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`Clinical and epidemiological research
`
`CONCISE REPORT
`Head-to-head, randomised, crossover study of oral
`versus subcutaneous methotrexate in patients
`with rheumatoid arthritis: drug-exposure limitations
`of oral methotrexate at doses ≥15 mg may be
`overcome with subcutaneous administration
`Michael H Schiff,1 Jonathan S Jaffe,2 Bruce Freundlich3,4
`
`Handling editor Tore K Kvien
`▸ Additional material is
`published online only. To view
`please visit the journal online
`(http://dx.doi.org/10.1136/
`annrheumdis-2014-205228).
`1Department of Rheumatology,
`University of Colorado, Denver,
`Colorado, USA
`2Clinical Development, Antares
`Pharma Inc, Ewing,
`New Jersey, USA
`3Medical Department, Antares
`Pharma Inc, Ewing,
`New Jersey, USA
`4University of Pennsylvania,
`Philadelphia, Pennsylvania,
`USA
`
`Correspondence to
`Dr Michael H Schiff,
`Department of Rheumatology,
`University of Colorado, School
`of Medicine, 5400 South
`Monaco Street, Greenwood
`Village, CO 80111, USA;
`michael.schiff@me.com
`
`Received 10 January 2014
`Revised 17 March 2014
`Accepted 22 March 2014
`Published Online First
`12 April 2014
`
`ABSTRACT
`Objective To compare the relative bioavailability, safety
`and tolerability of oral methotrexate (MTX) and
`subcutaneous (SC) MTX administered via an auto-injector
`(MTXAI) in patients with rheumatoid arthritis (RA).
`Methods In this randomised, multicenter, open-label,
`three-way crossover study, patients ≥18 years with adult
`RA undergoing treatment with MTX for ≥3 months were
`assigned to receive MTX 10, 15, 20 and 25 mg weekly in
`a random sequence of three treatments: oral, SC into the
`abdomen and SC into the thigh. For 24 h after
`administration of each treatment, blood samples were
`collected for pharmacokinetic analysis and injection sites
`were assessed.
`Results Forty-seven patients completed the study.
`Systemic exposure of oral MTX plateaued at doses
`≥15 mg/week. In contrast, SC MTX demonstrated a linear
`increase in systemic exposure that was greater than oral
`MTX at each dose. No unexpected AEs were noted for
`either formulation.
`Conclusions Unlike oral MTX, the systemic exposure of
`SC MTX did not plateau over the doses studied,
`particularly at doses ≥15 mg/week. In this study, higher
`systemic MTX exposure was not associated with increases
`in AEs. Patients with an inadequate clinical response to
`oral MTX may benefit from higher drug exposure by
`switching to SC MTX.
`Trial registration number NCT01618968.
`
`INTRODUCTION
`Methotrexate (MTX) is the disease-modifying anti-
`rheumatic drug of choice for rheumatoid arthritis
`(RA) worldwide.1 2 Gastrointestinal
`(GI)
`tract
`absorption limitations may compromise the bio-
`availability3 of higher oral doses. Studies have
`shown that the bioavailability of oral MTX varies
`widely among patients and decreases with increasing
`dose.4–6 The GI side effects of oral MTX, such as
`nausea and vomiting, also limit optimal use.4 5 7
`Doses greater than 15 mg/week are frequently used
`to control disease activity, but may be only partially
`effective in some patients and poorly tolerated by
`others. A previous study of oral and subcutaneous
`(SC) MTX in patients with RA suggested that limita-
`tions in systemic exposure of oral administration
`may affect efficacy. In that trial, clinical responses
`were significantly better in patients given SC MTX.8
`
`Open Access
`Scan to access more
`free content
`
`To cite: Schiff MH, Jaffe JS,
`Freundlich B. Ann Rheum
`Dis 2014;73:1549–1551.
`
`In the current phase II study, the relative bioavail-
`ability of oral MTX and SC MTX delivered via an
`MTX auto-injector (MTXAI) recently approved by
`the US Food and Drug Administration9 was
`explored in patients with RA.
`
`METHODS
`Patients
`Patients with RA were ≥18 years of age and treated
`with MTX for ≥3 months. Concomitant medica-
`tions had to be stable for ≥3 months. Women
`could not be pregnant or lactating. Patients with
`other serious medical conditions and those taking
`additional medications,
`including DMARDs, that
`could interfere with PK outcome measurements
`were excluded. Administration of non-steroidal
`anti-inflammatory drugs (NSAIDs) was not permit-
`ted within ±12 h of MTX administration.
