BRIEF REPORT
`
`91
`
`PHARMACOKINETICS OF METHOTREXATE ADMINISTERED BY
`
`INTRAMUSCULAR AND SUBCUTANEOUS INJECTIONS IN PATIENTS
`
`WITH RHEUMATOID ARTHRITIS
`
`PAUL J. BROOKS. WILLIAM J. SPRUILL. ROY C. PARISH, and DANIEL A. BIRCHMORE
`
`The serum concentrations and the pharmacoki-
`netics of low-dose methotrexate (MTX) were compared
`after both intramuscular (IM) and subcutaneous (SQ)
`
`injections in 5 patients with rheumatoid arthritis. Val-
`ues for the observed peak concentration, the time to the
`observed peak concentration, and the area under the
`time versus concentration curve for [M injections were
`not significantly difierent from these values for SQ
`injections. These results suggest that IM and SQ are
`interchangeable routes of administration. SQ adminis-
`tration may be a more convenient and less painful way
`of administering low-dose MTX.
`
`Methotrexate (MTX). a folic acid antagonist.
`has recently been approved by the Food and Drug
`Administration for use in patients with severe rheuma-
`toid arthritis that is refractory to conventional therapy.
`The proposed beneficial effect of MTX in treating
`rheumatic diseases is its ability to inhibit inflammatory
`synovial cell turnover. decrease exudation in thejoint
`spaces, and impair the response to histamine and other
`vasoactive substances (1-4). Treatment has centered
`
`From the Department of Pharmacy Practice. The Univer-
`sity of Georgia College of Pharmacy. Athens.
`Supported by a grant from The Upjohn Company.
`Paul J. Brooks, PharmD: Fellow in Adult Internal Medicine
`Pharmacy Practice (currently Clinical Assistant Professor of Phar-
`macy Practice. The University of North Carolina School of Phar-
`macy at Fayetteville Area Health Education Center): William J.
`Spruill. PharrnD: Associate Professor of Pharmacy Practice; Roy C.
`Parish. PharmD: Assistant Professor of Pharmacy Practice; Daniel
`A Birchmore. MD: Athens. GA.
`Address reprint requests to Paul J. Brooks. PharmD. Fay-
`etteville Area Health Education Center.
`I6{ll—B Owen Drive. Fay-
`etteville. NC 28304.
`Submitted for publication May I8. 1989; accepted in revised
`form August 14. 1989.
`
`Arthritis and Rheumatism, Vol. 33, No. 1 (January 1990)
`
`around the use of very low doses administered in
`weekly intervals by oral (P0), intravenous (IV). and
`intramuscular (IM) routes (3.S—9).
`The intramuscular route is a desirable choice
`
`for parenteral drug administration because of the corn-
`pleteness of absorption relative to the oral route. peak
`concentrations that are similar to those achieved using
`the IV route. and slower drug absorption and pro-
`longed exposure to the drug compared with IV-
`administered MTX (3,6—8). As an alternative method
`of administration, subcutaneous (SQ) injections may
`also exhibit these beneficial pharrnacokinetic patterns
`and would have the potential advantages of patient
`self—adrninistration at home and greater patient com-
`fort
`than with weekly IM injections given in the
`physician's office. In the present study, we compared
`the serum concentrations and the pharmacokinetic
`parameters of MTX after IM and SQ administration in
`patients with rheumatoid arthritis.
`Patients and methods. The study population
`consisted of 5 patients [age range 45-75 years) who
`had severe rheumatoid arthritis and were currently
`receiving MTX {Table 1}. All patients were under the
`care of a board-certified rheumatologist and had expe-
`rienced an unsatisfactory response to nonsteroidal
`antiintlammatory drugs and intramuscular gold ther-
`apy. The patients had no history of hepatic disease,
`alcoholism. active peptic ulcer disease, or renal insuf-
`ficiency. Patients who required additional antiinflam-
`rnatory medication were permitted to continue taking
`their medication while receiving MTX.
`l week
`Each patient received 2 treatments,
`apart, given in a randomly assigned order. One treat-
`ment consisted of the patient‘s usual dose adminis-
`tered IM (lateral midthigh}; the other treatment was
`
`Page 1 of 4
`Page 1 of 4
`
`ANTARES Exhibit 1008
`
`ANTARES Exhibit 1008
`
`

`
`92
`
`BRIEF REPORTS
`
`Table 1. Characteristics of the 5 rheumatoid arthritis patients
`studied
`
`* This dose was given on 2 occasions 1 week apart: intramuscularly
`(IM) followed by subcutaneously (SQ) I week later. or SQ followed
`by IM I week later.
