| The objective of this dissertation is to illustrate the importance of pharmacokinetic and pharmacodynamic (PK-PD) modeling approaches in addressing multiple aspects in preclinical and clinical drug development.;1. Kinetics of drug brain distribution via different administration routes (Chapter 2). It is generally desirable for central nervous system (CNS) agents to rapidly reach brain target sites with effective concentrations. It was suggested that intracarotid (IC) administration is superior over conventional systemic administration routes to produce rapid brain distribution, increased drug concentrations in brain tissue, and potentially lesser systemic side effects. A physiological-based pharmacokinetic (PB-PK) model was constructed and validated with brain parenchyma and cerebral blood compartments, based on published literature data.;2. Contribution of systemic glucose-insulin derangement to neurodegenerative disease; Published preclinical, clinical and epidemiological studies suggest a potential association of diabetes and Alzheimer's disease (AD). It was hypothesized that deranged glucose-insulin homeostasis contributed to the progression of AD through varied mechanisms involving excess insulin effects on beta-amyloid turnover. To test this hypothesis, we studied the effects of different methylprednisolone (MPL) dosing regimens on the alteration of glucose-insulin homeostasis (Chapter 3 and 4).;In the following study (Chapter 5), this MPL-induced diabetes rat model was used to evaluate the changes in an Alzheimer's biomarker, amyloid beta 42 (Abeta42) in brain cortex, hippocampus and cerebral spinal fluid (CSF). The Abeta42 concentrations in CSF, cortex and hippocampus were not significantly different in MPL-treated rats versus controls. (CSF: MPL 244.9+/-83.6 pg/ml vs. Control 254.6+/-112 pg/ml; Cortex: MPL 2192+/-360 pg/ml vs. Control 2078+/-981 pg/ml; Hippocampus: MPL 1152+/-846 pg/ml vs. Control 935.7+/-526 pg/ml). Furthermore, there were no correlations between Abeta42 concentrations and fasting glucose, insulin plasma concentration or insulin sensitivity. Our finding suggests that short-term MPL exposure may not be sufficient to alter Abeta 42 concentrations. Long term studies are needed, but are handicapped by a significant weight loss in rodents with long term steroid dosing.;3. In Chapter 6, plasma concentrations of both R- and S-baclofen enantiomers from 49 subjects were obtained following the last dose. The PK profiles of baclofen enantiomers were essentially identical. Delayed absorption of oral baclofen was observed. A two-compartment PK model with linear clearance (CL) and chained transit absorption steps adequately described both baclofen enantiomer concentration-time profiles. The population PK modeling results showed that mean of clearance (CL/F) was 0.273 L/hr/kg, while the volume of distribution (Vss/F) was 1.16 L/kg and the absorption mean transit time (MTT) was 0.388 hr. Less than 50% inter-individual variability (IIV) was found for CL/F and Vss/F, but relatively large IIV for absorption parameters. Covariate analysis revealed that body weight influenced clearance with a power coefficient (0.47), differing from the common expected value (0.75) in adults.;In the following assessment of baclofen PD effects (Chapter 7), muscle spasticity showed moderate decreases in knee and elbow muscles, measured by Modified Tardieu (MTD) and Ashworth (ASW) scales. Other clinical markers did not show changes with baclofen treatment. Epworth and Stanford sleepiness scales were used for sedation, a clinical marker for adverse effects. The doses of baclofen were well tolerated and no remarkable sedative effects were observed during the baclofen treatment, which may be due to a prolonged acclimatization period. This is the first study to characterize oral baclofen PK in children with CP using a population PK modeling approach, The results provide clinical evidence that an appropriate baclofen dose escalation strategy is reasonably safe for pediatric clinical use, and produces moderate effects in reducing in knee muscle spasticity for some children with cerebral palsy. (Abstract shortened by UMI.). |
