Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis.код для вставкиСкачать
3 84 STEADY-STATE SERUM SALICYLATE LEVELS IN HOSPITALIZED PATIENTS WITH RHEUMATOID ARTHRITIS Comparison of Two Dosage Schedules of Choline Magnesium Trisalicylate SIDNEY CASSELL, DANIEL FURST, SYDNEY DROMGOOLE, and HAROLD PAULUS 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- From the Division of Rheumatology. Department of Medicine. UCLA School of Medicine. Los Angeles. California. Supported in part by USPHS Grant G M 15759. USPHS Grant RR-865, and Purdue Frederick. Sidney Cassell, MD; Daniel Furst, MD; Sydney Dromgoole. PhD: Harold Paulus. MD. Address reprint requests to Harold E. Paulus. MD. 1004 Veteran Avenue, Los Angeles. California 90024. Submitted for publication October 4. 1978; accepted in revised form November 14. 1978. Arthritis and Rheumatism, Vol. 22, No. 4 (April 1979) 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 METHODS Choline 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 385 CHOLINE MAGNESIUM TRISALICYLATE Table 1. Clinical profile SD Patient Age Sex Weight (kg) Height (cm) Rheumatoid factor titer ARA functional class/progression state Hematocrit (70) Serum albumin (.w/dl) MR RT JL 24 50 50 F F M 47.8 156.5 57 I64 12 174.5 RM 56 M 74 wc 57 M 86.6 177.5 171 1/1280 1/320 1/1280 1/640 1/2560 1I1/III 39 I11/111 40 111/III 39 11/111 35 45 4.8 4.0 4.4 3.5 in both regimens. Hourly serum salicylate concentrations were measured during one or more dosing intervals daily for 2 consecutive days with each regimen (hospital days 4, 5 and 9, 10). The relationship of drug administration to meals was not controlled. Patients were allowed to continue nonsalicylate medications at a constant dose during the study. These included flurazepam hydrochloride, 30 mg at bedtime for SD and JL, propoxyphene 65 to 130 mg daily for SD. diazepam 2 to LO mg daily for J L and RT. secobarbital200 rng at bedtime daily for RM, prednisone 10 mg daily and indomethacin 50 mg rectally at bedtime daily for WC, intramuscular aurothioglucose 50 mg weekly for RT. and aurothiomalate 50 mg every 2 weeks for RM and WC. Serum salicylate concentration was assayed according to the semimicro method of Routh and Dryer (5). extracting with ethylene dichloride and back extracting with ferric nitrate. A coefficient of variation of 4.2% was observed in repeated spectrophotometric absorbance readings with serum containing 20 mg/dl of sodium salicylate as a standard. The paired t test was used to evaluate day to day, and regimen to regimen variation in data. III/III 4.2 - - - MEAN STEADY-STATE CONCENTRATION (6 S U K E C T S ) 1 t t A 0 12 HOUR DOSES I 0 1 1 10 20 I 30 1 40 RESULTS The hourly mean salicylate concentrations of the 6 patients for the first dosage interval of each of the 2 study days with each regimen are plotted in Figure I . Mean hourly salicylate concentrations ranged from 19.0 to 27.2 mg/dl with the 8 hour dosing regimen, and from 17.1 to 30.3 mg/dl with the 12 hour regimen. With either regimen, the average change in the mean serum salicylate concentration from one day to the next was only 1.4 mg/dl. No statistically significant day to day group differences could be demonstrated in the mean, maximum, or minimum serum salicylate concentration, or in day to day change in area under the time versus concentration curve with either regimen. Table 2 compares the salicylate concentrations obtained with each regimen and indicates the total and weight adjusted doses of choline magnesium trisalicylate. The salicylate dose range was 43 mg/kg/day Q 8 HOUR DOSES I 0 10 I I 29 30 1 40 HOURS Figure 1. Hourly mean serum salicylate concentrations (k standard errors) of 6 patients for the first dosage intervals of 2 consecutive days, during every 8 hour and every 12 hour administration of the same total daily dose of choline magnesium trisalicylate at steady-state. The heavy dashed line is the overall mean steady-state concentration. 