The Impact of Genotype on Plasma and Cerebral Spinal Fluid Pharmacokinetics of Celecoxib in Children - Full Text View

Purpose

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.

Condition	Intervention	Phase
Pharmacokinetics of Celecoxib in Children	Drug: Celecoxib	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
Official Title:	The Impact of Genotype on Plasma and Cerebral Spinal Fluid Pharmacokinetics of Celecoxib in Children

Resource links provided by NLM:

Drug Information available for: Celecoxib

U.S. FDA Resources

Further study details as provided by Children's Hospital of Eastern Ontario:

Primary Outcome Measures:

Change in Plasma and CSF concentrations of Celecoxib in children [ Time Frame: Day 0, the day of the procedure, after taking study medication. ] [ Designated as safety issue: No ]
Change in plasma and CSF concentrations of celecoxib 30, 60, 90, 120, 180, 300, 900 minutes after ingestion of study medication is measured in order to build a pharmacokinetic profile for celecoxib in children.

Secondary Outcome Measures:

Genomic testing and interpretation of the CYP2C9 genotype [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Polymorphisms of genotype CYP2C9 liver enzyme and correlations to drug levels
Pediatric Quality of life Inventory [ Time Frame: Participants will fill out inventory on Day 0 immediately before the procedure and again on Day 7 after the procedure ] [ Designated as safety issue: No ]
2. Pediatric Quality of life Inventory (PedsQL) version 4.0 scores before and 7 days after LP
1. Parent report for children aged 2-7, 8-12 and 13-18
2. Child report ages 8-12 and 13-18
Pediatric cancer module [ Time Frame: Participants will fill out inventory on Day 0 immediately before the procedure and again on Day 7 after the procedure ] [ Designated as safety issue: No ]
PedsQL Cancer module version 3.0 scores before and 7 days after LP
1. Parent report for children aged 2-7, 8-12 and 13-18
2. Child report ages 8-12 and 13-18
Multidimension Fatigue Inventory [ Time Frame: Participants will fill out inventory on Day 0 immediately before the procedure and again on Day 7 after the procedure ] [ Designated as safety issue: No ]
PedsQL Multidimension Fatigue Scale version 1.0 scores before and 7 days after LP
1. Parent report for children aged 2-7, 8-12 and 13-18
2. Child report ages 8-12 and 13-18
Pediatric Pain Inventory [ Time Frame: Participants will fill out inventory on Day 0 immediately before the procedure and every day up to and including Day 7 after the procedure ] [ Designated as safety issue: No ]
PedsQL Pediatric Pain Questionnaire baseline and daily scores for 7 days after LP.
1. Parent report for children aged 2-7, 8-12 and 13-18
2. Child report ages 5-7, 8-12 and 13-18
Demographics [ Time Frame: Baseline ] [ Designated as safety issue: No ]
Professional identity of the individual performing the LP+/-BM, description of the LP and BM needles used, number of attempts and degree of difficulty.

Estimated Enrollment:	20
Study Start Date:	May 2013
Estimated Study Completion Date:	December 2014
Estimated Primary Completion Date:	April 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Dose Timing Cohort 1. All patients and CSF Dose timing Cohort (Oral celecoxib 10 mg/kg pharmacokinetic profile) Mean Total and unbound plasma concentration ug/L at approximately the following time intervals (mins): 30, 60, 90, 120, 180, 300, 900 Mean CSF concentration ug/L at approximately the following time intervals (mins): 60, 120, 180, 300 and 900 Ratio CSF/unbound plasma concentration at approximately the following time intervals (mins): 60, 120, 180, 300 and 900 This information will be used to determine plasma and CSF mean +/- SD values for Maximum concentration (Cmax [ug/L]); Area under concentration curve from time 0 to infinity (AUC (0-∞) [ug/L∙h]); Apparent oral volume of distribution (Vd/F [L/kg]); Apparent oral clearance (CL/F [L∙h-1∙kg-1] and terminal elimination half -life (t1/2 [h]). A median value will be determined for time to maximum concentration (tmax[h])	Drug: Celecoxib All patients, on day of first scheduled LP, will receive celecoxib suspension 10 mg/kg by mouth 180 mins before their scheduled LP. Prior to beginning the second cycle of chemotherapy the patients will be randomly allocated to either of 2 cohorts (CSF dose timing cohort versus dose escalation cohort). The CSF dose timing cohort patients will be assigned to receive celecoxib 10 mg/kg at a predetermined time (60 mins, 120 mins, 300 mins and 900 mins before LP+/- BM) and they will rotate in chronological order for four chemotherapy cycles to complete the remaining time points of interest. The dose escalation cohort patients, at the beginning of each cycle of chemotherapy, will be administered either 6 or 14 mg/kg celecoxib 180 mins before LP for a total of 4 chemotherapy cycles. Approximately 8-12 hours after the first dose, each patient will be required to ingest a second dose of celecoxib suspension (one half of the premedication dose) with food. Other Name: Celebrex
Active Comparator: Dose Escalation Cohort 2. Dose escalation cohort (Oral celecoxib 6 mg/kg and 14 mg/kg pharmacokinetic profile) Mean Total and unbound plasma concentration ug/L at approximately the following time intervals (mins): 60,180 and 300 Mean CSF concentration ug/L at approximately 180 minutes Ratio CSF/unbound plasma concentration at approximately 180 minutes This information in conjunction with the pharmacokinetic profile established in the dose timing cohort (10 mg/kg) will be used to predict plasma and CSF values for tmax, Cmax, AUC, Vd/F, CL/F and t1/2 for 6 and 14 mg/kg oral doses respectively.	Drug: Celecoxib All patients, on day of first scheduled LP, will receive celecoxib suspension 10 mg/kg by mouth 180 mins before their scheduled LP. Prior to beginning the second cycle of chemotherapy the patients will be randomly allocated to either of 2 cohorts (CSF dose timing cohort versus dose escalation cohort). The CSF dose timing cohort patients will be assigned to receive celecoxib 10 mg/kg at a predetermined time (60 mins, 120 mins, 300 mins and 900 mins before LP+/- BM) and they will rotate in chronological order for four chemotherapy cycles to complete the remaining time points of interest. The dose escalation cohort patients, at the beginning of each cycle of chemotherapy, will be administered either 6 or 14 mg/kg celecoxib 180 mins before LP for a total of 4 chemotherapy cycles. Approximately 8-12 hours after the first dose, each patient will be required to ingest a second dose of celecoxib suspension (one half of the premedication dose) with food. Other Name: Celebrex