`
`Study design and treatments
`randomised-
`This was an 8-week, open-label,
`sequence, three-way crossover study conducted at
`four clinical
`sites
`in the USA. The allocation
`sequence was created by Medpace using a Williams
`design to balance variance from potential carry-
`over effects. At the time of enrolment, investigators
`selected dose based on patient’s then-current oral
`MTX regimen (10, 15, 20 or 25 mg weekly). Each
`patient received one dose of MTX via each of
`three routes: oral MTX (tablets), SC MTX into the
`abdomen and SC MTX into the thigh. Blood
`samples were obtained for pharmacokinetic (PK)
`analysis predose and at 0.25, 0.5, 0.75, 1.0, 1.25,
`1.5, 1.75, 2, 4, 6, 8, 10, 12 and 24 h after dosing.
`The study was conducted in accordance with the
`Declaration of Helsinki and was in compliance
`with Good Clinical Practice Guidelines. This trial is
`registered with clinicaltrials.gov (NCT01618968).
`
`Objectives
`The primary objectives were to compare the relative
`bioavailability of oral MTX with that of SC MTX
`using the MTXAI and to determine whether the
`two injection sites provided bioequivalent drug
`exposure. Secondary objectives were to compare the
`time of peak concentration (tmax), apparent terminal
`(λz) and terminal half-life (t1/2) of
`rate constant
`MTX for the three methods of administration. PK
`
`Schiff MH, et al. Ann Rheum Dis 2014;73:1549–1551. doi:10.1136/annrheumdis-2014-205228
`
`1549
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`Clinical and epidemiological research
`
`parameters were calculated with standard non-compartmental
`methods. Safety was evaluated for SC and oral MTX.
`
`Pharmacokinetic evaluations
`The PK population included patients with ≥1 postdose plasma
`MTX concentration value who did not have a major protocol
`deviation to affect data integrity. Plasma concentrations as deter-
`mined by AUC from time 0 to the last measurable concentration
`(AUC0–t), or extrapolating to infinity (AUC0–inf) and the
`maximum observed concentration (Cmax) for each dose level
`were compared. The linear trapezoidal method was used to cal-
`culate AUC when concentration data were increasing or con-
`stant, and the logarithmic trapezoidal method was used if
`concentration data were decreasing. Geometric mean and geo-
`metric coefficient of variation percentage (CV%) were calcu-
`lated for the AUCs and Cmax. The geometric CV% was
`calculated as 100·(exp [SD2] –1)0.5, where SD is the standard
`deviation of the log-transformed data. Intrasubject CV% was
`calculated as 100·√(EXP (Σ**2) – 1), where Σ**2 is the residual
`variance estimate from the SAS MIXED (SAS Institute Inc, Cary,
`North Carolina, USA) procedure (PROC MIXED).
`
`Safety assessments
`The safety population included randomised patients who
`received ≥1 dose (see table 1 for baseline demographics and
`clinical characteristics, and online supplementary table 1 for
`baseline disease characteristics). Adverse events (AEs) were mon-
`itored and severity, relationship to study drug, action taken,
`outcome and classification as
`serious or non-serious were
`recorded. An AE was considered to be treatment-emergent
`(TEAE) if it started on or after the first dose. Changes in safety
`laboratory parameters and vital signs were monitored, and
`administration sites were examined. During the MTXAI treat-
`ment periods,
`injection site assessments were performed
`predose and at 0.25, 1, 12 and 24 h postdose.
`
`Statistical analysis
`A sample size of approximately 48 patients (12 randomised
`patients per dose level, with no replacements) was planned to
`provide a sufficient number of patients to determine the relative
`bioavailability, safety and tolerability of MTX administered via
`the three methods. For comparisons among treatments, a
`mixed-model analysis that took into consideration sequence,
`treatment and treatment period as fixed effects and subjects
`nested within sequence as a random effect was used to compare
`dose-normalised logarithmically transformed values for Cmax,
`AUC0–t and AUC0–inf. Least-squares
`(LS) mean for each
`
`treatment, differences between treatment LS means and 90%
`CIs for differences between treatment LS means were obtained.
