Celecoxib for Pharmacokinetics of Celecoxib

Recruiting in Palo Alto (17 mi)

Overseen by Dr Kimmo Murto, MD

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Children's Hospital of Eastern Ontario

Must not be taking: CYP2C9 inhibitors, CYP2C9 inducers

Disqualifiers: Non-hematologic malignancies, AML, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

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. Furthermore, Celecoxib down-regulates P-glycoprotein (P-gp), a drug efflux transporter located at the blood brain barrier responsible for central nervous system (CNS) extrusion of ondansetron and possibly fentanyl; therefore celecoxib may augment the CNS effects of these drugs. 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.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically CYP2C9 inhibitors like fluconazole, amiodarone, and oxandrolone, as well as CYP2C9 inducers like rifampin and phenobarbitol. If you are taking high doses of methotrexate, you may also need to stop.

What data supports the effectiveness of the drug celecoxib?

Celecoxib is effective in treating osteoarthritis and rheumatoid arthritis, showing better results than a placebo and similar results to other anti-inflammatory drugs, with fewer stomach-related side effects. ^{1 2 3 4 5}

Is celecoxib generally safe for humans?

Celecoxib is generally considered safe for humans, with fewer stomach-related side effects compared to traditional pain relievers. However, it may increase the risk of heart-related issues, especially at higher doses, so it's important to discuss these risks with a doctor. ^{2 6 7 8 9}

How is the drug celecoxib unique compared to other treatments?

Celecoxib is unique because it is a selective COX-2 inhibitor, which means it targets a specific enzyme involved in inflammation, potentially offering better gastrointestinal and renal safety compared to other nonsteroidal anti-inflammatory drugs (NSAIDs). ^{10 11 12 13 14}

Research Team

Dr Kimmo Murto, MD

Principal Investigator

Children's Hospital of Eastern Ontario

Eligibility Criteria

This trial is for children aged 2-12 undergoing chemotherapy for certain blood cancers and in remission. They must not have kidney or liver issues, recent celecoxib use, be on conflicting medications, have a history of ulcers, extreme BMI, or other trials ongoing. Pregnant individuals or those with allergies to NSAIDs are excluded.

Inclusion Criteria

My child is 2-12 years old, in remission from leukemia or lymphoma, and receiving maintenance chemotherapy.

Exclusion Criteria

I am older than 12 years but younger than 2 years.

Participant and/or parents of any participants, irrespective of age, who suffer from dementia, psychosis or any impairment that would prohibit the understanding and giving of informed consent or study-related reporting

I have been diagnosed with acute myeloid leukemia (AML).

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive a single dose of celecoxib (7 mg/kg or 14 mg/kg) 121-180 minutes before lumbar puncture

1 day

1 visit (in-person)

Phase II Treatment

Participants receive a single dose of celecoxib (7 mg/kg or 14 mg/kg) or placebo at various time intervals before lumbar puncture

1 day

1 visit (in-person)

Follow-up

Participants are monitored for adverse events and pharmacokinetic data collection on Day 1 and Day 7 after ingestion

1 week

2 visits (in-person)

Treatment Details

Interventions

• Celecoxib (Nonsteroidal Anti-inflammatory Drug)
• Placebo (Other)

Trial Overview The study tests how Celecoxib behaves in the blood and cerebrospinal fluid of children and examines genetic factors affecting its metabolism. It compares Celecoxib's effects against a placebo to understand dosing for pain management post-surgery.

Participant Groups

Group I: Phase II: Group B: Study drug (Celecoxib 7 mg/kg) Active Control 1 Intervention

Study participants randomized to this group you will receive a single 7 mg/kg dose of celecoxib which will be in a liquid form, and the study participant will drink it. The timing of when the study participant in this group will take this medication will be determined in a second randomization: Group B.1: will take the study medication 15 to 24 hours prior to having their LP±BMA. The study medication will be taken at home. Group B.2: will take the study medication 5 to 15 hours prior to having their LP±BMA. The study medication will be taken at home. Group B.3: will take the study medication 3 to 5 hours prior to having their LP±BMA. The study medication will be taken at home. Group B.4: will take the study medication 1 to 2 hours prior to having their LP±BMA. The study medication will be taken at the hospital. Group B.5: will take the study medication 0 to 60 minutes prior to having your LP±BMA. The study medication will be taken at the hospital.

