Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis

Abstract

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a decrease of 1 mg/dl in mean minimum concentration.Salicylates are among the most effective antiinflammatory drugs used in the treatment of rheumatoid arthritis. At the serum concentrations recommended, salicylate serum half-life is prolonged (l,2). It is, therefore, theoretically possible to administer salicy- late at infrequent intervals in large fractions of the total daily dose.We studied two such regimens in which salicylate was administered at 8 and at 12 hour intervals to hospitalized patients with active rheumatoid arthritis. The hourly variation in steady-state salicylate concentration was measured. Choline magnesium trisalicylate (CMT) was used as the salicylate source since it may have fewer adverse effects on the gastrointestinal tract than aspirin, as judged by chromium-tagged red blood cell loss (3) and by endoscopic evaluation (4). MATERIALS AND METHODSCholine magnesium trisalicylate was administered to 6 patients, 3 men and 3 women ranging in age from 24 to 57. All had active classic or definite rheumatoid arthritis (according to ARA criteria). None had clinically important renal, hepatic. or gastrointestinal disease as judged by history, physical examination, serum creatinine, urinalysis, SGOT. alkaline phosphatase. bilirubin. and LDH. Their characteristics are noted in Table I .During an initial outpatient phase of about 6 weeks. each patient's total daily dose of CMT was individualized by trial and error to achieve serum salicylate concentrations between 20 and 35 mg/dl at steady-state.After a minimum of 7 days on the selected dose, patients were hospitalized for 10 days at the Clinical Research Center, Center for Health Sciences, Los Angleles, California. The total daily dose was divided into three fractions and administered at 8 hour intervals for 5 days; the regimen was then changed so that two fractional doses were administered at I2 hour intervals for 5 days. The same total daily dose was used

Clinical pharmacokinetics of salicylates: a re‐assessment.

“…Based on a pharmacokinetic analysis of this phenomenon, Levy & Giacomini (1978) have predicted that adequate plasma salicylate concentrations for anti-inflammatory therapy can be maintained by administering the drug only every 8 or 12 h rather than every 4-6 hours. This prediction has now been confirmed by several groups of investigators with respect to children (Makela, Yrjana & Mattila, 1979;Pachman, Olufs, Procknal & Levy, 1979) and adults (Cassell, Furst, Dromgoole & Paulus, 1979;Bensen, Laskin, Paton, Little & Fam, 1979;Cohen, Thomas & Cohen, 1978). It is important, however, that the large single doses of a salicylate required for a two or three times daily dosage regimen be administered in a form that minimizes gastric irritation.…”

“…This is a reasonable possibility in principle but seems unlikely in practice. The maximum plasma salicylate concentrations produced by either an 8or a 12-hourly dosing regimen (same daily dose individually adjusted to achieve timed average concentrations of about 23 mg per 100 ml) were 27.9 and 30.8 mg per 100 ml, respectively, in one very well controlled study (Cassell, Furst, Dromgoole & Paulus, 1979). Peak concentration differences between a 6-and 8-hourly dosage regimen are also rather small in the anti-inflammatory dose range (Levy & Giacomini, 1978).…”

Comparable serum salicylate concentrations from choline magnesium trisalicylate, aspirin, and buffered aspirin in rheumatoid arthritis

“…CMT has been previously shown to be adequately absorbed orally with a mean steady-state serum salicylate concentration of 20.2 mg/ 100 ml after 1.5 gm administered every 12 hours (7). A comparison of every 8-or every 12-hour administration of CMT indicated that giving 2.5 to 4.5 gm/day produced a range of steady-state salicylate concentrations between 19 to 27 mg/100 ml during an 8-hour interval between doses and between 17 and 30 mg/100 ml during a 12-hour interval (8). More recently, no significant differences were found between the absorption and elimination kinetics of aspirin and CMT after single doses (9).…”

Monitoring Plasma Concentrations of Salicylate

“…A satisfactorily detailed kinetic profile of salicylates ha<; been available for some time and has allowed the definition of major parameters and guidelines on which monitoring programmes could be based. The few interesting refinements more recently obtained (Makela et aI., 1979;Levy et aI., 1980;Cassell et at., 1979;Day et aI., 1979;Rumble et aI., 1980;Gunsberg et aI., 1980) have not changed the situation substantially. As is always the case, kinetic information is obtained in carefully selected groups of patients over usually short periods of time, where little can be learned on whether and how far large scale application of kinetic knowledge will contribute to clinical efficacy.…”