Pharmacokinetic and pharmacodynamic comparability study of moxetumomab pasudotox, an immunotoxin targeting CD22, in cynomolgus monkeys

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 PKPD 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. (c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:250261, 2013