Recently, population PK/PD modeling and simulation studies have enabled the development of evidence-based individualized dosing schemes for children with a limited number of subjects, thus improving drug safety and efficacy. The application of PK/PD…
ID
Source
Brief title
Condition
- Other condition
- Seizures (incl subtypes)
- Neonatal respiratory disorders
Synonym
Health condition
Pijn en sedatie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Pharmacokinetic endpoints are clearance en volume of distribution.
Secondary outcome
Pharmacodynamics of all drugs used will be explored in all included preterm
neonates. Drug specific effects of drugs (e.g. pain scores for morphine, blood
pressure for dopamine) as well as side effects and short term effects on
morbidity and outcome will be analyzed. Additional pharmacodynamic endpoints
for 8 of the 9 study drugs is the Drug target concentration for each drug that
is related to the desired effect. Fluconazole will only be studied for the PK.
The parameters to measure the effect of the drugs:
a) Fentanyl and paracetamol, used as analgetics; clinical endpoint is pain
relief, as routinely measured by the validated COMFORTneo scale and the NRS
scale.
b) Midazolam, phenobarbital and levetiracetam, used as anticonvulsive drugs;
clinical endpoint is control of convulsions, measured by Cerebral Function
Monitoring using amplitude-integrated EEG (aEEG).
c) Midazolam and fentanyl, used as a sedative drug during endotracheal
intubation; clinical endpoint is the intubation readiness score (IRS) and a
qualitative intubation score and sedation score.
d) Midazolam and fentanyl, used as a sedative drug during nursing care is
measured by the COMFORTneo scale.
e) Doxapram, used as treatment for neonatal apnea; clinical endpoint is control
of neonatal apnea and endotracheal intubation in case of failure. The first
endpoint can be measured by modern monitoring technology, in which central
post-monitoring data stored after initiation of treatment will reveal the
effect of doxapram on the reduction or elimination of apneas.
f) Sildenafil, a treatment for PPHN; clinical endpoints are level of
ventilatory support, oxygen need (repetitive oxygenation index analyses) and
BPD development.
g) Ibuprofen, a treatment for PDA; clinical endpoint is closure of the ductus
arteriosus. Echocardiographic imaging allows the measurement of the diameter of
the ductus and to calculate the LA/AO ratio (left atrial to aortic root ratio).
Inter- and intra-patient variability of the PD and PK parameters of the drugs
to be investigated. Parameters with effect on this variability will be
identified.
Tertiary outcome:
a) Development of a minimally invasive Dried Blood Spot analysis method to
perform future pharmacokinetic studies in neonates. The measured concentration
of the drugs in the dried blood spot samples will be compared with the
concentration of the blood samples in the vial, which is the current validated
standard method. The validity of the DBS method will be the endpoint.
b) Influence of specific polymorphisms involved in the metabolism of the
investigated drugs.
Background summary
Approximately 60% of drugs are used off-label in critically ill neonates in the
Neonatal Intensive Care Units (NICU). This is even more true for pre-term born
neonates in whom pharmacokinetics of these agents may be different due to
immature elimination pathways. The lack of sufficient data about efficacy and
safety of many of these drugs makes it difficult to have evidence based dosing
guidelines for these agents. Therefore the urge for drug research in this
population is of great importance.
The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of drugs in
premature infants are different from the characteristics found in term
neonates, older children and adults. These differences are caused among others
by a different body composition, by immaturity of the renal excretion systems,
the metabolic pathways in the liver and other organ functions as well as
immature drug receptors and transporters. After birth, there is a rapid
development of many of these functions, necessitating frequent adaptation of
dosage guidelines in the first few weeks of life. Besides age and size,
co-morbidity, co-administration of drugs and genetic heterogeneity may further
contribute to this extensive inter-individual variability in pharmacokinetics
and pharmacodynamics of premature infants. There is a critical lack of
evidence-based data of drug dosing in (extremely) preterm neonates.
Study objective
Recently, population PK/PD modeling and simulation studies have enabled the
development of evidence-based individualized dosing schemes for children with a
limited number of subjects, thus improving drug safety and efficacy. The
application of PK/PD modeling in the most critically ill population of
premature infants, with the highest variability in the pharmacokinetics of
drugs, and the greatest lack of adequate data underscoring optimal dosage, can
contribute to the development of rational, individualized and safe dosing
regimens.
This study will provide information on the pharmacokinetics, safety and
effectiveness of off-label drugs used in critically ill premature infants:
doxapram, fentanyl, midazolam, paracetamol, phenobarbital, sildenafil,
levetiracetam, ibuprofen and fluconazole. PK/PD analysis will result in
(adapted) dosage guidelines, thus contributing towards an improvement in the
quality of care and cost efficiency. Furthermore the development of Dried Blood
Spot (DBS) analysis is investigated for these drugs as a minimally invasive
method for conventional patient care and to perform pharmacological studies in
children. The adapted dosage guidelines will be implemented directly into
clinical practice in collaboration with the NKFK. Therefore the study is
designed as an observational multicenter study to be able to collect sufficient
data for the drugs of interest.
Study design
This is a prospective observational multicenter study on the pharmacokinetics
and pharmacodynamics of paracetamol, fentanyl, midazolam, phenobarbital,
doxapram, levetiracetam, sildenafil and ibuprofen, and the pharmacokinetics of
fluconazole routinely administered to preterm infants according to standard
protocols. The treatment regimen is left to the discretion of the treating
physician in accordance with current guidelines. During this study a limited
number of additional blood samples will be drawn from the participants for
pharmacokinetic analysis, never exceeding 3% of the total blood volume during
any four-week period or 1% at any single time.
It is standard care in the Netherlands for all premature born infants under 32
weeks to get seen by the paediatrician at the age of two years for a check on
growth and development. The visit to the day care clinic of the hospital of
their admission on birth, enables us to collect qualitative data on growth and
physiological development as well as from psychological and neurodevelopmental
standardised tests.The collected data enables us to gain a better description
of the subjects in our study and to further determine safety of the studied
drugs.
Study burden and risks
The risk in this study is minimal though the only intervention is additional
blood sampling. Blood will only be collected from indwelling arterial lines or
during routine blood sampling. Blood will be sampled by experienced
professionals according to unit policies, which include measures to minimize
pain and distress. If study sampling requires an invasive procedure (i.e. heel
prick method), this will only be performed when a blood sample is required for
clinical reasons, so study participants will not experience any additional
invasive procedures. Furthermore the samples will be obtained from remaining
clinical blood samples available in the hospital laboratories (after all
relevant routine analyses have been completed). In order to ensure the burden
is negligible, the additional sampling is limited to a maximum of 3% of the
total blood volume during any four-week period or 1% at any single time. This
is in accordance with the EMA guideline on neonatal research. The investigator
and attending physicians can decide to withdraw a subject from a scheduled
blood sample for medical reasons; ie too low Hb level.
According to the guideline of the Netherlands Federation of University Medical
Centres *Kwaliteitsborging mensgebonden onderzoek 2.0*, the risk of
participation in this study is categorized as negligible.
Dr Molenwaterplein 60
Rotterdam 3015 GJ
NL
Dr Molenwaterplein 60
Rotterdam 3015 GJ
NL
Listed location countries
Age
Inclusion criteria
* Gestational age < 32 weeks
* Admitted to 1 of the participating NICUs
* Use of one of the studied drugs as standard of care
* Signed Informed Consent by both parents or guardians
Exclusion criteria
None
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL47409.078.14 |