Group II: Phase II: Group C: Study drug (Celecoxib 14 mg/kg) Active Control 1 Intervention

Study participants randomized to this group you will receive a single 14 mg/kg dose of celecoxib which will be in a liquid form, and the study participant will drink it. The timing of when the study participant in this group will take this medication will be determined in a second randomization: Group C.1: will take the study medication 15 to 24 hours prior to having their LP±BMA. The study medication will be taken at home. Group C.2: will take the study medication 5 to 15 hours prior to having their LP±BMA. The study medication will be taken at home. Group C.3: will take the study medication 3 to 5 hours prior to having their LP±BMA. The study medication will be taken at home. Group C.4: will take the study medication 1 to 2 hours prior to having your LP±BMA. The study medication will be taken at the hospital. Group C.5: will take the study medication 0 to 60 minutes prior to having your LP±BMA. The study medication will be taken at the hospital.

Group III: Phase I: Study drug Group 1 (Celecoxib 7 mg/kg) Active Control 1 Intervention

Study participants randomized to this group will receive a single 7 mg/kg dose of celecoxib approximately 121-180 minutes before their scheduled LP ± BMA. The study medication will be a liquid and the study participant will be asked to drink it.

Group IV: Phase I: Study drug Group 2 (Celecoxib 14 mg/kg) Active Control 1 Intervention

Study participants randomized to this group will receive a single 14 mg/kg dose of celecoxib approximately 121-180 minutes before their scheduled LP ± BMA. The study medication will be a liquid and the study participant will be asked to drink it.

Group V: Phase II: Group A: Placebo Placebo Group 1 Intervention

Study participants will receive a single dose of placebo. Placebo will be liquid. The study participant will drink it. The timing of when the study participants in this group will take placebo will be determined in a second randomization: Group A.1: will take placebo 15 to 24 hours prior to having their LP±BMA. The study medication will be taken at home. Group A.2: will take placebo 5 to 15 hours prior to having their LP±BMA. The study medication will be taken at home. Group A.3: will take the placebo 3 to 5 hours prior to having their LP±BMA. The study medication will be taken at home. Group A.4: will take the study medication 1 to 2 hours prior to having their LP±BMA. The study medication will be taken at the hospital. Group A.5: will take the study medication 0 to 60 minutes prior to having their LP±BMA. The study medication will be taken at the hospital.

Celecoxib is already approved in Canada for the following indications:

Approved in Canada as Celebrex for:

• Symptomatic relief of osteoarthritis
• Symptomatic relief of rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea

Who Is Running the Clinical Trial?

Children's Hospital of Eastern Ontario

Lead Sponsor

Trials

134

Recruited

61,000+

Dr. Vera Etches

Children's Hospital of Eastern Ontario

Chief Executive Officer

MD from the University of Western Ontario

Dr. Carrol Pitters

Children's Hospital of Eastern Ontario

Chief Medical Officer since 2010

MD from the University of the West Indies

Findings from Research

Celecoxib is equally effective as other non-steroidal anti-inflammatory drugs (NSAIDs) in treating osteoarthritis and rheumatoid arthritis, based on a systematic review of 9 trials involving 15,187 patients.

Celecoxib significantly improves gastrointestinal safety, with a 46% lower withdrawal rate due to adverse gastrointestinal events and a 71% lower incidence of ulcers compared to other NSAIDs, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Deeks, JJ., Smith, LA., Bradley, MD.[2022]

Celecoxib is an effective treatment for osteoarthritis and rheumatoid arthritis, showing significantly better results than a placebo and comparable efficacy to traditional NSAIDs.

One of the key advantages of celecoxib is its superior gastrointestinal safety profile compared to traditional NSAIDs, making it a safer option for long-term use, especially in elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib clinical profile. Tive, L.[2022]

The phase 1 clinical study involving 40 healthy subjects showed that the nano-formulated lower-dose indomethacin (20 mg and 40 mg) was absorbed more quickly than the standard 50 mg formulation, indicating a potentially improved pharmacokinetic profile.

Safety and tolerability were comparable between the nano-formulated and standard indomethacin, suggesting that lower-dose formulations could provide effective pain relief with reduced safety concerns associated with higher doses of NSAIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study evaluating the pharmacokinetic profile of a novel, proprietary, nano-formulated, lower-dose oral indomethacin. Manvelian, G., Daniels, S., Altman, R.[2013]

Celecoxib, when administered at a dose of 200 mg, reaches its maximum concentration in the bloodstream approximately 2.5 hours after ingestion, indicating effective absorption in healthy individuals.

The study characterized key pharmacokinetic parameters of celecoxib, including an elimination half-life of about 8.79 hours and a large volume of distribution, which suggests that the drug is well-distributed throughout the body and is eliminated through biotransformation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetic of celecoxib in healthy Thai volunteers. Itthipanichpong, C., Chompootaweep, S., Wittayalertpanya, S., et al.[2015]

Celecoxib is associated with a slightly increased risk of certain adverse events, such as edema, hypertension, angioedema, and allergic reactions compared to placebo, but these risks are relatively small.

