Pediatric microdosing: elucidating age-related changes in oral absorption

Most oral drug formulations for adults are not suitable for children.
Therefore, oral drug formulations specifically developed and licensed for
children are highly needed. Bioavailability of a new oral formulation is
preferably tested in a cross-over design; for ethical and practical reasons,
however, this design is not suitable for pediatric studies. Better knowledge
on the ontogeny of intestinal and hepatic drug metabolizing enzymes involved in
oral drug disposition (e.g glucuronidation), as well as the use of innovative
methods , such as microdosing, to study ontogeny in vivo, may overcome some of
these limitations and help establish age-appropriate dosing guidelines.
Microdosing is applied in adults to estimate pharmacokinetics and is not
associated with therapeutic effect or adverse events (1). The EMA in 2003
endorsed the use of microdosing in the drug developmental process was (2).
Paracetamol is primarily metabolized by UDP-glucuronysyltransferases, which
show a developmental changes which have not been fully elucidated to date.
Hence, paracetamol microdosing could serve as surrogate marker for UGT ontogeny
in vivo.

Primary Objective:
To elucidate the effect of age on the UGT activities using the plasma
paracetamol to APAP-glucuronide clearance after a simultaneous intravenous
therapeutic dose and an oral microdose.

Secondary Objectives:
To determine the effect of age and other co-variates on paracetamol and
metabolite (APAP gluc, 4-O-sul, 3-O-sul, Cys, Mer) disposition in plasma, urine
and feces after a simultaneous intravenous therapeutic dose and an oral
microdose.
To show the feasibility of microdosing studies to elucidate drug kinetics and
the ontogeny of drug metabolism in the pediatric population.

Population pharmacokinetic microdosing study.

Methods: Children receiving paracetamol intravenously for clinical purposes
would receive a pathway specific 14C-labeled microdose simultaneously orally.
The plasma paracetamol to APAP-glucuronide clearance will be determined after
IV therapeutic dose and oral microdose. This will give us information on the
UGT activities and the effect of age will be studied.
Concentration of the labeled paracetamol and the metabolites will be measured
by Accelerated Mass Spectrometry (AMS). The concentration of the normal
paracetamol and the metabolites will be meausred by LC-MS-MS.

Data-analysis: Pharmacokinetic parameters will be determined using population
pharmacokinetics, which will make it possible to map the ontogeny of the UGT
pathway.

One time administration of labeled microdose paracetamol, 3 microgram/kg 14-C
paracetamol

Patients do not have potential benefit by participating in this study.
The burden of blood sampling is minimized due to the use of an already in situ
arterial or central venous line. The maximum blood volume sampled per patient
will not exceed 5% of circulating total blood volume (the estimated total blood
volume is 80 ml/kg).
AMS analysis of a microdose requires the use of rare radioactive isotopes
(e.g.14C). However, the individual dose children from age 0-2 years will
receive is extremely low: 1 microSv, which is far below exposure from one chest
x-ray (14 microSv), as confirmed by a report from the Dutch agency Nuclear
Services for Energy, Environment and Health. For this reason, the radiation
exposure proposed in this study is approved by Erasmus MC radiation office for
pediatric use.
This study can not be done in an adult population, as we specifically aim to
study ontogeny of drug metabolism.