COXLEON Capsule Ref.[51231] Active ingredients: Celecoxib

Absorption

When given under fasting conditions celecoxib is well absorbed, reaching peak plasma concentrations after approximately 2 to 3 hours. Dosing with food (high fat meal) delays absorption, resulting in a T_max of about 4 hours, and increases bioavailability by about 20%.

Distribution

Celecoxib exhibits linear and dose proportional pharmacokinetics over the therapeutic dose range. Plasma protein binding, which is concentration independent, is about 97% at therapeutic plasma concentrations and the drug is not preferentially bound to erythrocytes in the blood.

In the population >65 years there is a two-fold increase in mean C_max and AUC for celecoxib. This is predominantly weight related rather than age-related change, celecoxib levels being higher in lower weight individuals and consequently higher in the elderly population who are generally of lower mean weight than the younger population. Therefore, elderly females tend to have slightly higher drug plasma concentrations than elderly males.

Elimination

Metabolism

Celecoxib is metabolised in the liver by hydroxylation, oxidation and some glucuronidation and in vitro and in vivo studies indicate that metabolism is mainly by cytochrome P450 CYP2C9. Pharmacological activity resides in the parent drug. The main metabolites found in the circulation have no detectable COX-1 or COX-2 inhibitory activity.

Excretion

Elimination of celecoxib is mostly by hepatic metabolism with less than 1% of the dose excreted unchanged in urine. After multiple dosing, elimination half-life is 8 to 12 hours and the rate of clearance about 500 ml/min. With multiple dosing steady state plasma concentrations are reached before day 5. The intersubject variability on the main pharmacokinetic parameters (AUC, C_max, elimination half-life) is about 30%. The mean steady state volume of distribution is about 500 l/70 kg in young healthy adults after a single 200 mg dose, indicating wide distribution of celecoxib into the tissues. Pre-clinical studies indicate that the drug crosses the blood-brain barrier.

Hepatic Impairment

Plasma concentrations of celecoxib in patients with mild hepatic impairment are not significantly different from those of age and sex matched controls. In patients with moderate hepatic impairment, celecoxib plasma concentrations are about twice those of the matched controls. Patients with severe hepatic impairment have not been studied but can be expected to show accumulation of parent drug as the main route of metabolism is via the liver.

Renal impairment

In elderly volunteers with age-related reductions in glomerular filtration rate (GFR) (mean GFR >65 ml/min/1,73 m²) and in patients with chronic stable renal insufficiency (GFR 35-60 ml/min/1,73 m²), celecoxib pharmacokinetics were comparable to those seen in patients with normal renal function. No significant relationship was found between serum creatinine (or creatinine clearance) and celecoxib clearance.

Renal effects

At the present time the relevant roles of COX-1 and COX-2 in renal physiology are incompletely understood. Celecoxib reduces the urinary excretion of PGE₂ and 6–keto–PGF_1α (a prostacyclin metabolite), but leaves serum thromboxane B₂ (TXB₂) and urinary excretion of 11-dehydro-TXB₂, a thromboxane metabolite (both COX-1 products) unaffected. Specific studies have shown that celecoxib produces no decrease in GFR in the elderly or those with chronic renal insufficiency. These studies have shown transient reductions in fractional excretion of sodium.

Not applicable.