`
`the same dose administered SQ (lateral upper arm). An
`indwelling venous cannula was used to collect serial
`blood samples from each patient at 0 (baseline), 0.25,
`0.50. 035, 1.0, 1.5, 2.0, 4.0, and 8.0 hours after the
`injection. Blood was allowed to clot, and the serum
`was separated and stored at —10°C- The serum MTX
`concentration was determined in duplicate by a fluo-
`rescence polarization immunoassay technique using
`the Abbott TDx clinical analyzer (I0) (Abbott Labo-
`ratories, North Chicago, IL). This analyzer is reported
`to have a sensitivity of 0.01 rnolestliter, and has
`coefiicients of variation within assays and between
`assays of 8.09% and 9.20%, respectively, for the
`0.07-moleslliter control concentration, and 3.94% and
`5.15%, respectively,
`for the 5.0-molesiliter control
`concentration. Assay cross-reactivity of 7-hydroxy-
`methotrexate is reported as 1.5% (10).
`Time versus concentration data for each patient
`receiving each treatment were fitted to the appropriate
`exponential pharmacoltinetic model, using the
`RSTRIP pharmacol-tinetic computer software (Micro-
`Math, Salt Lake City, UT). Response variables exam-
`ined included the observed peak concentration
`(Cmax},
`time to the observed peak concentration
`
`Table 2. Pharrnacokinetic data comparing intramuscular {IM) and subcutaneous (SQ) administration of methotrexate in 5 rheumatoid arthritis
`patients‘
`
`Ke (hours' *1
`
`Kat (hours‘ '1
`
`Patient
`1
`2
`3
`4
`5
`
`IM
`0.23
`0.34
`0.30
`0.27
`0.22
`
`SQ
`0.33
`0.20
`0.29
`0.25
`0.14
`
`1M
`5.67
`2.72
`3.42
`L53
`35.30
`
`SQ
`2635
`5.24
`5.44
`5.36
`2.19
`
`Cmaxidose MTX
`
`(pmolesfliter >c
`mg}
`
`IM
`0.08
`0.10
`0.08
`0.07
`0.12
`
`SQ
`0.08
`0.0?
`009
`0.07
`0.0?
`
`Tmax (he-urs}
`
`IM
`0.53
`1.17
`L03
`1.50
`0.25
`
`SQ
`0.23
`0.70
`0.50
`1.25
`2.00
`
`AUC/dose MTX
`
`(,u.rr1oles x
`hoursfliter x mg)
`
`IM
`0.36
`0.43
`0.39
`0.41
`0.61
`
`SO
`0.48
`0.37
`0.41
`0.39
`0.71
`
`* Ke = elimination rate constant; Ka = absorption rate constant; Cmax = observed peak concentration; MTX = rnethotrexate; Trnax = time
`to the observed peak concentration; AUC = area under the time versus concentration curve.
`
`Page 2 of 4
`Page 2 of 4
`
`('l"n-tax}, area under the time versus concentration
`
`curve (AUC), and the elimination (kc) and absorption
`(ka) rate constants. The AUC was calculated using the
`trapezoidal rule. The rate constants kc and lta were
`estimated by iterative least-squares methods using the
`RSTRIP software. Cmax and AUC values were nor-
`
`malized for the dose, since patients received doses
`titrated to individual response, and are reported as
`Crnaxfdose and AUCfdose, respectively.
`The statistical significance of the observed dif-
`ferences in the pharmacoltinetic data after administra-
`tion by the different routes was evaluated using the
`paired-difference I-test for the response variables ke,
`Eta, Cmaxfdose, and AUCfdose. The Wilcoxon
`matched pairs signed rank test was used for differ-
`
`is unlikely that time is
`ences in Tmax because it
`normally distributed. P values less than 0.05 were
`considered significant.
`Results. Pharrnacokinetic data for the IM and
`
`SQ routes of MTX administration are shown in Table
`2. Values for the Cmax/dose were variable. Peak
`
`concentration data from the same patient after the 2
`routes of administration showed that the drug concen-
`trations were higher after the IM dose in 2 patients,
`higher after the SQ dose in 1 patient. and equivalent in
`2 patients. The peak concentration (T'max} occurred
`sooner and the rate of absorption (ka) was faster after
`the SQ injection in 4 of 5 patients. Percent differences
`in AUCidose measurements after SQ and IM injec-
`tions were 5% for patients 3 and 4, 14% for patients 2
`and 5, and 25% for patient 1. The elimination rate
`constant (kc) was variable. and ranged from 0.14
`hours" to 0.33 hours" after the SQ doses, and 0.22
`hours" to 0.34 hours" after the IM doses.
`
`Statistical data regarding the null hypothesis
`(that the mean dilference between treatments for each
`
`
`
`Patient
`I
`2
`3
`4
`5
`
`Agefsex
`4-SIF
`GSKF
`75J'F
`53!M
`56:"M
`
`Weight (kg)
`6!
`80
`90
`75
`66
`
`Methotrexate
`close (mg)*
`25.0
`15.0
`12.5
`25.0
`20.0
`
`

`
`BRIEF REPORTS
`
`93
`
`Table 3. Statistical analysis of the differences in the pharmacolo-
`netic data of the IM and SQ routes of MTX administration in 5
`rheumatoid arthritis patients‘
`
`Response
`variable
`
`Difference?
