Oxaprozin isa non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models. The mechanism of action of oxaprozin, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics (see Table 1)
Oxaprozin is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of oxaprozin absorption.
Table 1: Oxaprozin Pharmacokinetic Parameters [Mean (% CV)] (1200 mg)
|Healthy Adults (19 to 78 years)|
|Total Drug||Unbound Drug|
|Single N = 35||Multiple N = 12||Single N = 35||Multiple N = 12|
|Tmax (hr)||3.09 (39)||2.44 (40)||3.03 (48)||2.33 (35)|
|Oral Clearance (L/hr/70 kg)||0.150 (24)||0.301 (29)||136 (24)||102 (45)|
|Apparent Volume of Distribution at Steady State (Vd/F; L/70 kg)||11.7 (13)||16.7 (14)||6230 (28)||2420 (38)|
|Elimination Half-life (hr)||54.9 (49)||41.4 (27)||27.8 (34)||19.5 (15)|
In doseproportionality studies utilizing 600, 1200, and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution and not an increase in the half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing.
The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11 to 17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2 fold and 3 fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in humanmilk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated.
Several oxaprozin metabolites have been identifiedinhuman urine or feces.
Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin . On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low.
Oxaprozin's metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (< 5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited.
Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations.
A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N = 40) and juvenile rheumatoid arthritis (JRA) patients (≥ 6 years, N = 44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships as shown in Table 2. No pharmacokinetic data are available for pediatric patients under 6 years of age (see PRECAUTIONS, Pediatric Use).
Table 2: Dose to body weight range to achieve similar steady-state exposure (AUC0-24hr) to unbound oxaprozin in JRA patients relative to 70 kg adult rheumatoid arthritis patients administered oxaprozin 1200 mg QD1
|Dose (mg)||Body Weight Range (kg)|
|600||22 to 31|
|900||32 to 54|
As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetics reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging.
A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg QD) in 20 young (21 to 44 years) adults and 20 elderly (64 to 83 years) adults, did not show any statistically significant differences between age groups.
Pharmacokinetics differences due to race have not been identified.
Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, caution should be observed in patients with severe hepatic dysfunction.
Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin.
The pharmacokinetics of oxaprozin have been investigated in patients with renal insufficiency. Oxaprozin's renal clearance decreased proportionally with creatinine clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency (see WARNINGS, Renal Effects).