Pharmacokinetics and pharmacodynamics of the cytolytic anti‐CD38 human monoclonal antibody TAK‐079 in monkey – model assisted preparation for the first in human trial
Autor: | Stefan Roepcke, Glennda Smithson, Lin Zhao, Nele Plock, Josh Yuan, Gezim Lahu, Eric R. Fedyk |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male medicine.drug_class T-Lymphocytes Cell Pharmacology CD38 Monoclonal antibody Drug Administration Schedule Lymphocyte Depletion Flow cytometry anti‐CD38 antibody cytolytic antibody 03 medical and health sciences 0302 clinical medicine Pharmacokinetics medicine Animals Humans General Pharmacology Toxicology and Pharmaceutics PKPD modeling B-Lymphocytes Membrane Glycoproteins medicine.diagnostic_test biology Chemistry Antibodies Monoclonal Original Articles Models Theoretical ADP-ribosyl Cyclase 1 Killer Cells Natural Cytolysis Membrane glycoproteins Macaca fascicularis 030104 developmental biology medicine.anatomical_structure Neurology 030220 oncology & carcinogenesis Pharmacodynamics biology.protein Original Article Female |
Zdroj: | Pharmacology Research & Perspectives |
ISSN: | 2052-1707 |
Popis: | We are studying the fully human, IgG1λ cytolytic monoclonal antibody TAK‐079, which binds CD38. CD38 is expressed on plasma and natural killer (NK) cells constitutively and upregulated on subsets of B and T lymphocytes upon activation. TAK‐079 cross‐reacts with CD38 expressed by cynomolgus monkeys and depletes subsets of NK, B, and T cells. Therefore, safety and function of TAK‐079 was evaluated in this species, prior to clinical development, using bioanalytical, and flow cytometry assays. We pooled the data from eight studies in healthy monkeys (dose range 0.03‐100 mg/kg) and developed mathematical models that describe the pharmacokinetics and the exposure–effect relationship for NK cells, B cells, and T cells. NK cell depletion was identified as the most sensitive pharmacodynamic effect of TAK‐079. It was adequately described with a turnover model (C 50 = 27.5 μg/mL on depletion rate) and complete depletion was achieved with an IV dose of 0.3 mg/kg. Intermediate effects on T‐cell counts were described with a direct response model (C 50 = 11.9 μg/mL) and on B‐cell counts with a 4‐transit‐compartment model (C 50 = 19.8 μg/mL on depletion rate). Our analyses substantiate the observation that NK, B and T cells are cleared by TAK‐079 at different rates and required different time spans to replete the blood compartment. The models were used to simulate pharmacokinetic and cell depletion profiles in humans after applying a straightforward scaling approach for monoclonal antibodies in preparation for the first‐in‐human clinical trial. |
Databáze: | OpenAIRE |
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