Oxaprozin

OXAPROZIN- oxaprozin tablet, film coated
Rebel Distributors Corp

DESCRIPTION

Oxaprozin is a non-steroidal anti-inflammatory drug (NSAID), chemically designated as 4,5-diphenyl-2-oxazole-propionic acid, and has the following chemical structure:

Structural formula for oxaprozin

C18 H15 NO3 M.W. 293

Oxaprozin is a white to off-white powder with a slight odor and a melting point of 162°C to 163°C. It is slightly soluble in alcohol and insoluble in water, with an octanol/water partition coefficient of 4.8 at physiologic pH (7.4). The pKa in water is 4.3.

Oxaprozin oral tablets contain 600 mg of oxaprozin.

Inactive ingredients in oxaprozin oral tablets are carnauba wax, hypromellose, magnesium stearate, methylcellulose, microcrystalline cellulose, polacrilin potassium, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Oxaprozin is a 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)

Absorption

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)

Distribution

In dose proportionality 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 human milk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated.

Metabolism

Several oxaprozin metabolites have been identified in human 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.

Excretion

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.

Special Populations

Pediatric Patients

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 QD *
*
Model-based nomogram derived from unbound oxaprozin steady-state drug plasma concentrations of JRA patients weighing 22.1 to 42.7 kg or ≥ 45.0 kg administered oxaprozin 600 mg or 1200 mg QD for 14 days, respectively.
Dose (mg) Body Weight Range (kg)
600 22 to 31
900 32 to 54
1200 ≥ 55

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