Validation of a Physiological Based Pharmacokinetic Model by the Study of Paracetamol Distribution in the Brain Compartments in Brain Injured Patients

Brain is composed of several anatomical compartments separated by physiological barriers allowing the maintenance of homeostasis. Furthermore, brain-barriers restrain the diffusion of some drugs in cerebro spinal fluid (CSF) and in extracellular fluid (ECF) of brain tissue, making the development and optimization of dosing regimen of new drugs difficult. Most dosing regimen are determined from the plasma concentration because target site concentrations are difficult to obtain in the brain, hence making the prediction of the therapeutic effect, the adverse effect and the toxicity of a brain- diffused drug difficult. Although quantitative and qualitative differences exist in the processes governing pharmacokinetic (PK) in CSF and brain tissue, CSF is considered as the best surrogate of drugs penetration in the human brain.

A study previously published has evaluated in rats the cerebral distribution of paracetamol, used as a marker of passive diffusion in the ECF by microdialysis in the striatum and in the CSF by microdialysis in the ventricular lateralis and the cistern magna. Authors chose paracetamol, as it has the property to diffuse passively and rapidly in the central nervous system allowing the exclusive description of the relationship between the different compartments of the brain. This study has first revealed an unexpected important difference between the distribution profiles obtained in ECF and CSF. Based on these results, authors developed a physiologically based PK model (PBPK) to describe their results and thereby offering the possibility to perform interspecies simulations to predict central nervous system (CNS) distribution of paracetamol in human. In this study, authors used this model to perform pharmaceutical extrapolations between species converting data from animal to human by replacing obtained data from clinical past studies describing paracetamol distribution in the CSF and in plasma.

Microdialysis allows determination of free extracellular concentrations of drug in different tissues and also in brain. Our research team, INSERM U1070, has several past experiences with studies involving micro-dialysis to study the distribution of antibiotic in tissue in both animal and human including cerebral tissue in rat and human. Recommendation from the scholar society suggests that brain injured patients should benefit from a multimodal monitoring to optimize their care and brain perfusion. This invasive multimodal monitoring consists of measuring the intracranial pressure, the oxygen tissue-pressure, the estimation of the cerebral blood flow-rate by cranial Doppler as well as the monitoring of cerebral ischemic parameters by microdialysis. We also prevent systemic cerebral aggression among which, hyperthermia, explaining the prescription of paracetamol among a large number of brain injured patients. Furthermore setting up of an external ventricular draining (EVD) to treat an intra cranial hypertension is usually necessary to allow the continuous flow of the excess of CSF in the brain ventricle.

Few studies carried on human has aimed at comparing the distribution of drugs in both the CSF and the brain extracellular fluid though it is established that the brain barriers differ in their permeability as well as the drug's concentrations are different between brain compartments. Thus by mean of monitoring through microdialysis and/or through therapeutic EVD, required by brain-injured patients, we aim in our study to explore the pharmacokinetic of paracetamol in the brain ECF, the CSF and the plasma and to validate in man the PBPK developed in rat.