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments
Population pharmacokinetics–pharmacodynamics of alemtuzumab (Campath®) in patients with chronic lymphocytic leukaemia and its link to treatment response
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