Cerebrospinal fluid pharmacokinetics of paracetamol after intravenous propacetamol in a preterm infant

Anderson et al. illustrated that the pharmacokinetics (PK) of cerebrospinal fluid (CSF) approximate closer to the analgesic effect compartment than those of plasma after enteral administration of paracetamol in children. Peak plasma concentrations were reached at 90–120 min after enteral administration in children, with maximal analgesia ocurring 1 h later [1].

We recently reported data on the plasma pharmacokinetics of propacetamol in neonates [2]. Propacetamol is a pro-drug of paracetamol designed to allow intravenous (i.v.) administration [2]. In addition, we had the opportunity to study the CSF pharmacokinetics of propacetamol in a former preterm infant who already had a ventriculo-external drain (enabling continuous drainage of fluid from the lateral ventricle) inserted because of posthaemorrhagic hydrocephalus [3].

After undergoing retinal surgery, the infant who had a postconception age of 39 weeks, received i.v. tramadol. In addition, and after parental consent, a single i.v. dose of propacetamol (20 mg kg⁻¹ equivalent to 10 mg kg⁻¹ paracetamol) was administered over 20 min. A sample of CSF was collected before propacetamol was administered, and then hourly for the first 12 h after dosing. This protocol was approved by the local ethics commitee of the University Hospitals, Gasthuisberg, Leuven, Belgium.

The median rate CSF production was 0.7 ml h⁻¹. Analysis of the CSF sample immediately before drug administration showed no red or white blood cells to be present. Protein content was 1917 mg l⁻¹. CSF paracetamol concentrations were determined using high-performance liquid chromatography. After correction for the volume of the ventriculo-external drain (3 ml), maximum CSF paracetamol concentration was 5.8 mg l⁻¹ and was reached 150 min after drug administration (Figure 1). Assuming first-order pharmacokinetics, the terminal elimination half-life of paracetamol in the CSF in this infant was estimated to be 182 min, which is comparable to its plasma half-life (172 ± 59 min, mean ± SD) after single-dose i.v. administration of propacetamol to full-term infants [2].

Figure 1.

The mean (± SE) plasma paracetamol concentration–time profile (◊) from a single-dose study in neonates who were administered 20 mg kg⁻¹ propacetamol [2], and the CSF paracetamol concentration–time profile () in a single infant.

Although the maximum CSF paracetamol concentration after single-dose i.v. administration occurs sooner than after other routes of administration, the passage of paracetamol across the blood–brain barrier causes a lag time between maximum plasma and CSF concentrations, whereas drug clearance from the CSF is based on bulk flow back to plasma [1, 4].

This present finding is relevant, since the CSF paracetamol concentration profile approximates more closely to the analgesic effect compartment than does that of plasma. Effective analgesia will be reached sooner after i.v. administration of propacetamol compared with other routes.