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

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.

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Corresponding authors

Correspondence to Xin-Fu Zhou or Richard Upton.

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Funding

This work was supported by NHMRC grants (APP1020567, APP1021409) and a supporting grant from the University of South Australia. The authors also acknowledge the support provided to S. Kelliny by a Commonwealth Research and Training scholarship and the Egyptian Ministry of Higher Education. p75ECD-Fc was provided by Fujian Tiantai Medical Technology Ltd.

Conflict of interest

Xin-Fu Zhou is one of the inventors of p75ECD-Fc for the treatment of AD. The other authors declare no conflict of interest.

Ethical approval

All animal procedures performed in this study were approved by the Animal Ethics Committee (AEC) of the University of South Australia (approval number U14/16) and in compliance with the South Australian Animal Welfare Act 1985 and Regulations 2012.

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Data are available on negotiation with the authors.

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Code are available on negotiation with the authors.

Author Contributions

All authors participated in the study design and/or data interpretation. S.K. conducted the animal study and samples analysis. Statistical analysis, model development and evaluation were performed by R.U. and S.K. The first draft of the manuscript was written by S.K. and R.U. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Kelliny, S., Bobrovskaya, L., Zhou, XF. et al. 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. Eur J Drug Metab Pharmacokinet (2021). https://doi.org/10.1007/s13318-020-00662-0

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