Ignite Creation Date:
2024-05-06 @ 4:04 PM
Last Modification Date:
2024-10-26 @ 2:03 PM
Study NCT ID:
NCT04867993
Status:
UNKNOWN
Last Update Posted:
2021-04-30
First Post:
2021-02-24
Brief Title:
Amikacin Pharmacokinetics to Optimize Dosing Recommendations in Neonates With Perinatal Asphyxia Treated With Hypothermia
Sponsor:
University of Sarajevo
Organization:
University of Sarajevo
Study Overview
Official Title:
Amikacin Pharmacokinetics to Optimize Dosing Recommendations and PathoPhysiological Considerations in Neonates With Perinatal Asphyxia Treated With Hypothermia
Status:
UNKNOWN
Status Verified Date:
2021-04
Last Known Status:
RECRUITING
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:
Amicool
Brief Summary:
As a part of a project on perinatal clinical pharmacology the primary aim of the present project is to study amikacin pharmacokinetics PK and physiology in asphyxiated neonates treated with therapeutic hypothermia and to provide amikacin dosing recommendations which will be validated prospectively For this purpose we aim to first collect retrospective data on amikacin available in neonates treated with hypothermia in the neonatal intensive care unit NICUs in Leuven and Amsterdam and consequently to propose the dosing regimen to be used in the prospective amikacin PK study at our NICU in University Clinical Center UCC Sarajevo At our NICU we aim to collect amikacin PK observations and other covariates in at least 40 neonates while treated with hypothermia and after re-warming period a paired analysis and in asphyxiated neonates not treated with hypothermia control group
We hereby will use a stepwise approach as initially used to develop and to validate an amikacin dosing regimen in preterm and term neonates De Cock RFW et al 2012 Smits A et al 2015
A 3-step approach will be used of which different parts will be conducted in different contributing hospitals
1 Retrospective evaluation of amikacin therapeutic drug monitoring TDM in asphyxiated neonates treated with hypothermia University hospital Leuven VUmc Amsterdam
2 Development of population PK model derived amikacin dosing recommendation
3 Prospective PK study with validation of the new dosing regimen UCC Sarajevo UCC Tuzla
We hereby will use a stepwise approach as initially used to develop and to validate an amikacin dosing regimen in preterm and term neonates De Cock RFW et al 2012 Smits A et al 2015
A 3-step approach will be used of which different parts will be conducted in different contributing hospitals
1 Retrospective evaluation of amikacin therapeutic drug monitoring TDM in asphyxiated neonates treated with hypothermia University hospital Leuven VUmc Amsterdam
2 Development of population PK model derived amikacin dosing recommendation
3 Prospective PK study with validation of the new dosing regimen UCC Sarajevo UCC Tuzla
Detailed Description:
Step 1 Retrospective evaluation of amikacin TDM in asphyxiated neonates treated with hypothermia University hospital Leuven VUmc Amsterdam
11 Study patients All neonates admitted to the NICUs of the VUmc Amsterdam and University hospital Leuven who underwent treatment with hypothermia for perinatal asphyxia and who received amikacin during routine care were considered for inclusion in this retrospective analysis if TDM observations were available Patients hospitalized between January 2010 and December 2015 were eligible for inclusion Neonates already included in the Pharmacool trial de Haan et al BMC Pediatrics 2012 were excluded
Clinical characteristics at birth gestational age GA weeks birth bodyweight grams Apgar score at 1 5 and 10 minutes after birth as well as characteristics at the moment of amikacin TDM postmenstrual age PMA weeks postnatal age PNA days current bodyweight grams concurrent ibuprofen yesno or inotropic drugs yesno respiratory support ie continuous positive airway pressure or mechanical ventilation yesno mechanical ventilation conventional or high-frequency yesno were retrospectively extracted from the patient files Additionally blood culture results at the start of amikacin therapy were collected from the individual laboratory reports The daily nursing progress reports were used to collect amikacin prescription dose and interval data
12 Amikacin dosing regimen
University hospital Leuven Up to July 2011 amikacin dosing was based on Langendries JP et al 1998 Since July 2011 the simplified model-based dosing regimen published by De Cock RFM et al 2012 was used Since July 2014 an adapted dosing regimen based on prospective validation is applied Smits A et al 2015 In both regimens the dosing interval was prolonged with 10 hours when ibuprofen was co-administered or when asphyxia was diagnosedconsidered by the treating physician
Vumc Amsterdam Up to 24 March 2015 amikacin dosing was 12 mgkgdose Interval 24 hours or 36 hours was determined based on TDM value and subsequent clearance calculation see below From 24 March 2015 amikacin dosing was 15 mgkgdose
13 Drug administration and TDM sampling
University hospital Leuven amikacine Bristol-Myers Squibb is administered intravenously over 20 minutes As part of routine clinical care blood samples for amikacin TDM are collected just before trough administration of the second dose In a case of unexpected results or after dosing adaptation additional TDM samples are collected based on the decision of the treating physician
