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Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 11, November 2008, pp 3299–3308
DOI 10.1002/art.24034
© 2008, American College of Rheumatology
Pharmacokinetics of Oral Methotrexate in Patients With
Rheumatoid Arthritis
Judith M. Dalrymple, Lisa K. Stamp, John L. O’Donnell, Peter T. Chapman, Mei Zhang,
and Murray L. Barclay
Objective. There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu)
concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of
MTXGlu1–5 is required for optimal timing of blood
sampling. The aim of this study was to determine the
time to steady state and the half-life of accumulation
of red blood cell (RBC) MTXGlu1–5 in patients with
RA commencing oral MTX, and the time for RBC
MTXGlu1–5 to become undetectable and the half-life of
elimination of RBC MTXGlu1–5 in patients ceasing
treatment with oral MTX.
Methods. Ten patients beginning treatment and
10 patients stopping treatment with low-dose oral MTX
were recruited. Blood samples were initially collected
weekly, with gradual extension to monthly collection
over the study period. RBC MTXGlu1–5 concentrations
were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method.
Results. The median times to reach steady state in
RBCs (defined as 90% of the maximum concentration)
were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively,
for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and
MTXGlu5. The median half-life of accumulation for
RBC MTXGlu1–5 ranged from 1.9 weeks to 45.2 weeks.
The median times for MTXGlus to become undetectable
in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively,
for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and
MTXGlu5. The median half-life of elimination for RBC
MTXGlu1–5 ranged from 1.2 weeks to 4.3 weeks.
Conclusion. There is wide interpatient variability
of RBC MTXGlu1–5 accumulation and elimination in
adults with RA. These data also suggest that after a dose
change, >6 months are required for RBC MTXGlu1–5 to
reach steady state. Such delays in achieving steady state
suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.
Methotrexate (MTX) is one of the most commonly used disease-modifying antirheumatic drugs
(DMARDs). It is the first-line agent for the treatment of
rheumatoid arthritis (RA) (1,2) and is suggested to be
the “anchor” drug in all RA therapy (3,4).
Joint damage occurs early in the course of RA
(5,6) and once present is largely irreversible. Disease
activity is an important predictor of the progression of
joint damage (7,8) and the long-term requirement for
joint-replacement surgery (9). Effective control of RA
disease activity reduces radiographic progression of joint
damage and improves physical function and quality of
life (10–12). Thus, the primary goal of therapy is to
achieve rapid, effective disease control to prevent the
long-term damaging effects on joint structure and function.
Serum concentrations of MTX fall rapidly following intravenous administration (13). However, MTX is
transported intracellularly via the reduced folate carrier
and is retained within cells long after it has been
eliminated from serum. The parent drug contains 1 glutamate moiety and is also known as MTX glutamate 1
(MTXGlu1). Once inside red blood cells (RBCs), up to
ACTRN: 012606000275561.
Supported by the Health Research Council of New Zealand,
the New Zealand Pharmacy and Education Research Foundation,
Arthritis New Zealand, and the Canterbury Rheumatology and Immunology Research Trust.
Judith M. Dalrymple, BPharm, Grad Dip Clin Pharm, Lisa K.
Stamp, MBChB, FRACP, PhD, John L. O’Donnell, MBChB, FRACP,
FRCPA, Peter T. Chapman, MBChB, MD, FRACP, Mei Zhang, PhD,
Murray L. Barclay, MBChB, MD, FRACP: University of Otago,
Christchurch, New Zealand.
Address correspondence and reprint requests to Lisa K.
Stamp, MBChB, FRACP, PhD, Department of Medicine, University
of Otago, PO Box 4345, Christchurch 8140, New Zealand. E-mail:
lisa.stamp@cdhb.govt.nz.
Submitted for publication March 26, 2008; accepted in revised
form August 11, 2008.
