【Purpose/Background】 It is a measure premise for the drug, which is expected to have effect on the central nervous system (CNS), to pass through the blood-brain barrier and have sufficient exposure for the target CNS system after systemic administration. Cerebrospinal fluid (CSF) is a useful marker for in vivo assessment of CNS exposure. Collection of CSF has become an increasingly common procedure as part of a Phase I clinical development program to estimate CNS penetration, and to characterize PK and PD relationships related to dosing, allowing for correlations between peripheral and central compartments. Especially continuous CSF sampling is a strong tool to provides central PK/PD time courses and permits comparison with peripheral PK/PD measures that can be explored across a range of doses, informing optimal dose strategies for future efficacy studies.
【Results】 The continuous CSF sampling via an indwelling catheter was pioneered in the mid-1980s, and across our early phase clinical unit network, close to 70 studies conducted in the last 10 years involved single and/or continuous CSF sampling in healthy young and elderly volunteers and patients (Alzheimer’s disease, Parkinson’s disease, schizophrenia, and multiple sclerosis). The Los Angeles unit conducted 45 of these studies, of which 21 were in the last 5 years alone, and that includes continuous CSF sampling in at least 15 studies.
Based on many years’ experience, and by involving experienced anesthesiologist or neurologist, established procedure of the lumbar punctures and placement of spinal catheters, and minimizing risk of complications have been strongly contributed well tolerated continuous CSF sampling. The procedure makes it possible to do safety collection of 5-12 ml per sample, 120 ml per day total, and up to 40+ hours.
【Conclusion】 The developed continuous CSF collection PK/PD method has been extensively involved in several early phase trials of CNS drug as a valuable approach.