Vumc Amikacine Bristol-Meyers Squib and recently amikacine Hospira is administered intravenously over 60 minutes As part of routine clinical care the first amikacin TDM sample is taken at least 6 h - but preferably 12-18 h - after the first amikacin administration This blood sampling is preferably performed during fixed moments at the neonatal department Based on the amikacin dosing and TDM plasma concentration of the patient a dosing adaptation is suggested by the pharmacy department according to the maximum a posteriori Bayesian fitting method using the MWPharm computer program version 36 Mediware Groningen the Netherlands This approach allows variability in TDM sampling time between and within patients The predicted target trough level is 5 mgL httptdm-monografieorgmonografieamikacine
14 Amikacin assay
University hospital Leuven Until 31 May 2012 amikacin concentrations were measured with fluorescence polarization immunoassay Abbott TDx kit Abbott Laboratories Diagnostics Division Abbott Park IL USA The lower limit of quantification LLOQ was 08 mgL The coefficient of variation CV was 5 assessed at 5 15 and 30mgL From 31 May 2012 amikacin quantification was based on a kinetic interaction of microparticles in solution KIMS immunoassay RocheHitachi Cobas c systems Roche Diagnostics GmbH Mannheim Germany Also in this essay the LLOQ was 08 mgL The CV was 4
Vumc Until September 2011 amikacin plasma concentrations were measured with fluorescence polarization immunoassay Abbott TDx-FLx Abbott Diagnostics Abbott Park IL USA The LLOQ was 08 mgL The CV was 5 assessed at 5 15 and 30m gL From September 2011 amikacin quantification was based on a particle-enhanced turbidimetric inhibition immunoassay PETINIA ARCHITECT cSystems Abbott Abbott Laboratories Inc Abbott Park IL USA The limit of quantification for this amikacin assay was 20 µgmL The coefficient of variation was 4
15 Pharmacokinetic analysis The retrospectively collected amikacin TDM values of University hospital Leuven and VUmc Amsterdam will be added to a previously collected dataset of nearterm neonates receiving amikacin but not underwent hypothermia treatment Smits A et al 2015 All data will be implemented in the previously developed amikacin population PK model De Cock R et al 2012
Step 2 Development of population PK model derived amikacin dosing recommendation Since a relevant number of neonates treated with hypothermia will be included we hereby aim to compare pharmacokinetic parameters clearance CL volume of distribution Vd of this subgroup of neonates with those of term cases not treated with hypothermia Smits A et al 2015 Subsequently we aim to derive an appropriate model-based dosing regimen to be considered during hypothermia in near term cases
Step 3 Prospective PK study with validation of the new dosing regimen UCC Sarajevo and UCC Tuzla
A prospective observational cohort study conducted in NICU with the following aims
Primary aims
to collect amikacin PK observations renal elimination characteristics and other covariates in at least 40 asphyxiated neonates while treated with hypothermia and after the re-warming period a paired analysis UCC Sarajevo and in 40 asphyxiated neonates treated with amikacin but not treated with hypothermia control group UCC Tuzla
validation of the new dosing regimen
Secondary aims of this prospective study are
to evaluate amikacin pharmacodynamics PD characteristics minimal inhibitory concentration MIC90
to document the adverse effects of hypothermia UCC Sarajevo
31 Study patients Asphyxiated neonates routinely treated with IV amikacin and therapeutic hypothermia NICU UCC Sarajevo and asphyxiated neonates treated with IV amikacin but not treated with hypothermia control group NICU UCC Tuzla will be included in the study after parental informed written consent is obtained
32 Amikacin dosing regimen
The amikacin dosing regimen that is routinely used in our unit is based on NeoFax 2009 version and depends on PMA as follows
PMA of equal or more than 35 weeks 15 mgkg24 h with an additional dosing interval increase of 6 h for all ages if ibuprofen was co-administered or in the setting of perinatal asphyxia The dosing regimen current dosing interval 12 h 15 mgkg36h derived from asphyxiated neonates treated with hypothermia in Leuven and Amsterdam step 1-2 will be used in the prospective part of this study step 3
33 Drug administration and blood sampling Amikacin Likacin 500 mg2mL vial Lisapharma SpA Erba Italy is given to the neonate as an IV infusion via umbilical vein over 20 min by use of a syringe-pump Braun B Braun Medical Inc Bethlehem PA USA Infusion is followed by slow 05 mL Sodium chloride 09 flush
The collection of samples will be obtained to the current clinical and nursing standard procedures at both NICUs Blood samples for amikacin TDM and corresponding creatinine concentrations will be collected by venous line via umbilical catheter while collecting the sample for other laboratory findings according to the protocol 6 minutes before trough the Ctrough the second third fourth and fifth dose of amikacin than 1h after the initiation of administration near peak the maximal concentration Cmax of the second third and fourth dose of amikacin approximately 40 min after the 20-min IV infusion Allegaert K 2004 Langhendries JP 1998
