Pharmacokinetic and Pharmacodynamic Comparability Study of Moxetumomab Pasudotox, an Immunotoxin Targeting CD22, in Cynomolgus Monkeys

• Published in: Journal of pharmaceutical sciences Vol. 102; no. 1; pp. 250 - 261
• Main Authors: Wang, Bing, Liang, Meina, Yao, Zhenling, Vainshtein, Inna, Lee, Rozanne, Schneider, Amy, Zusmanovich, Mikhail, Jin, Feng, O'Connor, Kamille, Donato-Weinstein, Bettina, Iciek, Laurie, Lavallee, Theresa, Roskos, Lorin
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.01.2013; Wiley Subscription Services, Inc., A Wiley Company; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; B-lymphocyte lifespan; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Bacterial Toxins - administration & dosage; Bacterial Toxins - blood; Bacterial Toxins - pharmacokinetics; bioequivalence; biotechnology; CAT-8015; Cell Survival - drug effects; comparability; Cynomolgus; Exotoxins - administration & dosage; Exotoxins - blood; Exotoxins - pharmacokinetics; Feedback, Physiological; Immunotoxins - administration & dosage; Immunotoxins - blood; Immunotoxins - pharmacokinetics; Injections, Intravenous; Lymphocyte Count; Lymphocyte Depletion - methods; Macaca fascicularis; Models, Biological; Models, Statistical; moxetumomab pasudotox; pharmacodynamics; pharmacokinetics; population pharmacokinetics/pharmacodynamics; Primates; Sialic Acid Binding Ig-like Lectin 2 - blood; biotechnology; comparability; pharmacodynamics; pharmacokinetics; B-lymphocyte lifespan; population pharmacokinetics/pharmacodynamics; moxetumomab pasudotox; CAT-8015; bioequivalence
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.23343

Moxetumomab pasudotox is an immunotoxin currently being investigated in patients for the treatment of CD22-expressing B-cell malignancies. A single-cycle pharmacokinetic (PK)–pharmacodynamic (PD) study was conducted in cynomolgus monkeys for PK comparability assessment and population PK–PD modeling after major manufacturing process and site changes. Primates were randomized by body weight and baseline CD22 lymphocyte counts to receive intravenous administrations of 1 mg/kg moxetumomab pasudotox (n = 12/group) on Days 1, 3, and 5. PK and B-lymphocyte count data were modeled using a population approach. The 90% confidence intervals of the geometric mean ratios of PK exposure were within the 80%–125% range. The B lymphocytes were depleted to a similar extent, and the immunogenicity incidences were similar across the two groups. The B-cell depletion was described by a novel lifespan model in which moxetumomab pasudotox induced random destruction of B cells in each aging compartment. The endogenous de novo influx from bone marrow was subject to a negative feedback mechanism. The estimated B cell apparent lifespan was 51 days. Covariate analysis confirmed that the manufacturing change had no impact on PK or PD of moxetumomab pasudotox. Results from this study supported continued clinical investigation of moxetumomab pasudotox using the new material.