Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care (PTN_POPS)

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ClinicalTrials.gov Identifier: NCT01431326

Recruitment Status : Recruiting

First Posted : September 9, 2011

Last Update Posted : April 4, 2018

See Contacts and Locations

Sponsor:

Collaborators:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The EMMES Corporation

Information provided by (Responsible Party):

Daniel Benjamin, Duke University

Study Description

Brief Summary:

Understudied drugs will be administered to children per standard of care as prescribed by their treating caregiver and only biological sample collection during the time of drug administration will be involved. A total of approximately 7000 children aged <21 years who are receiving these drugs for standard of care will be enrolled and will be followed for up a maximum of 90 days. The goal of this study is to characterize the pharmacokinetics of understudied drugs for which specific dosing recommendations and safety data are lacking. The prescribing of drugs to children will not be part of this protocol. Taking advantage of procedures done as part of routine medical care (i.e. blood draws) this study will serve as a tool to better understand drug exposure in children receiving these drugs per standard of care. The data collected through this initiative will also provide valuable pharmacokinetic and dosing information of drugs in different pediatric age groups as well as special pediatric populations (i.e. obese).

Condition or disease	Intervention/treatment
Adenovirus Anesthesia Anxiety Anxiolysis Autism Autistic Disorder Bacterial Meningitis Bacterial Septicemia Benzodiazepine Bipolar Disorder Bone and Joint Infections Central Nervous System Infections Convulsions Cytomegalovirus Retinitis Early-onset Schizophrenia Spectrum Disorders Epilepsy General Anesthesia Gynecologic Infections Herpes Simplex Virus Infantile Hemangioma Infection Inflammation Inflammatory Conditions Intra-abdominal Infections Lower Respiratory Tract Infections Migraines Pain Pneumonia Schizophrenia Sedation Seizures Skeletal Muscle Spasms Skin and Skin-structure Infections Thromboprophylaxis Thrombosis Treatment-resistant Schizophrenia Urinary Tract Infections Withdrawal Sepsis Gram-negative Infection Bradycardia Cardiac Arrest Cardiac Arrhythmia Staphylococcal Infections Nosocomial Pneumonia Neuromuscular Blockade Methicillin Resistant Staphylococcus Aureus Endocarditis Neutropenia Headache	Drug: The POPS study is collecting PK data on children prescribed the following drugs of interest per standard of care:

Condition or disease

Intervention/treatment

Adenovirus Anesthesia Anxiety Anxiolysis Autism Autistic Disorder Bacterial Meningitis Bacterial Septicemia Benzodiazepine Bipolar Disorder Bone and Joint Infections Central Nervous System Infections Convulsions Cytomegalovirus Retinitis Early-onset Schizophrenia Spectrum Disorders Epilepsy General Anesthesia Gynecologic Infections Herpes Simplex Virus Infantile Hemangioma Infection Inflammation Inflammatory Conditions Intra-abdominal Infections Lower Respiratory Tract Infections Migraines Pain Pneumonia Schizophrenia Sedation Seizures Skeletal Muscle Spasms Skin and Skin-structure Infections Thromboprophylaxis Thrombosis Treatment-resistant Schizophrenia Urinary Tract Infections Withdrawal Sepsis Gram-negative Infection Bradycardia Cardiac Arrest Cardiac Arrhythmia Staphylococcal Infections Nosocomial Pneumonia Neuromuscular Blockade Methicillin Resistant Staphylococcus Aureus Endocarditis Neutropenia Headache

Drug: The POPS study is collecting PK data on children prescribed the following drugs of interest per standard of care:

Detailed Description:

The purpose of this study is to characterize the PK ( Pharmacokinetics) of understudied drugs administered to children per standard of care as prescribed by their treating caregiver. This will be accomplished by the collection of biological samples during the time of drug administration per standard of care as prescribed by the caregiver. The prescribing of drugs to children will not be part of this protocol.

Aim #1: Evaluate the PK of understudied drugs currently being administered to children.