Blood samples 05 mL will be collected in heparinized tubes The recommendations for the maximum predefined total amount of blood available for research purposes in a single neonate is 10 mLkg and will be respected
Blood samples will be centrifuged immediately after collection and subsequently stored at -80C until analysis Paired amikacin and creatinine concentrations will be determined
35 Amikacin and creatinine assays Amikacin serum will be determined based on a particle-enhanced turbidimetric inhibition immunoassay PETINIA ARCHITECT cSystems Abbott Abbott Laboratories Inc Abbott Park IL USA
Plasmaserum creatinin concentration will be quantified either by using the Jaffa method in Sarajevo or by using the corrected Jaffa method in Tuzla
MIC90 for amikacin will be determined in each Sarajevo and Tuzla NICU before the dosing
36 Pharmacokinetic analysis A compartmental pharmacokinetics approach will be performed at the Department of Pharmacology Clinical Pharmacology and Toxicology Medical faculty University of Sarajevo BH
The population pharmacokinetics approach comparing the data on PK already reported in neonates will be performed at Leiden Academic Centre for drug research Leiden University The Netherlands
11 Study patients All neonates admitted to the NICUs of the VUmc Amsterdam and University hospital Leuven who underwent treatment with hypothermia for perinatal asphyxia and who received amikacin during routine care were considered for inclusion in this retrospective analysis if TDM observations were available Patients hospitalized between January 2010 and December 2015 were eligible for inclusion Neonates already included in the Pharmacool trial de Haan et al BMC Pediatrics 2012 were excluded
Clinical characteristics at birth gestational age GA weeks birth bodyweight grams Apgar score at 1 5 and 10 minutes after birth as well as characteristics at the moment of amikacin TDM postmenstrual age PMA weeks postnatal age PNA days current bodyweight grams concurrent ibuprofen yesno or inotropic drugs yesno respiratory support ie continuous positive airway pressure or mechanical ventilation yesno mechanical ventilation conventional or high-frequency yesno were retrospectively extracted from the patient files Additionally blood culture results at the start of amikacin therapy were collected from the individual laboratory reports The daily nursing progress reports were used to collect amikacin prescription dose and interval data
12 Amikacin dosing regimen
University hospital Leuven Up to July 2011 amikacin dosing was based on Langendries JP et al 1998 Since July 2011 the simplified model-based dosing regimen published by De Cock RFM et al 2012 was used Since July 2014 an adapted dosing regimen based on prospective validation is applied Smits A et al 2015 In both regimens the dosing interval was prolonged with 10 hours when ibuprofen was co-administered or when asphyxia was diagnosedconsidered by the treating physician
Vumc Amsterdam Up to 24 March 2015 amikacin dosing was 12 mgkgdose Interval 24 hours or 36 hours was determined based on TDM value and subsequent clearance calculation see below From 24 March 2015 amikacin dosing was 15 mgkgdose
13 Drug administration and TDM sampling
University hospital Leuven amikacine Bristol-Myers Squibb is administered intravenously over 20 minutes As part of routine clinical care blood samples for amikacin TDM are collected just before trough administration of the second dose In a case of unexpected results or after dosing adaptation additional TDM samples are collected based on the decision of the treating physician
Vumc Amikacine Bristol-Meyers Squib and recently amikacine Hospira is administered intravenously over 60 minutes As part of routine clinical care the first amikacin TDM sample is taken at least 6 h - but preferably 12-18 h - after the first amikacin administration This blood sampling is preferably performed during fixed moments at the neonatal department Based on the amikacin dosing and TDM plasma concentration of the patient a dosing adaptation is suggested by the pharmacy department according to the maximum a posteriori Bayesian fitting method using the MWPharm computer program version 36 Mediware Groningen the Netherlands This approach allows variability in TDM sampling time between and within patients The predicted target trough level is 5 mgL httptdm-monografieorgmonografieamikacine
14 Amikacin assay
University hospital Leuven Until 31 May 2012 amikacin concentrations were measured with fluorescence polarization immunoassay Abbott TDx kit Abbott Laboratories Diagnostics Division Abbott Park IL USA The lower limit of quantification LLOQ was 08 mgL The coefficient of variation CV was 5 assessed at 5 15 and 30mgL From 31 May 2012 amikacin quantification was based on a kinetic interaction of microparticles in solution KIMS immunoassay RocheHitachi Cobas c systems Roche Diagnostics GmbH Mannheim Germany Also in this essay the LLOQ was 08 mgL The CV was 4
