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Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-8702-6654
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-9181-1321
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Drug Metabolism and Pharmacokinetics, Early Respiratory, Inflammation and Autoimmunity, R&D Biopharmaceuticals, AstraZeneca R&D, Gothenburg, Sweden.
2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 10, p. 3425-3433Article in journal (Refereed) Published
Abstract [en]

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.

Place, publisher, year, edition, pages
2019. Vol. 108, no 10, p. 3425-3433
Keywords [en]
blood-brain barrier, brain delivery, dose-response relationship, model-based approach, nanocarrier, pharmacokinetics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-395591DOI: 10.1016/j.xphs.2019.05.029ISI: 000495939800030PubMedID: 31163187OAI: oai:DiVA.org:uu-395591DiVA, id: diva2:1362786
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-12-04Bibliographically approved

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Hu, YangHammarlund-Udenaes, MargaretaFridén, Markus

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