3299
3300
4 additional glutamate moieties are added via the enzyme folylpolyglutamate synthetase (FPGS) (14). As a
group, these products of intracellular glutamation are
referred to as MTXGlun, where n represents the number
of glutamate moieties. Gamma-glutamyl hydrolase removes terminal glutamate molecules, returning MTX to
its monoglutamate form, which is rapidly transported
out of the cell by multidrug-resistant proteins. MTXGlus
can be measured inside RBCs, and concentrations
within RBCs are thought to be representative of concentrations within other cells such as lymphocytes.
The mechanism of action of MTX in RA is
unclear, but it appears to act as a folate antagonist (15).
Intracellular MTXGlun bind to dihydrofolate reductase
and other folate pathway enzymes, thereby providing
antiinflammatory effects.
The dose of MTX required for treatment of
individual patients with RA varies and is largely unpredictable. In patients with RA, both a trend toward a
dose-response relationship (16,17) and no association
between dose and response have been reported with oral
MTX (18). Serum MTX concentrations have been
shown to have no correlation with disease activity (19).
However, recent studies suggest a correlation between
RBC MTXGlun concentrations and disease activity
(18,20,21). The first of these studies in 65 patients with
RA showed that RBC MTXGlu1–5 concentrations were
significantly higher in responders (mean ⫾ SD 60.7 ⫾
18.9 nmoles/liter) and partial responders (50.8 ⫾ 23.3
nmoles/liter) to treatment than in nonresponders
(21.5 ⫾ 10.5 nmoles/liter) (20). The initial study by
Dervieux and colleagues (18) of 108 patients was then
extended to 226 patients (21), and patients with RBC
MTXGlu3 levels ⬍60 nmoles/liter were more likely to
have a poor clinical response. In addition, in a small
group of 23 patients commencing MTX treatment, a
higher RBC MTXGlu3 concentration at 3 months was
associated with a greater chance of better disease control at 6 months (22).
If MTXGlun drug concentrations are relevant to
the clinical response, then the time required for adequate drug concentrations to be achieved in patients
starting treatment with MTX is important. In New
Zealand, treatment of patients with RA generally begins
with oral MTX at a dosage of 7.5–10 mg/week, with dose
escalations made according to the clinical response. In
comparison, patients with inflammatory bowel disease
are started on a dosage of 25 mg/week, administered
subcutaneously. With the slower dosing strategy, valuable time to achieve adequate disease control may be
lost depending on the time required for adequate drug
DALRYMPLE ET AL
concentrations to be achieved. Currently, the accumulation and elimination rates of RBC MTX polyglutamates
are poorly defined. There are no data describing the
rate of accumulation of individual MTXGlun in human
RBCs, and only limited data are available describing
the rate of elimination of individual RBC MTXGlun in
children (23).
The aims of this study were to determine the time
to steady state of RBC MTXGlu1–5 in adult patients with
RA starting treatment with oral low-dose MTX and the
length of time required for MTXGlu1–5 to become
undetectable in the RBCs of adult patients with RA who
are stopping treatment with low-dose oral MTX. Finally,
we aimed to determine the half-life of accumulation and
elimination of RBC MTXGlu1–5 in adult patients with
RA.
PATIENTS AND METHODS
Ethical approval was obtained from the Upper South B
Regional Ethics Committee. Patients ages 18 years and older
with RA, as defined by the American College of Rheumatology (ACR; formerly, the American Rheumatism Association)
1987 revised criteria for the classification of RA (24), who
began or stopped treatment with oral MTX between October
2005 and October 2007 were invited to participate. Patients
stopping MTX were included only if they had been taking
MTX for at least 3 months, with a stable dosage for at least 1
month.
Baseline demographic data were collected for all patients, including ethnicity, sex, age, height and weight, duration
of RA, presence of rheumatoid factor, radiographic erosions
and rheumatoid nodules, and serum creatinine. An estimated
glomerular filtration rate from serum creatinine was calculated
according to the equation described by the Modification of
Diet in Renal Disease Study Group (25). Patients were seen at
weeks 8, 16, and 24, and a record of each patient’s current drug
therapy was obtained. In patients starting treatment, standard
MTX toxicity monitoring was undertaken, according to the
ACR recommendations.
