caa a22 4500 445313234 CHVBK 20180317142637.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s11095-011-0481-y doi (NATIONALLICENCE)springer-10.1007/s11095-011-0481-y Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor [Elektronische Daten] [Tarundeep Kakkar, Cynthia Sung, Leonid Gibiansky, Thuy Vu, Adimoolam Narayanan, Shao-Lee Lin, Michael Vincent, Christopher Banfield, Alex Colbert, Sarah Hoofring, Marta Starcevic, Peiming Ma] ABSTRACT: Purpose: For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. Methods: Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. Results: The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. Conclusion: The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure. Springer Science+Business Media, LLC, 2011 asthma nationallicence IL-4Rα nationallicence monoclonal antibody nationallicence pharmacodynamics nationallicence pharmacokinetics nationallicence Kakkar Tarundeep Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut Sung Cynthia Rainbow Pharma Consulting, Pte. Ltd., Singapore, Singapore aut Gibiansky Leonid QuantPharm LLC, North Potomac, Maryland, USA aut Vu Thuy Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut Narayanan Adimoolam Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut Lin Shao-Lee Department of General Medicine & Inflammation, Amgen Inc., 91320, Thousand Oaks, California, USA aut Vincent Michael Department of Early Development, Amgen Inc., 91320, Thousand Oaks, California, USA aut Banfield Christopher Department of Early Development, Amgen Inc., 91320, Thousand Oaks, California, USA aut Colbert Alex Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut Hoofring Sarah Department of Clinical Immunology & BSM, Amgen Inc., 91320, Thousand Oaks, California, USA aut Starcevic Marta Department of Clinical Immunology & BSM, Amgen Inc., 91320, Thousand Oaks, California, USA aut Ma Peiming Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2530-2542 0724-8741 28:10<2530 2011 28 11095 https://doi.org/10.1007/s11095-011-0481-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0481-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kakkar Tarundeep Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Sung Cynthia Rainbow Pharma Consulting, Pte. Ltd., Singapore, Singapore aut NATIONALLICENCE 700 1- Gibiansky Leonid QuantPharm LLC, North Potomac, Maryland, USA aut NATIONALLICENCE 700 1- Vu Thuy Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Narayanan Adimoolam Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Lin Shao-Lee Department of General Medicine & Inflammation, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Vincent Michael Department of Early Development, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Banfield Christopher Department of Early Development, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Colbert Alex Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Hoofring Sarah Department of Clinical Immunology & BSM, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Starcevic Marta Department of Clinical Immunology & BSM, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 700 1- Ma Peiming Department of Pharmacokinetics and Metabolism, Amgen Inc., 91320, Thousand Oaks, California, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2530-2542 0724-8741 28:10<2530 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer