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Type: Journal article
Title: Pharmacokinetic modelling of human recombinant protein, p75ECD-Fc: a novel therapeutic approach for treatment of Alzheimer’s disease, in serum and tissue of Sprague Dawley rats
Author: Kelliny, S.
Bobrovskaya, L.
Zhou, X.F.
Upton, R.
Citation: European Journal of Drug Metabolism and Pharmacokinetics, 2021; 46(2):235-248
Publisher: Springer Nature
Issue Date: 2021
ISSN: 0378-7966
Statement of
Sally Kelliny, Larisa Bobrovskaya, Xin‑Fu Zhou, Richard Upton
Abstract: Background and Objective: p75ECD-Fc is a novel antagonist of toxic amyloid beta protein and other neurodegenerative factors with potential for the treatment of Alzheimer’s disease (AD). Preclinical studies showed that it can alleviate the AD pathologies in animal models of dementia. In a previous paper, we used non-compartmental pharmacokinetic analysis to obtain preliminary pharmacokinetic data for p75ECD-Fc in Sprague Dawley (SD) rats. We also studied the tissue distribution in terms of drug metabolism that helped us to understand possible mechanisms of action. Here, we aim to develop population pharmacokinetic models that can describe the pharmacokinetics of p75ECD-Fc in serum and tissues. Methods: p75ECD-Fc was delivered to SD rats via two routes (intravenous and subcutaneous) at a single dose of 3 mg/kg (n = 15). Blood (n = 12) and tissue samples (n = 10–15) were then separated at different time points for a total duration of 42 days post dosage. The concentration of p75ECD-Fc in serum and tissues was measured using an enzyme-linked immunosorbent assay. Results: Data were best fitted to a 2-compartment model with linear elimination kinetics. The population parameter estimates for clearance, and volume of central and peripheral compartments were 0.000176 L/h, 0.0145 L and 0.0263 L, respectively. The presence of anti-drug antibodies was added to the final model as a covariate on clearance. The subcutaneous bioavailability was estimated to be 53.5% with a first-order absorption rate constant of 0.00745 1/h. By modeling of individual tissue concentrations, p75ECD-Fc was found to exhibit modest tissue distribution with estimated tissue/plasma partition coefficients (R) ranging from 0.004 to 0.2. Conclusion: This is the first report of a pharmacokinetic model for p75ECD-Fc and these results may facilitate the ongoing development of p75ECD-Fc and translation to clinical studies.
Keywords: Animals
Rats, Sprague-Dawley
Recombinant Proteins
Enzyme-Linked Immunosorbent Assay
Injections, Intravenous
Injections, Subcutaneous
Biological Availability
Tissue Distribution
Models, Biological
Time Factors
Rights: © Springer Nature Switzerland AG 2021
DOI: 10.1007/s13318-020-00662-0
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