Hypothesis #1: The PK of understudied drugs in children will differ from adults and within children according to pediatric age groups or special population.

Aim #2: Explore the pharmacodynamics (PD) of understudied drugs currently being administered to children.

Hypothesis #2: The PD of targeted drugs in children will differ from adults.

Aim #3: Evaluate the influence of genetic factors, metabolic and protein profiles on therapeutic exposure.

Hypothesis #3: Genetic polymorphisms in drug metabolizing enzymes and metabolic and proteomic profiles will impact drug exposure in children.

Study Design


Study Type :	Observational
Estimated Enrollment :	10000 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Official Title:	Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care
Study Start Date :	November 2011
Estimated Primary Completion Date :	February 2020
Estimated Study Completion Date :	February 2020

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Bipolar disorder Pyridoxal 5'-phosphate-dependent epilepsy Schizophrenia

Genetic and Rare Diseases Information Center resources: Granulocytopenia Bacterial Meningitis Cytomegalovirus Retinitis Cytomegalic Inclusion Disease

U.S. FDA Resources

Groups and Cohorts

Intervention Details:

Drug: The POPS study is collecting PK data on children prescribed the following drugs of interest per standard of care:
Other Names:
- ceftazidime
- cidofovir
- ciprofloxacin
- diazepam
- meropenem
- methylprednisolone
- midazolam
- timolol
- valproic acid
- tobramycin
- alfentanil
- clozapine
- fosphenytoin
- haloperidol
- heparin (low molecular weight)
- hydromorphone
- lurasidone
- molindone
- pentobarbital
- warfarin (oral)
- ziprasidone
- amikacin
- atropine
- cefepime
- dexmedetomidine
- etomidate
- lidocaine
- nafcillin
- piperacillin-tazobactam
- rocuronium
- vecuronium
- vancomycin

Outcome Measures

Primary Outcome Measures :

Composite of pharmacokinetic outcomes for understudied drugs in children [ Time Frame: Data will be collected throughout the hospital or outpatient stay up to 90 days ]
As appropriate for each study drug, the following additional PK parameters will be estimated:
- maximum concentration (Cmax)
- time to achieve maximum concentration (Tmax)
- absorption rate constant (ka)
- elimination rate constant (kel)
- half-life (t1/2)
- area under the curve (AUC)
Penetration into body fluids will be determined by comparing exposure (i.e. AUC, Cmax) ratios between the body fluid and plasma or comparison of concentrations in paired samples.

Secondary Outcome Measures :

Composite pharmacodynamic outcomes of understudied drugs in children [ Time Frame: Data will be collected throughout the hospital or outpatient stay up to 90 days ]
When applicable, Monte Carlo simulations will be performed to evaluate therapeutic target attainment rates (pharmacodynamics) in the population of interest. The final PK model and parameters estimated in the population PK analysis will be used to perform these simulations.
Biomarkers associated with understudied drugs in children [ Time Frame: Data will be collected throughout the hospital or outpatient stay up to 90 days ]
The dosing, sampling, and demographic information recorded on the electronic data collection forms will be merged with the bioanalytical information to create a biomarker dataset for each study drug. Biomarkers will be identified using metabolomics/proteomics and pharmacogenomics methodologies. Samples for biomarker analysis will be stored for future use in a PTN designated biorepository. Associations between biomarkers and drug exposure will be explored by visual inspection (i.e. scatter plots) and statistical comparisons as needed.