`
`P
`
`Power to detect
`. ._.-.__
`.
`20% difference 30% difference
`
`Ke
`Ka
`Cmax
`AUC
`Trnax
`
`0.03 i 0.09
`0.74 : 19.80
`-0.0] :t 0.03
`0.03 i 0.08
`0.02
`
`0.49
`0.94
`0.27
`0.37
`>005
`
`<05:
`(0.51
`0.88§
`0.6li
`ND
`
`<05:
`40.51:
`0.99§
`0.90§
`ND
`
`* N1) = not determined; see Table 2 for other definitions.
`1 IM — SQ. Tmax value is the median; other values are the mean :
`SD.
`1 Difference between [M value and SQ value was not large enough
`to enable rejection of the null hypothesis.
`§ Null hypothesis accepted.
`
`parameter is 0) are shown in Table 3. Calculated P
`
`values exceeded the significance value of 0.05 for
`every response variable. To estimate the possibility of
`a Type II statistical error (i.e., falsely accepting the
`null hypothesis}. an analysis of power was performed
`to determine the power of the tests to detect clinically
`important differences at the 0.05 significance level.
`The power to detect a 3.20% difference in Cmax was
`0.88, and the power to detect a 230% difference in the
`AUC was 0.90. Using these results from the power
`analysis, the null hypothesis for difierences in Cmax
`and AUC was accepted. However, there was insuffi-
`cient statistical evidence to either reject or accept the
`null hypothesis for the other parameters (Table 3).
`Discussion. Several studies have compared the
`pharmacokinetics of MTX by the IV, IM, and PO
`routes of administration (63,11). MTX administered
`
`by injection has been shown to produce higher serum
`concentrations and more complete absorption than
`does orally administered MTX. Specifically, intramus-
`cularly administered MTX resulted in rapid and com-
`plete absorption and in higher serum concentrations
`than did oral administration, and it provided peak
`concentrations similar to those observed following IV
`administration. Balis et al (12) compared pharmacoki-
`netic data obtained after low doses of MTX were
`
`administered subcutaneously and orally to rhesus
`monkeys and to children with lymphoblastic leukemia.
`Those authors concluded that SQ administration was a
`feasible way to deliver MTX because it was well
`tolerated, efficiently absorbed, and it overcame prob-
`lems of variable absorption seen after oral dosing (12).
`The results of this study suggest that the SQ
`route achieves serum concentration versus time
`
`Page 3 of 4
`Page 3 of 4
`
`curves similar to the IM route. Statistical analysis
`suggests that the pharmacokinetic parameters are sim-
`ilar for these 2 routes of administration. No statisti-
`
`cally significant ditferences were observed for any
`response variable. However, an acceptable analysis of
`power value of 80% was reached for the variables
`Cmax and AUC, but not for the variables kc and ka.
`Thus, undetected differences in Re and ka may exist.
`Although changes in ke should not be dependent upon
`the administration technique, differences in ice would
`not be unexpected, since samples were taken 1 week
`apart, and intrasubject variability after drug therapy is
`not uncommon.
`
`The ka values showed considerable variability.
`The absorption rate was more rapid after SQ injection
`than after IM injection in all but 1 patient, whose rate
`of absorption was more rapid after IM administration.
`It is interesting to note that this patient had very little
`muscle mass, which may have affected the absorption
`rate. Slight differences in absorption rates (ka) would
`be expected when changing drug administration sites.
`Other possible factors altering the absorption rate
`include changes in the injection technique and differ-
`ences in the distribution of blood circulation at dif-
`ferent times.
`
`The metabolite T-hydroxymethotrexate has
`displayed significant blood concentration during me-
`tabolism and may contribute to the clinical effect of
`methotrexate (5). However, the concentration of this
`
`metabolite was not determined in this study, because
`its formation should not influence drug absorption.
`The sampling interval of 8 hours seemed appro-
`priate because ‘it exceeded 2 drug half-lives in every
`case, and the drug concentrations during the 8-hour
`sample period approximated the limits of detection of
`the assay. The'll"east-squares approach used to calcu-
`late kc and ka utilizes information from all data points
`to calculate the‘ optimal fit of the function to the data;
`this eliminates the need for observations over several
`drug half-lives.
`Although patient acceptance was not assessed
`as part of this investigation, no patients complained of
`problems associated with SQ administration. and most
`patients reportedithat the SQ injection was less painful
`than the IM injection.
`that MTX concentra-
`These findings suggest
`tions achieved by each method of delivery are statis-
`tically and clinically similar, and that IM and SQ
`injections are interchangeable routes of MTX adminis-
`tration. Although this study is considered preliminary
`because of the small sample size, our data support the
`
`

`
`94
`
`BRIEF REPORTS
`
`roufine use of submnaneous srrx adnunfiuafion,
`allowing flexibility in the treatment of rheumatoid
`anhfifis
`
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