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The Impact of Genotype on Plasma and Cerebral Spinal Fluid Pharmacokinetics of Celecoxib in Children

Information source: Children's Hospital of Eastern Ontario
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pharmacokinetics of Celecoxib in Children

Intervention: Celecoxib (Drug)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: Children's Hospital of Eastern Ontario

Official(s) and/or principal investigator(s):
Dr Kimmo Murto, MD, Principal Investigator, Affiliation: Children's Hospital of Eastern Ontario

Overall contact:
Dr Kimmo Murto, MD, Phone: 613-737-7600, Ext: 3065, Email: kmurto@cheo.on.ca

Summary

Background: Celecoxib is effective for reducing postoperative pain in adults. Children use celecoxib more rapidly than adults and require higher doses. Celecoxib is partially metabolized in the liver by a certain enzyme. A person's genetic variation of this enzyme can influence how well their body uses Celecoxib. Understanding the blood and cerebrospinal fluid (CSF) profile of celecoxib in children and the influence of genetics on metabolism would help to develop appropriate celecoxib dosing in children for various treatment options. Objective(s) and Hypothesis: Our primary objective will be to create a pediatric profile of celecoxib in the blood and the central nervous system as well as explore the relationship between CYP2C9 polymorphisms and documented adverse events The investigators hypothesize that the CSF concentrations of Celecoxib post dose are lower than plasma levels, take longer to reach peak concentration and are directly related to dose, genetics, and age. The investigators expect that Celecoxib will improve quality of life and reduce discomfort when administered before and after a lumbar puncture and bone marrow aspirate. Potential Impact: The results of this study will establish the safety of celecoxib in children as well as help us define the best dosing for acute pain. It may also help reduce the incidence of acute pain evolving into chronic pain. Finally, it may provide insight into celecoxib's future use in chemotherapy.

Clinical Details

Official title: The Impact of Genotype on Plasma and Cerebral Spinal Fluid Pharmacokinetics of Celecoxib in Children

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Change in Plasma and CSF concentrations of Celecoxib in children

Secondary outcome:

Genomic testing and interpretation of the CYP2C9 genotype

Pediatric Quality of life Inventory

Pediatric cancer module

Multidimension Fatigue Inventory

Pediatric Pain Inventory

Demographics

Detailed description: Background: Celecoxib is a selective cyclooxygenase-2 (Cox-2) inhibitor belonging to the non-steroidal anti-inflammatory drugs (NSAIDs) class of medications. Adult studies have evaluated single dose and short term courses of Celecoxib and shown improved postoperative analgesia. One pharmacokinetic (PK) study suggested that celecoxib had faster clearance in pediatric patients implying the need for a higher dose in children. Adult literature has reported Cox-2 inhibitor administration up to 10 times the typical dose without adverse side effects. One adult chemotherapy drug trial involved high dose Celecoxib for a median of 8. 4 months with very limited side effects. Another study demonstrated that blood brain barrier (BBB) permeable selective Cox-2 inhibitors effectively reduced central nervous system Prostaglandin (PG) E2, (a surrogate marker of Cox-2 activity) concentrations and postoperative pain. Genotypic variability of the CYP2C9 liver enzymes has been implicated in altered PK of celecoxib in humans. Understanding the blood and CSF pharmacokinetics of celecoxib in children and the influence of genetics on metabolism would aid in the development of appropriate celecoxib dosing schedules for various pain models. At our institution, children diagnosed with hematologic malignancies routinely undergo general anesthesia for bone marrow aspiration/biopsy (BM) and diagnostic/ therapeutic lumbar punctures (LP). Post intervention site pain may be associated with a post dural puncture or atypical headache. Recently there have been reports of elevated Cox-2 expression in patients with CML and lymphomas. Data suggests that the combination of Cox-2 inhibitors with standard chemotherapeutics may enhance the potential of treatment for some hematological malignancies. Access to blood and cerebral spinal fluid provide a unique opportunity to determine celecoxib concentrations in the respective compartments. Objectives and Hypothesis: Our primary objective will be to create a pediatric pharmacokinetic profile of celecoxib in the blood and the central nervous system as well as explore the relationship between CYP2C9 polymorphisms and documented adverse events. The investigators hypothesize that the CSF concentrations of Celecoxib post ingestion are lower than plasma levels with a delayed peak concentration and directly related to dose, genotype, and age. The investigators expect that Celecoxib will improve quality of life and reduce discomfort when administered before and after a LP +/- BM. Experimental Design The study consists of two prospective cohort arms. A dose timing cohort to develop the pharmacokinetic profile for blood and CSF concentrations, and a dose escalation cohort in which increasing doses of a celecoxib suspension will be administered. A single blood sample to determine the CYP2C9 alleles will be drawn from each patient upon study entry. Potential Impact: CSF penetration of Cox-2 inhibitors may reduce the incidence of acute pain evolving into a chronic pain model. The results of this study will establish the safety of this class of medications in children and enable a more rational approach to their dosing in acute pain models and perhaps future chemotherapeutic protocols

Eligibility

Minimum age: 2 Years. Maximum age: 19 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Children with non-hematologic malignancies.

- Children undergoing treatment who are expected to undergo at least five (5) LPs

Exclusion Criteria:

- Serum creatinine > 2 X UNL (upper normal limit)

- Children undergoing a bone marrow aspiration (BMA) only

- Abnormal liver function; namely alanine aminotransferase (ALT) > 1. 5 X UNL,

alkaline phosphatase (ALP) > 5X UNL, total bilirubin > 2 X UNL

- History of peptic ulcer disease.

- Allergy to celecoxib, sulfonamide compounds or NSAIDs.

- Patients receiving CYP2C9 inhibitors fluconazole, amiodarone, oxandrolone or

high (≥ 5 gm/m2) and/ or escalating doses of methotrexate.

- Patients receiving CYP2C9 inducers rifampin and phenobarbitol

- Extremes of body mass index (BMI) (BMI <10th percentile or >90th percentile)

- Parents of any participants, irrespective of age, who are unable to read and

understand instructions relayed in English or French

- Participant and/or parents of any participants, irrespective of age, who suffer

from dementia, psychosis, significant developmental delay or other impairment that would prohibit the understanding and giving of informed consent or assent or the participation in self-care or toxicity reporting

Locations and Contacts

Dr Kimmo Murto, MD, Phone: 613-737-7600, Ext: 3065, Email: kmurto@cheo.on.ca

Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada; Not yet recruiting
Dr Kimmo Murto, MD, Phone: 613-737-7600, Ext: 3065, Email: kmurto@cheo.on.ca
Dr Kimmo Murto, MD, Principal Investigator
Additional Information

Link to Children's Hospital of Eastern Ontario anesthesiology research page.

Starting date: July 2015
Last updated: February 18, 2015

Page last updated: August 20, 2015

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