In contrast, celecoxib shows a lower risk of gastrointestinal issues like hemorrhage and ulceration compared to non-selective NSAIDs, suggesting it may be a safer option for patients concerned about GI side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of celecoxib compared with placebo and non-selective NSAIDs: cumulative meta-analysis of 89 randomized controlled trials. Essex, MN., Zhang, RY., Berger, MF., et al.[2022]

Celecoxib, a selective COX-2 inhibitor, offers the benefit of fewer gastrointestinal side effects compared to traditional nonsteroidal anti-inflammatory drugs (NSAIDs), making it a safer option for managing musculoskeletal symptoms and pain.

While higher doses of celecoxib do increase cardiovascular risk, this risk is similar to that associated with nonselective NSAIDs, highlighting the need for careful consideration of individual patient risks and benefits when prescribing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Celecoxib in arthritis: relative risk management profile and implications for patients. McKellar, G., Singh, G.[2021]

Celecoxib is primarily metabolized by the CYP2C9 enzyme, with significant differences in metabolism rates based on genetic variants; specifically, the CYP2C9*3 variant shows markedly slower metabolism compared to the CYP2C9*1 variant.

The formation of the major metabolite, carboxycelecoxib, is dependent on liver cytosol and involves alcohol dehydrogenase enzymes, particularly ADH1 and ADH2, highlighting a complex metabolic pathway for celecoxib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase. Sandberg, M., Yasar, U., Strömberg, P., et al.[2022]

In a study of 77 NSAID-sensitive patients, celecoxib was administered safely without any adverse effects, indicating it can be tolerated by individuals with a history of NSAID reactions.

Celecoxib does not exhibit cross-intolerance with other NSAIDs, making it a promising alternative for patients who have experienced adverse reactions to traditional NSAIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The selective cyclooxygenase-2 inhibitor celecoxib is a safe alternative in patients with pseudo-allergic reactions to nonsteroidal anti-inflammatory drugs]. Ahlbach, S., Usadel, KH., Kaufmann, R., et al.[2015]

Celecoxib, a COX-2 inhibitor, is primarily metabolized in rats through a single oxidative pathway, resulting in minimal unchanged drug excretion (less than 2%) after intravenous administration.

After oral administration, celecoxib is well distributed in tissues, especially in the gastrointestinal tract, with most of the drug excreted in feces (88-94%) and a significant portion as metabolites, indicating effective metabolism and elimination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats. Paulson, SK., Zhang, JY., Breau, AP., et al.[2022]

A new sensitive and selective method for quantifying celecoxib in human plasma was developed using HPLC and mass spectrometry, allowing for rapid analysis with a limit of quantification of 5 microg/L.

In a study of 12 healthy volunteers, pharmacokinetic analysis showed that extensive metabolizers had a mean half-life of 7.8 hours, while a poor metabolizer had a higher area under the curve (AUC) of 12561 microg h/L, but no significant increase in half-life was observed for the poor metabolizer after a single dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the pharmacokinetics of celecoxib by liquid chromatography-mass spectrometry. Werner, U., Werner, D., Pahl, A., et al.[2015]

Celecoxib is metabolized differently in beagle dogs, with about 45% of dogs eliminating it quickly (EM phenotype) and 53.5% eliminating it slowly (PM phenotype), leading to significant differences in drug clearance and half-life.

The metabolism of celecoxib is primarily facilitated by the CYP2D subfamily of cytochrome P-450 enzymes, particularly CYP2D15, while other CYP subfamilies may also play a role in the variability of drug metabolism among dogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib. Paulson, SK., Engel, L., Reitz, B., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Celecoxib clinical profile. [2022]

3. England pubmed.ncbi.nlm.nih.gov

A phase I study evaluating the pharmacokinetic profile of a novel, proprietary, nano-formulated, lower-dose oral indomethacin. [2013]

4. Germany pubmed.ncbi.nlm.nih.gov

Cellular membranes function as a storage compartment for celecoxib. [2021]

5. Thailand pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetic of celecoxib in healthy Thai volunteers. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Safety of celecoxib compared with placebo and non-selective NSAIDs: cumulative meta-analysis of 89 randomized controlled trials. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Celecoxib in arthritis: relative risk management profile and implications for patients. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

[The selective cyclooxygenase-2 inhibitor celecoxib is a safe alternative in patients with pseudo-allergic reactions to nonsteroidal anti-inflammatory drugs]. [2015]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Influence of genetic polymorphisms on the pharmacokinetics of celecoxib and its two main metabolites in healthy Chinese subjects. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Investigation of the pharmacokinetics of celecoxib by liquid chromatography-mass spectrometry. [2015]

13. Belgium pubmed.ncbi.nlm.nih.gov

[Pharma-clinics. The drug of the month. Celecoxib (Celebrex)]. [2015]

14. United States pubmed.ncbi.nlm.nih.gov

Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib. [2015]