386 CASSELL ET AL Table 2. Comparison of regimens Mean salicylate concentration (mg/dl) Patient SD MR JL RT RM wc Daily dose of salicylate 73 mg/kg (3500 mg) 78.9 mg/kg (4500 mg) 53.9 mg/kg (2500 mg) 55.6 mg/kg (4000 mg) 47.3 mg/kg (3500 mg) 43.4 mg/kg (3750 mg) Area under 24 hr time versus concentration curve mg/dl (hr) Mean maximum concentration (mg/dl) Mean minimum concentration (mg/dl) 8 hour 12 h o u r 8 hour 12 hour 8 hour 12 hour 8 hour 12 hour 19.9 25. I 478 605 25.5 32.0 13.5 17.8 31.9 32.0 800 768 36.5 41.5 29.5 25.8 28.4 30.0 680 723 36.0 37.3 21.3 23.5 19.8 17.8 458 426 24.8 24.3 16.0 13.0 16. I 13.4 382 320 17.8 19.3 13.5 8.5 22.6 22.5 529 539 26.8 30.5 16.8 15.0 Group means 58.7 mg/kg (3625 mg) 23. I 23.5 554 564 27.9 30.8 18.4 17.3 SD 14.2 mg/kg (666 mg) 5.8 6.9 155 I72 6.9 8. I 6.0 6.3 to 79 mg/kg/day (2500 mg/day to 4500 mg/day). Individual dose-serum level responses were quite variable. For example, a dose of 53.9 mg/kg/day was associated with a mean serum salicylate Concentration of 28.4 mg/ dl during the 8 hour regimen in patient JW. A much larger dose of 73 mg/kg/day produced a mean concentration of only 19.9 mg/dl in patient SD. Mean concentrations, during the 8 hour interval, for individual patients ranged from 16.1 mg/dl to 3 1.9 mg/dl, and during the 12 hour interval from 13.4 mg/dl to 32 mg/dl. In 2 individuals (RT and WC) the areas under the 24 hour time versus concentration curve generated by the two dosing regimens were calculated directly by use of 24 consecutive hourly salicylate measurements, and the method of area approximation by trapezoid construction. For these 2 patients, the directly calculated areas from each regimen varied from one another by -6% and +2% respectively. These small differences in area support our assumption that the patients were studied at equilibrium, and this finding is expected since the total daily dose is constant for both regimens. Based on this, areas under the 24 hour salicylate curves were calculated for the 4 other patients using the formulae: 3 x mean area 8 hour curve and 2 x mean area 12 hour curve, for the two dosing regimens. In the 6 patients, changing the dosing interval from 8 to 12 hours resulted in a mean increase of 11% in peak concentration (increase of 3 mg/dl). This was statistically significant at P < 0.05. The resultant decrease of 7% in minimum concentration (decrease of 1 mg/dl) was not statistically significant. Mean salicylate concentration and area under the time versus concentration curve remained virtually unchanged (< 1% change). Three patients (JL, RT, WC) noted mild continuous tinnitus during the hospitalization; there was no difference in tinnitus with the two dosage regimens. N o other adverse experiences were noted. During the initial outpatient phase, one patient (RT) had an exacerbation of arthritis when his regimen was changed from 5.3 gm of aspirin to 3 gm of CMT daily. His symptoms improved to baseline when his CMT dose was increased to 4 gm daily. After this experience, the initial dose of CMT for the other patients was chosen to be more nearly equivalent to the patient’s prior salicylate regimen, and exacerbations in disease activity were not noted. N o exacerbations occurred with the changes between every 8 to every 12 hour dosage schedules. DISCUSSION Mean hourly serum salicylate concentrations fluctuated within a clinically acceptable therapeutic range of 15-30 mg/dl with both the 8 and the 12 hour dosing regimens in patients with rheumatoid arthritis CHOLINE MAGNESIUM TRISALICYLATE selected for this study. Extrapolation from previous salicylate kinetic studies (1,2) and computer assisted projections (6) have suggested that infrequent dosing regimens could provide sustained therapeutic serum salicylate concentrations. Our direct hourly observations during steady-state support this concept. After their optimal individualized daily dose had been determined, subjects responded to this regimen with very similar serum concentrations from one day to the next. Between individuals, however, serum concentration responses to similar weight adjusted doses were quite variable and unpredictable. This is consistent with observations reported earlier (7) and emphasizes that the dose of salicylate required to achieve desired steadystate therapeutic serum salicylate concentrations must be found empirically for each individual patient, using serum concentration as a guide. These data suggest that a measurement of serum salicylate concentration just prior to a choline magnesium trisalicylate dose is a reliable approximation of the minimum concentration for either an 8 or a 12 hour dose interval. Peak concentrations, however, were more variable with respect to time. This may be due to the effect of food or of single dose size on the rate of salicylate absorption. As the serum salicylate concentration increases, salicylate serum half-life increases, and the time required until a new equilibrium is achieved after a change in total daily dosage increases (8). Catabolism shifts increasingly toward first order processes, i.e. urinary pH dependent excretion of free salicylic acid and the excretion of salicyl acyl glucuronide and gentisic acid (9,lO). In addition, the volume of distribution of salicylate increases with the size of the dose ( l l ) , and, therefore, serum levels