PTN_POPS: Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care

• Sponsor: Daniel Benjamin (Other)
• Overall Status: Completed
• CT.gov ID: NCT01431326
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), The Emmes Company, LLC (Industry)
• Enrollment: 3,520
• Locations: 52
• Actual Duration (Months): 96
• Patients Per Site: 67.7
• Patients Per Site Per Month: 0.7

Study Details

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	Phase
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; 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; Fibrinolytic Bleeding; Pulmonary Arterial Hypertension; CMV Retinitis; Hypertension; Chronic Kidney Diseases; Hyperaldosteronism; Hypokalemia; Heart Failure; Hemophilia; Heavy Menstrual Bleeding; Insomnia	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
• Actual Enrollment: 3520 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care
• Actual Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Nov 1, 2019
• Actual Study Completion Date: Nov 1, 2019

Outcome Measures

Primary Outcome Measures

1. Composite of pharmacokinetic outcomes for understudied drugs in children [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

1. Composite pharmacodynamic outcomes of understudied drugs in children [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.

2. Biomarkers associated with understudied drugs in children [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)
• 1. Known pregnancy as determined via interview or testing if available.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alaska Native Medical Center	Anchorage	Alaska	United States	99508
2	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
3	University of California at San Diego Medical Center	La Jolla	California	United States	92093
4	Axis Clinical Trials	Los Angeles	California	United States	90036
5	University of California, Los Angeles Medical Center	Los Angeles	California	United States	90095
6	The Children's Hospital Colorado	Aurora	Colorado	United States	80045
7	Yale New Haven Children's Hospital	New Haven	Connecticut	United States	06504
8	Alfred I. DuPont Hospital for Children	Wilmington	Delaware	United States	19803
9	Children's National Medical Center	Washington	District of Columbia	United States	20010
10	University of Florida Jacksonville Shands Medical Center	Jacksonville	Florida	United States	32209
11	Kapiolani Womens and Childrens Medical Center	Honolulu	Hawaii	United States	96826
12	Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60614
13	Riley Hospital for Children at Indiana University	Indianapolis	Indiana	United States	46202
14	University of Kansas Medical Center	Fairway	Kansas	United States	66205
15	Children's Mercy Hospital and Clinics	Kansas City	Kansas	United States	66160
16	Wesley Medical Center	Wichita	Kansas	United States	67214
17	Norton Children's Hospital	Louisville	Kentucky	United States	40202
18	Tulane University Health Science Center	New Orleans	Louisiana	United States	70112
19	Ochsner Baptist Clinical Trials Unit	New Orleans	Louisiana	United States	70115-6969
20	University of Maryland	Baltimore	Maryland	United States	21201
21	Children's Hospital of Michigan	Detroit	Michigan	United States	48201
22	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
23	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
24	University of Montana	Missoula	Montana	United States	59804
25	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
26	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
27	University of New Mexico, Health Sciences Center	Albuquerque	New Mexico	United States	87131
28	UNC Hospital Neonatal-Perinatal Medicine	Chapel Hill	North Carolina	United States	27599
29	Duke University Medical Center (PICU / NICU)	Durham	North Carolina	United States	27710
30	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
31	Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106
32	Akron Children's Hospital	Cleveland	Ohio	United States	44313
33	Board of Regents of the University of Oklahoma	Oklahoma City	Oklahoma	United States	73104
34	Oregon Health and Science University	Portland	Oregon	United States	97201-2701
35	Rhode Island Hospital	Providence	Rhode Island	United States	02903
36	Medical University of South Carolina	Charleston	South Carolina	United States	29425
37	University of South Carolina	Columbia	South Carolina	United States	29203
38	University of Utah Hospitals and Clinics	Salt Lake City	Utah	United States	84108
39	University of Vermont Medical Center	Burlington	Vermont	United States	05405
40	University of Virginia Children's Hospital	Charlottesville	Virginia	United States	22908-0386
41	Seattle Children's Hospital	Seattle	Washington	United States	98105
42	West Virginia University Hospital	Morgantown	West Virginia	United States	26506
43	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
44	Manitoba Institute of Child Health	Winnipeg	Manitoba	Canada	R3E 3P4
45	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
46	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
47	Hospital Sainte-Justine	Montreal	Quebec	Canada	T3T 1C5
48	Assaf Harofeh Medical Center	Zerifin	Tel Aviv	Israel	70300
49	Schneider Children's Medical Center of Israel	Petah Tikva		Israel	49202
50	KK Women's and Children's Hospital Pte Ltd	Singapore		Singapore	229899
51	Southampton General Hospital	Southampton	Hampshire	United Kingdom	SO16 6YD
52	Alder Hey Children's Hospital	Liverpool	Merseyside	United Kingdom	L12 2AP