Blood sampling strategy. Blood samples for RBC
MTXGlu1–5 assays were obtained within 36 hours prior to
administration of the weekly MTX dose (i.e., a trough concentration). In patients starting MTX treatment, samples were
collected weekly until week 8, then fortnightly until the MTX
dose had been titrated to the clinically effective dose. Thereafter, blood samples were drawn every 4 weeks until 24 weeks
after reaching the maintenance dose, or until the patient
withdrew from the study. In those patients stopping MTX,
samples were collected weekly for 8 weeks, then fortnightly for
8 weeks, and then every 4 weeks for 24–32 weeks after
treatment with MTX ceased.
High-performance liquid chromatography (HPLC) of
RBC MTXGlun. A 5-ml whole-blood sample was collected in
an EDTA-coated tube and centrifuged to isolate the RBCs.
The RBCs were washed twice in 2 volumes of saline and
centrifuged at 1,250g for 5 minutes. The washed RBCs were
MTX PHARMACOKINETICS
counted to normalize MTXGlu1–5 concentrations to 8 ⫻ 1012
RBCs, so that results were comparable and not confounded by
changes in the RBC count between patients and between visits.
The concentrations of MTXGlun in RBCs were analyzed by
HPLC with fluorescence detection, using a modification of a
previously described method (26,27). All samples were analyzed in duplicate, and the mean concentration of each RBC
MTXGlun concentration from each sample was used in the
analysis.
MTXGlu terminology. MTX, the parent drug, contains
1 glutamate moiety and will be referred to as MTXGlu1. The
products of intracellular glutamation are referred to as
MTXGlu2–5. The sum of concentrations of MTXGlu1 and its
glutamated intracellular metabolites (RBC MTXGlu2–5) will
be referred to as RBC MTXtotal. The MTXtotal concentration
was not measured directly but was calculated as the sum of
each RBC MTXGlun concentration, where n refers to the
number of glutamate groups.
Pharmacokinetics analysis. MTXGlun concentrations
were graphed and analyzed using GraphPad Prism 4 software
(San Diego, CA). A first-order exponential model was fitted to
the data to calculate a half-life of accumulation, starting from
the time of the final dose adjustment or from the start of
therapy if there was no dose adjustment. Using the accumulation rate constant in the first-order exponential model, as
calculated in Prism 4, the time for each RBC MTXGlun
concentration to reach 90% of the modeled maximum concentration was calculated, and this was reported as the time to
reach steady state.
In patients stopping MTX, the time for each RBC
MTXGlun concentration to become undetectable in RBCs for
individual patients was reported directly from the raw data as
the time when the concentration was below the limit of
quantification (LOQ) for the assay. A median time for each
RBC MTXGlun concentration to reach undetectable concentrations was then calculated. MTXGlun concentrations were
fitted to a first-order exponential model in GraphPad Prism 4
to calculate the terminal half-life of elimination for each
MTXGlun concentration. The model was applied using the
data points from the time when a steady decline in the
concentrations could be observed. Several patients had very
low concentrations of MTXGlu4–5 from the time they ceased
MTX treatment. To increase the ability to calculate the
elimination half-life, raw values for MTXGlu1–5 were used,
even when such values were below the LOQ. The half-lives of
accumulation and elimination for MTXtotal were calculated
using a first-order exponential method, as described for the
individual MTXGlun concentrations.
For each data-fitting analysis described above, the
coefficient of determination (R2) was calculated using GraphPad Prism 4 software for the nonlinear regression aspect of the
modeling. When the R2 value was ⬍0.7, the results were
excluded from the values for calculation of the median half-lives
of accumulation, because it was considered that these regression
analysis results were too inaccurate to be meaningful.
