Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling |
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| Affiliation: | 1. Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University, Uppsala, Sweden;2. Department of Drug Metabolism and Pharmacokinetics, Early Respiratory, Inflammation and Autoimmunity, R&D Biopharmaceuticals, AstraZeneca R&D, Gothenburg, Sweden;1. Department of Pharmacology and Clinical Pharmacology, Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea;2. Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Bangladesh;3. Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Republic of Korea;1. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, San Diego, California 92121;1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;2. Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan;3. Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan;4. School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia;5. Faculty of Pharmaceutical Sciences, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan;1. Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan;2. Department of Cardiovascular and Thoracic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan;3. Health Sciences University of Hokkaido, School of Nursing and Social Services, Tobetsu-cho, Japan;4. Vascular Biology and Molecular Pathology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan;1. Research Center Pharmaceutical Engineering GmbH (RCPE), Graz, Austria;2. University of Technology, Institute of Process and Particle Engineering, Graz Austria;1. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China;2. Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China;3. National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China |
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| Abstract: | 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. |
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| Keywords: | nanocarrier brain delivery blood-brain barrier pharmacokinetics dose-response relationship model-based approach BBB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0045" }," $$" :[{" #name" :" text" ," _" :" blood-brain barrier CNS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" central nervous system NC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" nanocarrier PEG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" polyethylene glycol DOX" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" doxorubicin MTX" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" methotrexate PK" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" pharmacokinetics PD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" pharmacodynamics steady-state unbound brain-to-plasma concentration ratio ISF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" interstitial fluid area under the curve of unbound drug in brain ISF during a dosing interval at steady-state peak concentration of unbound drug in plasma during a dosing interval at steady-state RES" },{" #name" :" keyword" ," $" :{" id" :" kwrd0165" }," $$" :[{" #name" :" text" ," _" :" reticuloendothelial system |
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