Biospecimen Retention: Samples With DNA

whole blood

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	up to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Children (<21 years of age) receiving drugs per standard of care as prescribed by treating caregiver

Criteria

Inclusion Criteria:

1) Children (< 21 years of age) who are receiving understudied drugs of interest per standard of care as prescribed by their treating caregiver

Exclusion Criteria:

1) Failure to obtain consent/assent (as indicated)
2) Known pregnancy as determined via interview or testing if available.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01431326

Contacts


Contact: Barrie Harper, MT (ASCP), PMP	919-668-8291	barrie.harper@duke.edu
Contact: POP01 StudyMailbox		POP01@dm.duke.edu

Show 54 Study Locations

Sponsors and Collaborators

Daniel Benjamin

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The EMMES Corporation

Investigators


Principal Investigator:	Michael Cohen-Wolkowiez, MD	Duke University
Study Chair:	Chiara Melloni, MD	Duke University

More Information

Publications of Results:

Phan H, Leder M, Fishley M, Moeller M, Nahata M. Off-label and unlicensed medication use and associated adverse drug events in a pediatric emergency department. Pediatr Emerg Care. 2010 Jun;26(6):424-30. doi: 10.1097/PEC.0b013e3181e057e1.

Shah SS, Hall M, Goodman DM, Feuer P, Sharma V, Fargason C Jr, Hyman D, Jenkins K, White ML, Levy FH, Levin JE, Bertoch D, Slonim AD. Off-label drug use in hospitalized children. Arch Pediatr Adolesc Med. 2007 Mar;161(3):282-90. Erratum in: Arch Pediatr Adolesc Med. 2007 Jul;161(7):655.

de Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Vancomycin population pharmacokinetics in neonates. Clin Pharmacol Ther. 2000 Apr;67(4):360-7.

García B, Barcia E, Pérez F, Molina IT. Population pharmacokinetics of gentamicin in premature newborns. J Antimicrob Chemother. 2006 Aug;58(2):372-9. Epub 2006 Jun 16.

Wade KC, Wu D, Kaufman DA, Ward RM, Benjamin DK Jr, Sullivan JE, Ramey N, Jayaraman B, Hoppu K, Adamson PC, Gastonguay MR, Barrett JS; National Institute of Child Health and Development Pediatric Pharmacology Research Unit Network. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother. 2008 Nov;52(11):4043-9. doi: 10.1128/AAC.00569-08. Epub 2008 Sep 22.

Capparelli E, Hochwald C, Rasmussen M, Parham A, Bradley J, Moya F. Population pharmacokinetics of cefepime in the neonate. Antimicrob Agents Chemother. 2005 Jul;49(7):2760-6.

Spooner N, Lad R, Barfield M. Dried blood spots as a sample collection technique for the determination of pharmacokinetics in clinical studies: considerations for the validation of a quantitative bioanalytical method. Anal Chem. 2009 Feb 15;81(4):1557-63. doi: 10.1021/ac8022839.

Cheung CY, van der Heijden J, Hoogtanders K, Christiaans M, Liu YL, Chan YH, Choi KS, van de Plas A, Shek CC, Chau KF, Li CS, van Hooff J, Stolk L. Dried blood spot measurement: application in tacrolimus monitoring using limited sampling strategy and abbreviated AUC estimation. Transpl Int. 2008 Feb;21(2):140-5. Epub 2007 Oct 17.

Allanson AL, Cotton MM, Tettey JN, Boyter AC. Determination of rifampicin in human plasma and blood spots by high performance liquid chromatography with UV detection: a potential method for therapeutic drug monitoring. J Pharm Biomed Anal. 2007 Aug 15;44(4):963-9. Epub 2007 Apr 19.

Hibberd SG, Alveyn C, Coombes EJ, Holgate ST. Acute and chronic pharmacokinetics of asymmetrical doses of slow release choline theophyllinate in asthma. Br J Clin Pharmacol. 1986 Sep;22(3):337-41.

Meyer DM, Jessen ME. Results of extracorporeal membrane oxygenation in children with sepsis. The Extracorporeal Life Support Organization. Ann Thorac Surg. 1997 Mar;63(3):756-61.

Green TP, Timmons OD, Fackler JC, Moler FW, Thompson AE, Sweeney MF. The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure. Pediatric Critical Care Study Group. Crit Care Med. 1996 Feb;24(2):323-9.

