Celecoxib Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Celecoxib (brand name Celebrex) is a prescription nonsteroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2), an enzyme involved in the inflammatory pathway.

It is commonly used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, and acute pain. By reducing inflammation, celecoxib helps relieve pain and improve joint function.

Celecoxib works by selectively blocking COX-2, which decreases the production of prostaglandins—chemicals that cause inflammation and pain—while sparing COX-1, which helps protect the stomach lining.

Relevant Genes and Their Roles

The primary gene affecting celecoxib metabolism is CYP2C9, a member of the cytochrome P450 enzyme family. CYP2C9 is responsible for oxidizing celecoxib in the liver, converting it into forms that can be excreted.

Variations in CYP2C9 can alter enzyme activity. For example, some variants reduce function, causing slower clearance of the drug and higher blood concentrations, while others may increase activity, leading to faster elimination.

Impact of Genetics on Drug Response

Genetic variations in CYP2C9 result in different metabolizer phenotypes—poor, intermediate, normal, and potentially rapid metabolizers—impacting drug levels, therapeutic effectiveness, and risk of side effects. Poor metabolizers process celecoxib slowly and may have higher drug concentrations and increased risk of toxicity, while rapid metabolizers may clear the drug too quickly, reducing efficacy.

Expected Clinical Effects of Genetic Variation

Ultra-rapid/Rapid Metabolizer

Effect: Increased enzyme activity leads to faster metabolism and lower drug levels.
Clinical consequence: Potential reduced pain relief due to lower plasma concentrations.
Side effects: Lower likelihood of typical NSAID side effects, but risk of under-treatment is increased.

Normal Metabolizer

Effect: Standard metabolism maintains typical drug levels.
Clinical consequence: Expected therapeutic effect with standard dosing.
Side effects: Risk of side effects as listed in prescribing information (e.g., gastrointestinal upset) at normal frequency and severity.

Intermediate Metabolizer

Effect: Moderately reduced metabolism leads to higher drug levels.
Clinical consequence: Increased exposure may require dose adjustment or monitoring.
Side effects: Mild to moderate gastrointestinal and renal side effects may be more frequent.

Poor Metabolizer

Effect: Significantly reduced metabolism leads to substantially higher drug levels and prolonged half-life.
Clinical consequence: Elevated exposure increases risk of toxicity and adverse events.
Side effects: Severe gastrointestinal bleeding and renal impairment may occur more frequently.

Indeterminate/Not Available

Effect: Unknown.
Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.

Dosing Guidelines

The following dosing guidelines are based on the available guidelines for CYP2C9 genotype from CPIC.

CYP2C9 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Normal Metabolizer	Your body processes this drug normally, so the usual starting dose applies.	Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
Intermediate Metabolizer (mild, AS=1.5)	Your body slows the drug down slightly, but usually the normal starting dose is fine.	Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
Intermediate Metabolizer (moderate, AS=1.0)	Your body slows the drug noticeably, so you should start at a lower dose and increase carefully if needed.	Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events, such as blood pressure and kidney function, during course of therapy.
Poor Metabolizer	Your body processes the drug very slowly, so you should start at a much lower dose, increase carefully, or use a different drug.	Initiate therapy with 25–50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25–50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady-state is reached (at least 8 days for celecoxib). Carefully monitor adverse events such as blood pressure and kidney function. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.
Indeterminate	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.
Not available	The impact of your genotype on response to this drug is unknown.	Initiate therapy with recommended starting dose.

Alternative Treatment Options

Examples of alternative treatment options include non-NSAID analgesics (e.g., acetaminophen), other pain management strategies, or NSAIDs that are minimally metabolized by CYP2C9. These are examples from guideline suggestions and are not medical advice.

Celecoxib