Ignite Creation Date:
2024-05-06 @ 4:00 AM
Last Modification Date:
2024-10-26 @ 11:41 AM
Study NCT ID:
NCT02421068
Status:
COMPLETED
Last Update Posted:
2024-04-03
First Post:
2014-09-25
Brief Title:
Population PKPD of Off Label Drugs in Premature Neonates
Sponsor:
Sinno HP Simons
Organization:
Erasmus Medical Center
Study Overview
Official Title:
Pharmacokinetic and Pharmacodynamic Modelling of Routinely Used Off Label Drugs in Premature Neonates
Status:
COMPLETED
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DINO
Brief Summary:
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 PKPD analysis with NONMEM non-linear mixed effects modelling 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
Detailed Description:
BACKGROUND 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
OBJECTIVE Recently population PKPD 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 PKPD 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 only studied for the PK PKPD 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
DESIGN This is a prospective observational multicenter study on the pharmacokinetics and pharmacodynamics of paracetamol fentanyl midazolam phenobarbital doxapram levetiracetam sildenafil ibuprofen and 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 testsThe collected data enables us to gain a better description of the subjects in our study and to further determine safety of the studied drugs
POPULATION All preterm infants born with gestational age 32 weeks who are admitted to one of the participating NICUs are eligible for inclusion The participating departments are all level III Neonatal Intensive Care Units Three are situated in an academic hospital Rotterdam Nijmegen and Maastricht and one in a non--academic hospital Veldhoven Patients admitted to the 4 NICUs consist of both inborn and outborn neonates with different gestational ages 24--42 weeks All admitted patients need intensive or high care treatment Most patients will be admitted on the first postnatal day but sometimes are referred at older post natal ages 14 days to the NICU
OUTCOME
Primary study parametersoutcome of the study
1 Pharmacokinetic endpoints for all 9 drugs are clearance en volume of distribution
Secondary study parametersoutcome of the study if applicable
Pharmacodynamics of paracetamol fentanyl midazolam phenobarbital doxapram levetiracetam and sildenafil will be explored in all included preterm neonates Fluconazole will only be studied for the pharmacokinetics Drug specific effects of drugs eg 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 the 7 PKPD study drugs is the drug target concentration for each drug that is related to the desired effect
The parameters to measure the effect of the drugs
1 Fentanyl and paracetamol used as analgetics clinical endpoint is pain relief as routinely measured by the validated COMFORTneo scale and the NRS numeric rating scale scale
2 Midazolam phenobarbital and levetiracetam used as anticonvulsive drugs clinical endpoint is control of convulsions measured by Cerebral Function Monitoring using amplitude--integrated EEG aEEG
3 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
4 Midazolam and fentanyl used as a sedative drug during nursing care is measured by the COMFORTneo scale
5 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
6 Sildenafil a treatment for PH pulmonary hypertension clinical endpoints are level of ventilatory support oxygen need repetitive oxygenation index analyses and BPD broncho pulmonary dysplasia development
7 Ibuprofen is used to close patent ductus arteriosus PDA in different dosages orally and intravenously in the recruiting sites Endpoints are measured by cardiac ultrasound ductus closure yesno ductal diameter and LAAO 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
1 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
2 Influence of specific polymorphisms involved in the metabolism of the investigated drugs
OBJECTIVE Recently population PKPD 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 PKPD 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 only studied for the PK PKPD 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
DESIGN This is a prospective observational multicenter study on the pharmacokinetics and pharmacodynamics of paracetamol fentanyl midazolam phenobarbital doxapram levetiracetam sildenafil ibuprofen and 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 testsThe collected data enables us to gain a better description of the subjects in our study and to further determine safety of the studied drugs
POPULATION All preterm infants born with gestational age 32 weeks who are admitted to one of the participating NICUs are eligible for inclusion The participating departments are all level III Neonatal Intensive Care Units Three are situated in an academic hospital Rotterdam Nijmegen and Maastricht and one in a non--academic hospital Veldhoven Patients admitted to the 4 NICUs consist of both inborn and outborn neonates with different gestational ages 24--42 weeks All admitted patients need intensive or high care treatment Most patients will be admitted on the first postnatal day but sometimes are referred at older post natal ages 14 days to the NICU
OUTCOME
Primary study parametersoutcome of the study
1 Pharmacokinetic endpoints for all 9 drugs are clearance en volume of distribution
Secondary study parametersoutcome of the study if applicable
Pharmacodynamics of paracetamol fentanyl midazolam phenobarbital doxapram levetiracetam and sildenafil will be explored in all included preterm neonates Fluconazole will only be studied for the pharmacokinetics Drug specific effects of drugs eg 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 the 7 PKPD study drugs is the drug target concentration for each drug that is related to the desired effect
The parameters to measure the effect of the drugs
1 Fentanyl and paracetamol used as analgetics clinical endpoint is pain relief as routinely measured by the validated COMFORTneo scale and the NRS numeric rating scale scale
2 Midazolam phenobarbital and levetiracetam used as anticonvulsive drugs clinical endpoint is control of convulsions measured by Cerebral Function Monitoring using amplitude--integrated EEG aEEG
3 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
4 Midazolam and fentanyl used as a sedative drug during nursing care is measured by the COMFORTneo scale
5 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
6 Sildenafil a treatment for PH pulmonary hypertension clinical endpoints are level of ventilatory support oxygen need repetitive oxygenation index analyses and BPD broncho pulmonary dysplasia development
7 Ibuprofen is used to close patent ductus arteriosus PDA in different dosages orally and intravenously in the recruiting sites Endpoints are measured by cardiac ultrasound ductus closure yesno ductal diameter and LAAO 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
1 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
2 Influence of specific polymorphisms involved in the metabolism of the investigated drugs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None