Cohen P, Collart L, Prober CG, Fischer AF, Blaschke TF. Gentamicin pharmacokinetics in neonates undergoing extracorporal membrane oxygenation. Pediatr Infect Dis J. 1990 Aug;9(8):562-6.

Amaker RD, DiPiro JT, Bhatia J. Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 1996 May;40(5):1139-42.

Dagan O, Klein J, Bohn D, Koren G. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Crit Care Med. 1994 Jul;22(7):1099-101.

Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006 Apr 5;295(13):1549-55.

Srinivasan V, Nadkarni VM, Helfaer MA, Carey SM, Berg RA; American Heart Association National Registry of Cardiopulmonary Resuscitation Investigators. Childhood obesity and survival after in-hospital pediatric cardiopulmonary resuscitation. Pediatrics. 2010 Mar;125(3):e481-8. doi: 10.1542/peds.2009-1324. Epub 2010 Feb 22.

Winnike JH, Li Z, Wright FA, Macdonald JM, O'Connell TM, Watkins PB. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther. 2010 Jul;88(1):45-51. doi: 10.1038/clpt.2009.240. Epub 2010 Feb 24.

Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Lamba J, Bowman P, Burckart GJ. The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Hum Immunol. 2002 Sep;63(9):765-70.

Other Publications:

Wilson JT. An update on the therapeutic orphan. Pediatrics. 1999 Sep;104(3 Pt 2):585-90.

Ceci A, Felisi M, Baiardi P, Bonifazi F, Catapano M, Giaquinto C, Nicolosi A, Sturkenboom M, Neubert A, Wong I. Medicines for children licensed by the European Medicines Agency (EMEA): the balance after 10 years. Eur J Clin Pharmacol. 2006 Nov;62(11):947-52. Epub 2006 Oct 5.

Benjamin DK Jr, Smith PB, Murphy MD, Roberts R, Mathis L, Avant D, Califf RM, Li JS. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA. 2006 Sep 13;296(10):1266-73.

't Jong GW, Vulto AG, de Hoog M, Schimmel KJ, Tibboel D, van den Anker JN. Unapproved and off-label use of drugs in a children's hospital. N Engl J Med. 2000 Oct 12;343(15):1125.

Pullen J, Stolk LM, Nieman FH, Degraeuwe PL, van Tiel FH, Zimmermann LJ. Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates. Ther Drug Monit. 2006 Apr;28(2):226-31.

Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003 Sep 18;349(12):1157-67. Review.

Fischer S, Bohn D, Rycus P, Pierre AF, de Perrot M, Waddell TK, Keshavjee S. Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry. J Heart Lung Transplant. 2007 May;26(5):472-7.

Lequier L. Extracorporeal life support in pediatric and neonatal critical care: a review. J Intensive Care Med. 2004 Sep-Oct;19(5):243-58. Review.

Frenckner B, Radell P. Respiratory failure and extracorporeal membrane oxygenation. Semin Pediatr Surg. 2008 Feb;17(1):34-41. Review.

Rajagopal SK, Almond CS, Laussen PC, Rycus PT, Wypij D, Thiagarajan RR. Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: a review of the Extracorporeal Life Support Organization registry. Crit Care Med. 2010 Feb;38(2):382-7. doi: 10.1097/CCM.0b013e3181bc8293.

Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. 2003;42(5):403-17. Review.

Southgate WM, DiPiro JT, Robertson AF. Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 1989 Jun;33(6):817-9.

Dodge WF, Jelliffe RW, Zwischenberger JB, Bellanger RA, Hokanson JA, Snodgrass WR. Population pharmacokinetic models: effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation. Ther Drug Monit. 1994 Dec;16(6):552-9.

Bhatt-Mehta V, Johnson CE, Schumacher RE. Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. 1992;12(1):28-32.

Munzenberger PJ, Massoud N. Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation. ASAIO Trans. 1991 Jan-Mar;37(1):16-8.

