Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Carbamates/administration & dosage , Carbamates/therapeutic use , Deglutition Disorders/complications , Hepatitis C, Chronic/drug therapy , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Sofosbuvir/administration & dosage , Sofosbuvir/therapeutic use , Drug Combinations , Humans , Male , Middle Aged , Stroke/complicationsABSTRACT
The blood-brain barrier (BBB) limits the access of drugs to the brain. Intensive research is being conducted on the development of nanoparticulate drug carriers that mediate transfer across the BBB. A question that has been neglected so far is the potential accumulation of the carrier in the brain upon long-term exposure. Here, we address this question by implementing a kinetic model to relate drug loading, required concentration of drug in the brain, and drug clearance to the degradation half-life of the carrier. As a test case with clinical relevance we chose poly-lactic-co-glycolic-acid (PLGA) as a carrier material and a chemotherapeutic for which the required parameters could be recovered from the literature. For methotrexate with a drug load of 8.5 %, a required concentration of free drug of 1â µm, a release from PLGA of 6â hours, a drug clearance from the brain of 3â hours and a half-life of polymer degradation of 28â days, a steady-state accumulation of 1.3â g polymer would be reached in the brain (1.5â L) after seven months. While this number is surprisingly small, further physiological research is warranted to assess to which degree this will be in a tolerable range.