Pharmacokinetics of single-dose administration of paracetamol by nasoduodenal tube throughout childhood

Paracetamol is an effective analgesic and antipyretic and is commonly
prescribed to treat mild-moderate pain or fever in neonates and children.
Paracetamol can be administered orally, rectally, intravenously or by duodenal
tube. The last 10 years, PK studies have been conducted for the first mentioned
3 routes of administration in the pediatric population which resulted in
different PK parameters (e.g. clearance and volume of distribution) compared to
adults; leading to different dosing regimens in the pediatric population.
However,nothing is yet known about the PK of paracetamol over the pediatric
age-span following paracetamol administration by the duodenal tube, despite the
fact that this route is commonly used in the Intensive Care Unit setting.

o To develop a population PK model *based on the observed concentrations of
paracetamol and metabolites after duodenal administration throughout childhood
(0-18 years) -to simulate a dosing regimen.
The emphasis will be on the early phase of the concentration time curve
where absorption takes place -to see if there will be a lag in absorption
after duodenal administration.
o To evaluate to what extent this newly suggested dosing regimens differs from
the currently used dosing regimen.
Paracetamol hereby serves as a model compound to explore potential impact if
duodenal compared to oro-gastric administration.
o To further investigate if this developed dosing regime is the same as the one
now used for paracetamol duodenal administration in clinical practice.
* to compare the PK parameters derived from the duodenal administration with
information derived from IV administration of PK paracetamol studies in the
same age-span ( IV data is already available)

this is a population pharmacokinetic study and will be conducted in a single
centre non-randomized open label single dose design

The potential adverse effects of paracetamol are mild. Dosing is based on the
Dutch*s Children*s Formulary. Furthermore paracetamol is administered through
the duodenal tube, as clinical care. As there is a lot of experience with
duodenal administration of paracetamol, we consider the risks as very low. This
practice has even already been reported in the microdosing studies. The only
additional burden for the patient will be the additional blood sampling. To
minimize the burden there will be: 1) random sampling 2) minimal volume 3)
sampling will be taken from the already available arterial or venous line (line
present as part of clinical care). The maximum blood volume samples per
patient will not exceed 5% of circulating total blood volume (the estimated
total blood volume is 80 ml/kg); this sample volume is considered safe and is
commonly used in pediatric studies. Another matter is that paracetamol liquid
solution will be administered through the duodenal tube whereas it is
registered for oral administration. However, the risk is considered to be
minimal as there is already a lot of experience from the clinical care with
administrating paracetamol through the duodenal route and one of the
recommendations of the handbook enteralia is to administer paracetamol solution
through a tube. Overall we consider the risks and burden as (very) low.