Hoie EB, Swigart SA, Leuschen MP, Willett LD, Bolam DL, Goodrich PD, Bussey ME, Nelson RM Jr. Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation. Clin Pharm. 1990 Sep;9(9):711-5.

Buck ML. Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. 1998 Sep-Oct;18(5):1082-6.

Bhatt-Meht V, Annich G. Sedative clearance during extracorporeal membrane oxygenation. Perfusion. 2005 Oct;20(6):309-15.

Mehta NM, Halwick DR, Dodson BL, Thompson JE, Arnold JH. Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment. Intensive Care Med. 2007 Jun;33(6):1018-24. Epub 2007 Apr 3.

Mulla H, Lawson G, von Anrep C, Burke MD, Upton DU, Firmin RK, Killer H. In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation. Perfusion. 2000 Jan;15(1):21-6.

Poggesi I, Benedetti MS, Whomsley R, Le Lamer S, Molimard M, Watelet JB. Pharmacokinetics in special populations. Drug Metab Rev. 2009;41(3):422-54. doi: 10.1080/10837450902891527. Review.

Buhimschi IA, Buhimschi CS. The role of proteomics in the diagnosis of chorioamnionitis and early-onset neonatal sepsis. Clin Perinatol. 2010 Jun;37(2):355-74. doi: 10.1016/j.clp.2010.03.002. Review.

Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB. Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes. 2009 Nov;58(11):2429-43. doi: 10.2337/db09-0580.

Laiakis EC, Morris GA, Fornace AJ, Howie SR. Metabolomic analysis in severe childhood pneumonia in the Gambia, West Africa: findings from a pilot study. PLoS One. 2010 Sep 9;5(9). pii: e12655. doi: 10.1371/journal.pone.0012655.

Husain A, Loehle JA, Hein DW. Clinical pharmacogenetics in pediatric patients. Pharmacogenomics. 2007 Oct;8(10):1403-11. Review.


Responsible Party:	Daniel Benjamin, Professor of Pediatrics, Duke University
ClinicalTrials.gov Identifier:	NCT01431326 History of Changes
Other Study ID Numbers:	Pro00029638 IND 113645 ( Other Identifier: FDA ) IND 114369 ( Other Identifier: FDA ) IND 114531 ( Other Identifier: FDA ) IND 118358 ( Other Identifier: FDA ) HHSN20100006 ( Other Grant/Funding Number: NICHD ) HHSN27500020 ( Other Grant/Funding Number: NICHD ) HHSN27500027 ( Other Grant/Funding Number: NICHD ) HHSN27500043 ( Other Grant/Funding Number: NICHD ) HHSN27500049 ( Other Grant/Funding Number: NICHD )
First Posted:	September 9, 2011 Key Record Dates
Last Update Posted:	April 4, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	Completed study datasets (limited PHI) may be requested from https://pediatrictrials.org/data-sharing-opportunities Study data may be posted to the NICHD Data and Specimen Hub (DASH)


Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Daniel Benjamin, Duke University:


adenovirus anaesthetic anesthesia anticoagulant anti-epileptic anti-inflammatory antimicrobial anti-psychotic antiviral anxiety anxiolysis anxiolytic autism autistic disorder benzodiazepine	bipolar disorder convulsions epilepsy headaches herpes simplex virus herpes simplex virus (HSV) hypertension infantile hemangioma infection inflammation influenza lower respiratory tract infection (LRTI) meningitis migraines muscle spasms

Additional relevant MeSH terms:


Disease Infection Communicable Diseases Schizophrenia Inflammation Pneumonia Epilepsy Migraine Disorders Thrombosis Bipolar Disorder Headache Seizures Heart Arrest Urinary Tract Infections Neutropenia	Meningitis Respiratory Tract Infections Retinitis Adenoviridae Infections Herpes Simplex Autistic Disorder Staphylococcal Infections Endocarditis Bradycardia Hemangioma Arrhythmias, Cardiac Intraabdominal Infections Cytomegalovirus Retinitis Hemangioma, Capillary Port-Wine Stain

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