may somewhat underestimate tissue levels. Hence, care must be used in finding a daily salicylate dose for an individual. Sufficient time (approximately 7 to 10 days) must be allowed for a new equilibrium to be reached before new increments are undertaken, and attention must be given to factors that may change renal function or urinary pH (12,13). The similarity in concentration parameters between the 8 hour and 12 hour dosing regimens suggests that when a therapeutic daily dose of salicylate has been found for an individual, changes in the time interval between fractional doses and in the size of the fractional dose have only minor effects on the steady-state salicylate concentrations. At therapeutic serum salicylate concentrations, factors such as patient convenience and side effects may be more important in governing the distri- 387 bution of the total dose throughout the patient’s day. Although the 12 hour dosing regimen produced somewhat higher peak concentrations, these patients did not have signs or symptoms of salicylate intoxication with either regimen, except for tinnitus. Theoretically, our results apply to serum salicylate, rather than to the particular precursor drug (CMT) administered. However, because of possible differences in absorption and toxicity, they should not be extrapolated to other sources of salicylate until confirmed by direct studies with these drugs. Especial caution is warranted with respect to the potential gastric toxicity of the large single doses of aspirin that would be required for a twice daily dosage schedule. Further, our findings cannot be extrapolated to patients with hypoalbuminemia, or with substantial renal, hepatic, or gastrointestinal dysfunction, and they are not valid for mean steady-state serum salicylate concentrations of less than 15 mg/dl. The regimens studied were convenient and well tolerated by these 6 patients. Further investigation with special attention to toxicity is needed before these regimens can be recommended. However, infrequent dosing regimens appear to provide adequate therapeutic serum concentrations and may improve patient acceptance of the intensive, chronic salicylate therapy required for optimal antiinflammatory treatment in rheumatoid arthritis. This may improve patient compliance. REFERENCES I. Paulus HE, Siege1 M, Mongan E, Okun R, Calabro JJ: 2. 3. 4. 5. 6. 7. 8. Variations of serum concentrations and half-life of salicylate in patients with rheumatoid arthritis. Arthritis Rheum 14:527-532, 1971 Levy G: Pharmacokinetics of salicylate elimination in man. J Pharm Sci 54:959-967, 1965 Cohen A, Garber HE: Comparison of choline magnesium trisalicylate and acetylsalicylic acid in relation to fecal blood loss. Curr Therap Res 23:187-193, 1978 Sun DH, Roth S: Salicylate therapy. Florida Family Physician Journal 28 (l):3341, 1978 Routh JI, Paul WD, Arredondo E, Dryer RL: Semimicro method for determination of salicylate levels in blood. Clin Chem 2:432-438, 1958 Levy G, Giacomini K: Rational aspirin dosage regimens. Clin Pharmacol Therap 23:247-252, 1978 Gupta N, Sarkissian E, Paulus H: Plateau serum salicylate levels: correlation with the rate of salicylate metabolism. Clin Pharmacol Therap 18:350-355, 1975 Levy G, Tsuchiya T: Salicylate accumulation kinetics in man. N Engl J Med 287:430432, 1971 CASSELL ET AL 388 9. Levy G, Tsuchiya T, Amsel LP: Limited capacity for salicylphenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. Clin Pharmacol Therap 13:258-268, 1972 10. Smith PK, Gleason HL, Stoll CG, Ogarzalek S: Studies on the pharmacology of salicylates. J Pharmacol Exp Ther 87:237-255, 1946 1 1 . Levy G, Yaffe SF: Relationship between dose and appar- ent volume of distribution of salicylate in children. Pediatrics 54:7 13-7 17, 1974 12. Levy G, Lampman T, Kamath BL, Garrettson LK: Decreased serum salicylate concentrations in children with rheumatic fever treated with antacid. N Engl J Med 293:323-325, 1975 13. Levy G, Leonards JR: Urine pH and salicylate therapy. JAMA 21731, 1971 Postgraduate Course in Rheumatology The University of Colorado School of Medicine will hold a Postgraduate Course in Rheumatology entitled, “Update in Rheumatology,” June 27-29, 1979, at the Given Institute of Pathobiology in Aspen, Colorado. The course will be a review of the recent advances in pathogenesis, diagnosis, and treatment of the rheumatic diseases. The faculty will consist of guest speakers and staff of the University of Colorado School of Medicine. For further information, contact the Office of Postgraduate Medical Education, University of Colorado School of Medicine, 4200 East Ninth Avenue, Denver, Colorado 80262.