`Results were transformed back to the original scale to obtain
`geometric LS means, point estimates of the geometric test and
`LS mean ratios, and 90% CI for these ratios. Relative bioavail-
`ability comparisons were based on route and/or location of
`administration at each dose level using analysis of variance
`(ANOVA). For bioequivalence assessments of abdomen and
`thigh SC administration sites, the dose-normalised PK para-
`meters were used in the ANOVA model. Bioequivalence was
`established if the 90% CI for point estimates of the geometric
`test and reference LS mean ratios were within the prespecified
`range of 80% to 125%.
`If bioequivalence was established
`among the SC injection sites, the data from the SC injection
`sites were pooled for comparison with oral administration.
`
`RESULTS
`Patients
`Patients participated from May through August 2012. Of the 54
`patients screened, 50 were randomised and 49 took ≥1 dose of
`study drug and were included in the safety and PK analyses. The
`study was completed by 47 patients; two patients discontinued
`the study after the first dose of MTX (one due to an AE and
`one due to death).
`
`PK assessments
`The Cmax of MTX was comparable across routes and doses
`(table 2). However, the AUC from 0 to 24 h (AUC0–24h) and
`AUC0–inf values were consistently higher at all dose levels for
`the SC MTXAI compared with oral MTX. There was consist-
`ently greater bioavailability of SC MTX compared with oral
`MTX administration at all dose levels (figure 1). For oral MTX,
`the mean AUC plateaued at doses ≥15 mg. In contrast to the
`plateau in exposure seen with oral MTX, the exposure of MTX
`increased in a dose-proportional manner with SC MTX.
`Pharmacokinetic measures for SC MTX in the thigh and
`abdomen demonstrated bioequivalence.
`Dose-normalised MTX PK parameters are presented in table 2.
`The ratio of the dose-normalised AUC0–24h and Cmax of the SC
`MTX compared with oral MTX was 127.61 (90% CI 122.30 to
`133.15) and 94.88 (90% CI 87.95 to 102.37), respectively. The
`relative systemic bioavailability of SC MTX at 10, 15, 20 and
`25 mg was 121%, 114%, 131% and 141%, respectively, of that
`seen with oral dosing. For the secondary analysis variables, tmax, λz
`and t1/2, PK results were consistent across dose and route of
`administration.
`
`Table 1 Baseline demographic and clinical characteristics of the patients in the safety population
`
`MTX
`
`10 mg (n=13)
`
`15 mg (n=12)
`
`20 mg (n=12)
`
`25 mg (n=12)
`
`Overall (N=49)
`
`Mean age,* y (SD)
`Women, n (%)
`White, n (%)
`Black, n (%)
`Mean (SD) BMI, kg/m2
`Mean (SD) duration of RA,* years
`
`62.9 (12.51)
`11 (84.6)
`12 (92.3)
`1 (7.7)
`30.7 (7.64)
`13.9 (9.29)
`
`*At informed consent.
`BMI, body mass index; MTX, methotrexate; RA, rheumatoid arthritis.
`
`63.4 (7.49)
`5 (41.7)
`11 (91.7)
`1 (8.3)
`31.1 (5.35)
`14.4 (7.33)
`
`60.0 (10.40)
`8 (66.7)
`10 (83.3)
`2 (16.7)
`30.5 (5.54)
`11.6 (8.76)
`
`59.0 (11.53)
`7 (58.3)
`11 (91.7)
`1 (8.3)
`30.6 (7.43)
`13.4 (10.32)
`
`61.4 (10.53)
`31 (63.3)
`44 (89.9)
`5 (10.2)
`30.7 (6.39)
`13.3 (8.78)
`
`1550
`
`Schiff MH, et al. Ann Rheum Dis 2014;73:1549–1551. doi:10.1136/annrheumdis-2014-205228
`
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`Clinical and epidemiological research
`
`Table 2 Dose-normalised MTX PK parameters by treatment (PK analysis population)
`λz (L/h)
`
`Cmax (ng/mL)
`
`tmax (h)
`
`t½ (h)
`
`AUC0–24h (ng·h/mL)
`
`AUC0–inf (ng·h/mL)
`
`Oral MTX (n=47)
`22.697 (7.4967)
`Mean (SD)
`33.0
`CV%
`21.586
`Geometric mean
`32.7
`Geometric CV%
`SC MTXAI (abdomen and thigh, n=96)
`138.69 (46.477)
`3.887 (0.7017)
`Mean (SD)
`20.222 (7.1509)
`33.5
`18.1
`CV%
`35.4
`131.72
`–129.38
`Geometric mean
`19.081
`32.8
`–31.9
`Geometric CV%
`35.1
`λz, apparent terminal rate constant; AUC0–24, area under the concentration versus time curve from 0 to 24 h; AUC0–inf, area under the concentration versus time curve from time 0 to
`infinity; Cmax, maximum observed concentration; CV%, coefficient of variation percentage; MTX, methotrexate; MTXAI, methotrexate auto-injector; PK, pharmacokinetic; t½, terminal
`half-life; tmax, time to reach maximum observed concentration.
