Clinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of... Show moreClinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of efficacy during clinical development. To improve the prediction of CNS drug effects, knowledge of the drug concentration at the CNS target-site is indispensable. Unfortunately, measuring drug concentrations in the human CNS has major practical and ethical constraints. Therefore, alternative approaches to predict the drug pharmacokinetics (PK) at the target-site(s) in the human CNS should be searched for.In this research, a comprehensive CNS physiologically based PK (PBPK) model for prediction of drug concentration-time profiles in multiple CNS compartments was developed for both rats and humans. The CNS PBPK model only requires knowledge of physicochemical properties of the drugs, with the influence of the net active transporters on the drug exchange across the BBB and the BCSFB that can be obtained from in silico predictions, literature information and in vitro studies (if needed). Because of this, the developed CNS PBPK model is a powerful tool to predict drug PK in the CNS in the early stage of the drug development. Show less
Alzheimer's Disease (AD) is the main contributor to the syndrome dementia, one for which no cure has yet been developed. One of the key issues with developing a cure is the presence of the blood... Show moreAlzheimer's Disease (AD) is the main contributor to the syndrome dementia, one for which no cure has yet been developed. One of the key issues with developing a cure is the presence of the blood-brain barrier (BBB), a restrictive network involving the cerebral vasculature which prevents passage of therapeutics into the brain. Currently many if not all of the clinically most advanced therapeutic avenues involve the use of antibodies to target the production, oligomerization and aggregation of the peptide Amyloid beta. In this thesis, an antibody variant derived from camelids, such as llamas, is examined. The llama antibody is devoid of the light chain, and therefore significantly smaller and easier to manipulate than conventional antibodies. Various strategies have been explored, including the use ofdirect intrathecal injections, liposomes and adeno associated virusses to allow the llama antibody fragment to enter and remain in the brain of mouse models of AD. Various imaging modalities are used to determine the success of BBB passage, including micro-SPECT, intravital multiphoton microscopy, in vivo whole body fluorescence imaging and ex vivo IHC and IF. The thesis supplies a foundation for delivery of llama antibody fragments into the brain. Show less
