Early Stage Clinical

Serial CSF Sampling for PK and Biomarker Analysis

Timed interval CSF sampling by indwelling catheterization can be a valuable tool for PK and PD assessment of novel and existing drugs. CSF sampling in studies of drug candidates for Alzheimer's Disease has been conducted for the evaluation of several biomarkers, including acetylcholine, tau proteins, amyloid precursor protein (APP) and beta-amyloid fragments. QPS has recently performed a validation study to investigate the safety and feasibility, including subject burden, of serial CSF sampling in healthy volunteers within a CRO environment.

This study [see publication: den Daas et al. 2013] was conducted in 8 healthy males (55 -75 years). After eligibility assessments, the subjects entered the clinical pharmacology unit (CPU) 2 days before CSF sampling. Prehydration with 2 normal saline was performed for 24 h before the CSF sampling procedure, and Fraxiparine (nadroparine calcium) was given 12 h and 36 h after intradural catheterization, for prophylactic purposes. CSF catheterization (Braun Spinocat®) was performed by a board-certified anesthesiologist and CSF sampling—by the investigator, under aseptic conditions. CSF and blood samples were collected for ACh analysis by interval sampling over a 30 hour period. Questionnaires for subjective experience were administered regularly. Subjects could move freely in the CPU during the sampling period, but were required to stay in a horizontal position for at least 24 hours after removal of the catheter. The 30 h serial CSF sampling was well-tolerated by all healthy volunteers and none objected to undergoing the procedure again in the future. Bioanalysis of ACh in CSF samples showed low inter-individual variability. In our hands, serial CSF sampling is a sophisticated and promising tool for drug evaluation and development.

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Tolerability of CSF sampling: the subjects were asked: "Overall, how would you rate your experience of the insertion of the spinal tube in terms of problems?" (asked an average of 3 times during the clinic stay; N=7).

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Tolerability/safety: All subjects (N=7) were interviewed with a VAS (Visual Analog Scale, ranging from 0-100 mm) concerning headache and back pain on Day -1 (1x), Day 1 (2x), Day 2 (3x), Day 3 (3x), Day 4 (2x) and follow up visit (1x) (error bars are S.D.)

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Biomarkers in CSF: Average acetylcholine (Ach) concentration (pg/ml) over time (h) in the CSF of 7 healthy volunteers (error bars are S.E.M.)

Serial CSF sampling over a period of 30 h via an indwelling spinal catheter in healthy volunteers: headache, back pain, tolerability and measured acetylcholine profile

Den Daas I, Wemer J, Abou Farha K, Tamminga W, de Boer T, Spanjersberg R, Struys MM, Absalom AR; Eur J Clin Pharmacol; November 2012

CSF-studies currently conducted at QPS:
  • Currently, a serial CSF validation study in Alzheimer's patients with mild cognitive deficiency is ongoing at QPS, where sampling is performed for 36 h for quantification of Aβ-fragments, Tau, pTau and APP.

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