Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling.

Hu, Yang,1989-Uppsala universitet,Institutionen för farmaceutisk biovetenskap (author)

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.

Hammarlund-Udenaes, MargaretaUppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)marghamm (author)
Fridén, MarkusUppsala universitet,Institutionen för farmaceutisk biovetenskap,Department of Drug Metabolism and Pharmacokinetics, Early Respiratory, Inflammation and Autoimmunity, R&D Biopharmaceuticals, AstraZeneca R&D, Gothenburg, Sweden,tPKPD(Swepub:uu)mafri535 (author)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

In:Journal of Pharmaceutical Sciences: Elsevier BV108:10, s. 3425-34330022-35491520-6017

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

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