Arms

Assigned Interventions

Active Comparator: Dose Timing Cohort

1. All patients and CSF Dose timing Cohort (Oral celecoxib 10 mg/kg pharmacokinetic profile)

Mean Total and unbound plasma concentration ug/L at approximately the following time intervals (mins): 30, 60, 90, 120, 180, 300, 900
Mean CSF concentration ug/L at approximately the following time intervals (mins): 60, 120, 180, 300 and 900
Ratio CSF/unbound plasma concentration at approximately the following time intervals (mins): 60, 120, 180, 300 and 900
This information will be used to determine plasma and CSF mean +/- SD values for Maximum concentration (Cmax [ug/L]); Area under concentration curve from time 0 to infinity (AUC (0-∞) [ug/L∙h]); Apparent oral volume of distribution (Vd/F [L/kg]); Apparent oral clearance (CL/F [L∙h-1∙kg-1] and terminal elimination half -life (t1/2 [h]). A median value will be determined for time to maximum concentration (tmax[h])

Drug: Celecoxib

All patients, on day of first scheduled LP, will receive celecoxib suspension 10 mg/kg by mouth 180 mins before their scheduled LP. Prior to beginning the second cycle of chemotherapy the patients will be randomly allocated to either of 2 cohorts (CSF dose timing cohort versus dose escalation cohort). The CSF dose timing cohort patients will be assigned to receive celecoxib 10 mg/kg at a predetermined time (60 mins, 120 mins, 300 mins and 900 mins before LP+/- BM) and they will rotate in chronological order for four chemotherapy cycles to complete the remaining time points of interest. The dose escalation cohort patients, at the beginning of each cycle of chemotherapy, will be administered either 6 or 14 mg/kg celecoxib 180 mins before LP for a total of 4 chemotherapy cycles.

Approximately 8-12 hours after the first dose, each patient will be required to ingest a second dose of celecoxib suspension (one half of the premedication dose) with food.

Other Name: Celebrex

Active Comparator: Dose Escalation Cohort

2. Dose escalation cohort (Oral celecoxib 6 mg/kg and 14 mg/kg pharmacokinetic profile)

Mean Total and unbound plasma concentration ug/L at approximately the following time intervals (mins): 60,180 and 300
Mean CSF concentration ug/L at approximately 180 minutes
Ratio CSF/unbound plasma concentration at approximately 180 minutes
This information in conjunction with the pharmacokinetic profile established in the dose timing cohort (10 mg/kg) will be used to predict plasma and CSF values for tmax, Cmax, AUC, Vd/F, CL/F and t1/2 for 6 and 14 mg/kg oral doses respectively.

Drug: Celecoxib

All patients, on day of first scheduled LP, will receive celecoxib suspension 10 mg/kg by mouth 180 mins before their scheduled LP. Prior to beginning the second cycle of chemotherapy the patients will be randomly allocated to either of 2 cohorts (CSF dose timing cohort versus dose escalation cohort). The CSF dose timing cohort patients will be assigned to receive celecoxib 10 mg/kg at a predetermined time (60 mins, 120 mins, 300 mins and 900 mins before LP+/- BM) and they will rotate in chronological order for four chemotherapy cycles to complete the remaining time points of interest. The dose escalation cohort patients, at the beginning of each cycle of chemotherapy, will be administered either 6 or 14 mg/kg celecoxib 180 mins before LP for a total of 4 chemotherapy cycles.

Approximately 8-12 hours after the first dose, each patient will be required to ingest a second dose of celecoxib suspension (one half of the premedication dose) with food.

Other Name: Celebrex

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

Ages Eligible for Study:	2 Years to 19 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01344200

Contacts

Contact: Dr Kimmo Murto, MD

613-737-7600 ext 3065

kmurto@cheo.on.ca

Locations

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

Sponsors and Collaborators

Children's Hospital of Eastern Ontario

Investigators

Principal Investigator:

Dr Kimmo Murto, MD

Children's Hospital of Eastern Ontario

More Information

Additional Information:

Link to Children's Hospital of Eastern Ontario anesthesiology research page. This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Kimmo Murto, Medical Director of Daycare and Recovery Room, Children's Hospital of Eastern Ontario
ClinicalTrials.gov Identifier:	NCT01344200 History of Changes
Other Study ID Numbers:	09/09E
Study First Received:	April 21, 2011
Last Updated:	April 17, 2013
Health Authority:	Canada: Health Canada

Keywords provided by Children's Hospital of Eastern Ontario:

Pharmacokinetics
Celecoxib
Pediatric
Peds QL
CYP2C9

Additional relevant MeSH terms:

Celecoxib
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic

Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Therapeutic Uses
Central Nervous System Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on May 19, 2013