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Preclinical Study of the Pharmacokinetics of p75ECD-Fc, a Novel Human Recombinant Protein for Treatment of Alzheimer’s Disease, in Sprague Dawley Rats

[ Vol. 21 , Issue. 3 ]

Author(s):

Sally Kelliny, Ho Yin Lam, Ankit Parikh, Yan-Jiang Wang, Larisa Bobrovskaya, Richard Upton and Xin-Fu Zhou*   Pages 235 - 244 ( 10 )

Abstract:


Background: p75ECD-Fc is a recombinant human protein that has recently been developed as a novel therapy for Alzheimer’s disease. Current studies showed that it is able to alleviate Alzheimer’s disease pathologies in animal models of dementia. Thus, knowledge about the pharmacokinetic behavior and tissue distribution of this novel protein is crucial in order to better understand its pharmacodynamics and more importantly for its clinical development.

Methods: The aim of this study is to characterize the pharmacokinetics of p75ECD-Fc after single intravenous and subcutaneous injection of 3mg/kg in Sprague Dawley rats. We calculated the bioavailability of the SC route and studied the distribution of that protein in different tissues, cerebrospinal fluid and urine using ELISA and immunofluorescence techniques. In-vitro stability of the drug was also assessed. Data obtained were analyzed with Non-compartmental pharmacokinetic method using R.

Results: Results showed that the bioavailability of SC route was 66.15%. Half-life time was 7.5 ± 1.7 and 6.2 ± 2.4 days for IV and SC injection, respectively. Tissue distribution of p75ECD-Fc was modest with the ability to penetrate the blood brain barrier. It showed high in vitro stability in human plasma.

Conclusion: These acceptable pharmacokinetic properties of p75ECD-Fc present it as a potential candidate for clinical development for the treatment of Alzheimer’s disease.

Keywords:

Alzheimer's disease, pharmacokinetics, p75ECD-Fc, amyloid-β, p75 neurotrophin receptor, non-compartmental analysis.

Affiliation:

School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, Australian Centre for Pharmacometrics, University of South Australia, Adelaide, School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide

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