`
`109.47 (39.190)
`35.8
`103.23
`35.3
`
`107.64 (37.732)
`35.1
`
`135.87 (44.274)
`32.6
`
`1.388 (0.8378)
`60.4
`–
`
`0.188 (0.0333)
`17.7
`–
`
`–
`
`–
`
`3.804 (0.6574)
`17.3
`–101.73
`–34.6
`
`1.523 (0.9175)
`60.3
`–
`
`0.184 (0.0331)
`18.0
`–
`
`–
`
`–
`
`Safety
`Treatments in both the oral MTX and SC MTX arms were gen-
`erally safe and well tolerated. No new treatment-related safety
`signals were identified within the study (see online supplemen-
`tary table 2).
`
`DISCUSSION
`Prior PK studies comparing oral to parenteral MTX mostly
`tested MTX dosed in mg/m2 and never clearly established a con-
`tinuum of bioavailability over the range of commonly used oral
`doses.4 The current study is the first to compare bioavailability
`across commonly prescribed doses of oral and SC MTX and
`raises the possibility that there is no advantage to increasing the
`oral MTX dose above 15 mg/week, a common clinical practice.
`Subcutaneous MTX exhibited a
`linear, dose-proportional
`increase in exposure with no plateau. At each dose level, SC
`administration achieved higher MTX exposure than the compar-
`able oral dose and continued to increase through doses of 25 mg/
`week. Potential confounders of the comparison of dosage forms
`were minimised by the random sequence crossover design. No
`increases in AEs were observed with SC MTX. These findings
`suggest that the SC administration may overcome some of the
`
`Figure 1 Mean±SEM AUC by MTX dose. Mean oral MTX exposure
`plateaus at doses ≥15 mg/week. AUC, area under the concentration
`versus time curve; MTX, methotrexate; SC, subcutaneous; SEM, SE of
`the mean.
`
`limitations of oral MTX and allow for optimisation of MTX in
`the treatment of RA as defined in treatment guidelines.1 2
`
`Acknowledgements All authors designed the study, interpreted the results, made
`a substantial contribution to the information submitted for publication, and have
`read and approved the final manuscript. Antares Pharma Inc participated in study
`design, execution and interpretation of the analysis, preparation of the manuscript
`and decision to submit the manuscript.
`Funding Medical writing services were funded by Antares Pharma Inc, Ewing,
`NJ, USA.
`Competing interests MHS is a consultant for Antares Pharma Inc. JSJ and BF are
`employees of Antares Pharma Inc.
`Ethics approval Institutional Review Board.
`Provenance and peer review Not commissioned; externally peer reviewed.
`Open Access This is an Open Access article distributed in accordance with the
`Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which
`permits others to distribute, remix, adapt, build upon this work non-commercially,
`and license their derivative works on different terms, provided the original work is
`properly cited and the use is non-commercial. See: http://creativecommons.org/
`licenses/by-nc/3.0/
`
`2
`
`3
`
`4
`
`5
`
`REFERENCES
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`6 Wegrzyn J, Adeleine P, Miossec P. Better efficacy of methotrexate given by
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`Schiff MH, et al. Ann Rheum Dis 2014;73:1549–1551. doi:10.1136/annrheumdis-2014-205228
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`
`Head-to-head, randomised, crossover study
`of oral versus subcutaneous methotrexate
`in patients with rheumatoid arthritis:
`drug-exposure limitations of oral
` 15‡methotrexate at doses
`
`mg may be
`
`administrationovercome with subcutaneous
`Michael H Schiff, Jonathan S Jaffe and Bruce Freundlich
`
`Ann Rheum Dis
`12, 2014
`doi: 10.1136/annrheumdis-2014-205228
`
` 2014 73: 1549-1551 originally published online April
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`References
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`This article cites 7 articles, 4 of which can be accessed free at:
`http://ard.bmj.com/content/73/8/1549.full.html#ref-list-1
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`Open Access
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`license, which permits others to distribute, remix, adapt, build upon this
`work non-commercially, and license their derivative works on different
`terms, provided the original work is properly cited and the use is
`non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
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