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

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.
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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.