Vumc Until September 2011 amikacin plasma concentrations were measured with fluorescence polarization immunoassay Abbott TDx-FLx Abbott Diagnostics Abbott Park IL USA The LLOQ was 08 mgL The CV was 5 assessed at 5 15 and 30m gL From September 2011 amikacin quantification was based on a particle-enhanced turbidimetric inhibition immunoassay PETINIA ARCHITECT cSystems Abbott Abbott Laboratories Inc Abbott Park IL USA The limit of quantification for this amikacin assay was 20 µgmL The coefficient of variation was 4
15 Pharmacokinetic analysis The retrospectively collected amikacin TDM values of University hospital Leuven and VUmc Amsterdam will be added to a previously collected dataset of nearterm neonates receiving amikacin but not underwent hypothermia treatment Smits A et al 2015 All data will be implemented in the previously developed amikacin population PK model De Cock R et al 2012
Step 2 Development of population PK model derived amikacin dosing recommendation Since a relevant number of neonates treated with hypothermia will be included we hereby aim to compare pharmacokinetic parameters clearance CL volume of distribution Vd of this subgroup of neonates with those of term cases not treated with hypothermia Smits A et al 2015 Subsequently we aim to derive an appropriate model-based dosing regimen to be considered during hypothermia in near term cases
Step 3 Prospective PK study with validation of the new dosing regimen UCC Sarajevo and UCC Tuzla
A prospective observational cohort study conducted in NICU with the following aims
Primary aims
to collect amikacin PK observations renal elimination characteristics and other covariates in at least 40 asphyxiated neonates while treated with hypothermia and after the re-warming period a paired analysis UCC Sarajevo and in 40 asphyxiated neonates treated with amikacin but not treated with hypothermia control group UCC Tuzla
validation of the new dosing regimen
Secondary aims of this prospective study are
to evaluate amikacin pharmacodynamics PD characteristics minimal inhibitory concentration MIC90
to document the adverse effects of hypothermia UCC Sarajevo
31 Study patients Asphyxiated neonates routinely treated with IV amikacin and therapeutic hypothermia NICU UCC Sarajevo and asphyxiated neonates treated with IV amikacin but not treated with hypothermia control group NICU UCC Tuzla will be included in the study after parental informed written consent is obtained
32 Amikacin dosing regimen
The amikacin dosing regimen that is routinely used in our unit is based on NeoFax 2009 version and depends on PMA as follows
PMA of equal or more than 35 weeks 15 mgkg24 h with an additional dosing interval increase of 6 h for all ages if ibuprofen was co-administered or in the setting of perinatal asphyxia The dosing regimen current dosing interval 12 h 15 mgkg36h derived from asphyxiated neonates treated with hypothermia in Leuven and Amsterdam step 1-2 will be used in the prospective part of this study step 3
33 Drug administration and blood sampling Amikacin Likacin 500 mg2mL vial Lisapharma SpA Erba Italy is given to the neonate as an IV infusion via umbilical vein over 20 min by use of a syringe-pump Braun B Braun Medical Inc Bethlehem PA USA Infusion is followed by slow 05 mL Sodium chloride 09 flush
The collection of samples will be obtained to the current clinical and nursing standard procedures at both NICUs Blood samples for amikacin TDM and corresponding creatinine concentrations will be collected by venous line via umbilical catheter while collecting the sample for other laboratory findings according to the protocol 6 minutes before trough the Ctrough the second third fourth and fifth dose of amikacin than 1h after the initiation of administration near peak the maximal concentration Cmax of the second third and fourth dose of amikacin approximately 40 min after the 20-min IV infusion Allegaert K 2004 Langhendries JP 1998
Blood samples 05 mL will be collected in heparinized tubes The recommendations for the maximum predefined total amount of blood available for research purposes in a single neonate is 10 mLkg and will be respected
Blood samples will be centrifuged immediately after collection and subsequently stored at -80C until analysis Paired amikacin and creatinine concentrations will be determined
35 Amikacin and creatinine assays Amikacin serum will be determined based on a particle-enhanced turbidimetric inhibition immunoassay PETINIA ARCHITECT cSystems Abbott Abbott Laboratories Inc Abbott Park IL USA
Plasmaserum creatinin concentration will be quantified either by using the Jaffa method in Sarajevo or by using the corrected Jaffa method in Tuzla
MIC90 for amikacin will be determined in each Sarajevo and Tuzla NICU before the dosing
36 Pharmacokinetic analysis A compartmental pharmacokinetics approach will be performed at the Department of Pharmacology Clinical Pharmacology and Toxicology Medical faculty University of Sarajevo BH
The population pharmacokinetics approach comparing the data on PK already reported in neonates will be performed at Leiden Academic Centre for drug research Leiden University The Netherlands
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None