Sponsors and Collaborators

• Daniel Benjamin
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• The Emmes Company, LLC

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Understudied Drugs Project Summary

Publications

• 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.
• 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.
• Bhatt-Meht V, Annich G. Sedative clearance during extracorporeal membrane oxygenation. Perfusion. 2005 Oct;20(6):309-15.
• Bhatt-Mehta V, Johnson CE, Schumacher RE. Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. 1992;12(1):28-32.
• Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. 2003;42(5):403-17. Review.
• Buck ML. Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. 1998 Sep-Oct;18(5):1082-6.
• 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.
• 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.
• 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.
• 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.
• Frenckner B, Radell P. Respiratory failure and extracorporeal membrane oxygenation. Semin Pediatr Surg. 2008 Feb;17(1):34-41. Review.
• 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.
• Husain A, Loehle JA, Hein DW. Clinical pharmacogenetics in pediatric patients. Pharmacogenomics. 2007 Oct;8(10):1403-11. Review.
• 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.
• 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.
• 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.
• 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.
• Munzenberger PJ, Massoud N. Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation. ASAIO Trans. 1991 Jan-Mar;37(1):16-8.
• 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.
• 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.
• 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.
• Southgate WM, DiPiro JT, Robertson AF. Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 1989 Jun;33(6):817-9.
• '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.
• Wilson JT. An update on the therapeutic orphan. Pediatrics. 1999 Sep;104(3 Pt 2):585-90.

• Responsible Party: Daniel Benjamin, Professor of Pediatrics, Duke University
• ClinicalTrials.gov Identifier: NCT01431326
• Other Study ID Numbers: Pro00029638; IND 113645; IND 114369; IND 114531; IND 118358; HHSN20100006; HHSN27500020; HHSN27500027; HHSN27500043; HHSN27500049
• First Posted: Sep 9, 2011
• Last Update Posted: Dec 20, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daniel Benjamin, Professor of Pediatrics, 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; pain; pneumonia; prophylaxis; retinitis; schizophrenia; sedation; sedative; seizures; septicemia; swelling; urinary tract infection; urinary tract infection (UTI); withdrawal; empiric therapy; staphylococci; Fibrinolytic Bleeding; pulmonary arterial hypertension; CMV retinitis; control of serum phosphorus; Hyperaldosteronism; hypokalemia; heart failure; hemophilia; Heavy Menstrual Bleeding; insomnia
• Additional relevant MeSH terms: Infections; Communicable Diseases; Pneumonia; Urinary Tract Infections; Herpes Simplex; Respiratory Tract Infections; Adenoviridae Infections; Staphylococcal Infections; Intraabdominal Infections; Cytomegalovirus Retinitis; Healthcare-Associated Pneumonia; Sepsis; Toxemia; Meningitis, Bacterial; Central Nervous System Infections; Hemangioma; Hemangioma, Capillary; Muscle Cramp; Pulmonary Arterial Hypertension; Epilepsy; Seizures; Meningitis; Spasm; Hyperkinesis; Retinitis; Kidney Diseases; Renal Insufficiency, Chronic; Menorrhagia; Hypertension; Heart Failure; Arrhythmias, Cardiac; Endocarditis; Bradycardia; Hemophilia A; Neutropenia; Port-Wine Stain; Hypokalemia; Potassium Deficiency; Hyperaldosteronism; Disease; Inflammation; Hemorrhage; Headache; Schizophrenia; Bipolar Disorder; Autistic Disorder; Vancomycin; Ciprofloxacin; Tazobactam; Piperacillin; Tobramycin; Amikacin; Fosfomycin; Cefepime; Piperacillin, Tazobactam Drug Combination; Nafcillin; Cidofovir; Methylprednisolone; Bosentan; Labetalol; Nifedipine; Spironolactone; Pentobarbital; Oxycodone; Alfentanil; Haloperidol; Zolpidem; Ziprasidone; Lurasidone Hydrochloride; Clozapine; Molindone; Warfarin; Tranexamic Acid; Aminocaproic Acid; Rocuronium; Sevelamer

Study Results

No Results Posted as of Dec 20, 2019