Celecoxib for Pharmacokinetics of Celecoxib

Overseen By Dr Kimmo Murto, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital of Eastern Ontario

Must not be taking: CYP2C9 inhibitors, CYP2C9 inducers

Disqualifiers: Non-hematologic malignancies, AML, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the pain relief medication celecoxib (also known as Celebrex) functions in children undergoing chemotherapy for blood cancers like leukemia. Researchers are examining how genetics influence the way children's bodies process the drug to determine the best dosing. Participants will receive varying doses of celecoxib or a placebo to assess its effects in their blood and spinal fluid. Children aged 2-12 years in remission from certain blood cancers and undergoing maintenance chemotherapy may be suitable for this study. As a Phase 2 trial, this research focuses on evaluating celecoxib's effectiveness in an initial, smaller group of children, providing an opportunity to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that celecoxib is generally a safe medication. In previous studies, no overdoses occurred, even when participants took high doses of up to 2400 mg per day for 10 days. This indicates that most patients tolerate the drug well. However, celecoxib can increase the risk of serious heart problems, such as heart attacks or strokes. Consider this risk when thinking about joining a clinical trial with celecoxib. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pain?

Researchers are excited about celecoxib because it offers a unique approach to managing inflammation and pain, typically addressed by nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or naproxen. Unlike these standard treatments, celecoxib specifically targets the COX-2 enzyme, potentially reducing the risk of gastrointestinal side effects commonly associated with other NSAIDs that inhibit both COX-1 and COX-2 enzymes. Additionally, celecoxib is administered in a liquid form, which can be beneficial for individuals who have difficulty swallowing pills. This targeted action and alternative delivery method make celecoxib a promising option for patients seeking effective pain relief with potentially fewer side effects.

What evidence suggests that celecoxib could be an effective treatment for reducing postoperative pain in children?

Studies have shown that celecoxib can help reduce pain after surgery. For example, patients who used it during hip or knee replacement surgeries felt less pain. This suggests that celecoxib may be effective for managing post-surgical pain. Celecoxib works by blocking certain enzymes that cause inflammation, reducing pain and swelling. While the results in adults are promising, this trial will study different dosages of celecoxib to understand how children process the drug and determine the right dose. The research aims to use celecoxib safely and effectively for pain relief in children. ^{1 3 5 6 7}

Who Is on the Research Team?

Dr Kimmo Murto, MD

Principal Investigator

Children's Hospital of Eastern Ontario

Are You a Good Fit for This Trial?

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).

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Celecoxib
• Placebo

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Celebrex for:

• Pain relief
• Inflammation
• Osteoarthritis
• Rheumatoid arthritis
• Menstrual cramps
• Colorectal polyps prevention

Approved in European Union as Celebrex for:

• Symptomatic relief in osteoarthritis
• Symptomatic relief in rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea
• Adenomatous polyposis coli

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+

Published Research Related to This Trial

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]

Celecoxib is a selective COX-2 inhibitor used primarily for treating osteoarthritis and rheumatoid arthritis, with a typical dosage of 200 mg daily, which can be increased to 400 mg if needed.

Compared to other nonsteroidal anti-inflammatory drugs (NSAIDs), celecoxib has a better safety profile, particularly in terms of gastrointestinal and renal tolerance, due to its selectivity for the COX-2 enzyme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharma-clinics. The drug of the month. Celecoxib (Celebrex)]. Scheen, AJ.[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 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]

The study involving 52 healthy Chinese male subjects found that the CYP2C9*3 genetic variant significantly increased the exposure to celecoxib, with a 90.6% increase in the area under the curve (AUC) and a 45.8% increase in peak concentration (Cmax), indicating that individuals with this variant may require dosage adjustments to avoid potential toxicity.

No severe adverse events were reported during the study, demonstrating that celecoxib is safe and well-tolerated in this population, while the CYP2D6*10 variant did not significantly affect celecoxib metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of genetic polymorphisms on the pharmacokinetics of celecoxib and its two main metabolites in healthy Chinese subjects. Liu, R., Gong, C., Tao, L., et al.[2015]

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 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]

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]

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]

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]

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, accumulates in human cells at concentrations five to ten times higher than in plasma, which may enhance its effectiveness against cancer by interacting with non-COX-2 proteins.

This intracellular accumulation is linked to celecoxib integrating into cellular membranes, leading to increased COX-2 inhibition and disruption of cell membrane integrity, suggesting a unique mechanism of action compared to other coxibs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cellular membranes function as a storage compartment for celecoxib. Maier, TJ., Schiffmann, S., Wobst, I., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3303994/

Celecoxib pathways: pharmacokinetics and ... In the Adenoma Prevention with Celecoxib (APC) trial, celecoxib 400 mg twice a day exhibited a greater than three-fold risk for combined endpoints of ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK535359/

Celecoxib - StatPearls - NCBI Bookshelf Study results have shown that administering celecoxib peri-operatively for elective procedures such as total hip arthroplasties, total knee arthroplasties ...

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/98/20998AP_clinphrmr_P1.pdf

clinical pharmacology and biopharmaceutics review(s) Study 032. This study was conducted to evaluate the effects of 600 mg celecoxib BID versus 500 mg naproxen BID on platelet function in normal healthy subjects.

4. go.drugbank.com go.drugbank.com/drugs/DB00482

Celecoxib: Uses, Interactions, Mechanism of Action The effective half-life of celecoxib is approximately 11 hours when a single 200 mg dose is given to healthy subjects. The terminal half-life of celecoxib ...

5. ijclinmedcasereports.com ijclinmedcasereports.com/pdf/IJCMCR-RA-01130.pdf

Clinical Pharmacology of Celecoxib The aim of this study is to review the efficacy and safely of celecoxib, the prophylaxis with celecoxib, the treatment of patients with ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/1998/20998lbl.pdf

celebrex - accessdata.fda.gov The empirical formula for celecoxib is C17H14F3N3O2S, and the molecular weight is 381.38. CELEBREX oral capsules contain 100 mg and 200 mg of celecoxib.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2008/020998s026lbl.pdf

CELEBREX celecoxib capsules Cardiovascular Risk Cardiovascular Risk. • CELEBREX may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, ...