RESULTS
Demographics. The demographic details for the
10 patients starting MTX treatment and the 10 patients
3301
Table 1. Baseline demographic characteristics of patients starting
oral MTX and patients stopping oral MTX*
Characteristic
Female sex
New Zealand European
ethnicity
Age, median (range) years
Height, median (range) cm
Weight, median (range) kg
Estimated creatinine clearance,
median (range) ml/minute
Duration of RA, median (range)
months
Rheumatoid factor positive
Radiographic erosions
Rheumatoid nodules
Starting MTX
(n ⫽ 10)
Stopping MTX
(n ⫽ 10)
60
90
60
100
60 (42–72)
173.0 (158–182)
76.5 (50–110)
73.0 (54–84)
59 (43–68)
168.5 (158–186)
70.0 (46–88)
78.0 (57–93)
34.0 (2–216)
132.0 (3.5–480)
90
60
10
60
70
50
* Except where indicated otherwise, values are the percent. MTX ⫽
methotrexate; RA ⫽ rheumatoid arthritis.
stopping MTX treatment are shown in Table 1. Of the
10 patients starting MTX, 4 were receiving another
DMARD (2 were receiving sulfasalazine, and 2 were
receiving sulfasalazine plus hydroxychloroquine). Eight
patients were receiving a nonsteroidal antiinflammatory
drug, and 5 were receiving prednisone. Of the 10 patients stopping MTX, 5 were receiving another DMARD
(4 were receiving leflunomide, and 1 was receiving
sulfasalazine). Eight patients were receiving a nonsteroidal antiinflammatory drug, and 3 were receiving prednisone.
Time for RBC MTXGlun to become detectable in
patients starting MTX. Patients commenced treatment
with oral MTX at a median dosage of 10 mg/week (range
5–10 mg/week). The MTX dosage was titrated according
to the clinical response to a median dosage of 15 mg/week
(range 10–20 mg/week). The final dose of MTX was 10 mg
in 2 patients, 12.5 mg in 2 patients, 15 mg in 3 patients,
and 20 mg in 3 patients. The dosage of MTX was stable
for a median of 28 weeks (range 18–32 weeks). Patients
remained in the study for a median of 40 weeks (range
24–48 weeks). All patients received folic acid at a dosage
of 5 mg/week, 3–4 days after the dose of MTX was
administered.
In 9 of 10 patients, MTXGlu1 was detectable in
RBCs 1–2 weeks following administration of the first
dose of MTX. MTXGlu2 was detectable in RBCs at a
median of 2 weeks (range 1–4 weeks) after commencement of MTX treatment. In 9 patients, MTXGlu3 was
detectable in RBCs at a median of 3 weeks (range 1–5
weeks) after commencing MTX. In 9 patients, concentrations of RBC MTXGlu4 were detectable after a
median of 8 weeks (range 1–28 weeks). One patient had
3302
DALRYMPLE ET AL
Figure 1. Concentration-time profiles for each red blood cell methotrexate polyglutamate moiety (RBC MTXGlun) and MTXtotal (the
sum of concentrations of MTXGlu1 and its glutamated intracellular metabolites) for a patient with no dose changes. The line is fitted to
a nonlinear exponential accumulation (first-order) model as calculated using GraphPad Prism 4 software. Broken lines indicate the limit
of quantification of the assay.
no detectable RBC MTXGlu5 at any time during the
first 40 weeks of MTX therapy. In the remaining 9
patients, MTXGlu5 was detectable after a median of 7
weeks (range 1–28 weeks).
Accumulation of RBC MTXGlun in patients
starting MTX. Figure 1 shows a representative
concentration-time profile for MTXGlun in a patient
commencing MTX treatment who had no dose changes
for the duration of the study. The dose of MTX was
unchanged during the study in only 2 patients. The other
8 patients had at least 1 dose alteration during the study
period. Figure 2 shows a representative concentrationtime profile for a patient commencing MTX in whom
the dose was changed during the study period.
Some of the concentration-time data fit the firstorder exponential model poorly, in which case GraphPad Prism 4 calculated an R2 value ⬍0.7 or the R2 value
could not be calculated using a first-order exponential
model. There were 10 such sets of concentration-time
data among the total of 50. These results were then
excluded from the calculation of the median times to
reach steady state and half-lives of accumulation. The
medians of the time to reach steady state for the
remaining MTXGlun concentration data are presented
in Table 2.
The estimated median half-life of accumulation
of RBC MTXtotal was 8.3 weeks (range 2.0–18.8 weeks).
Following administration of a stable dose of MTX, the
median time until 90% of the maximum steady-state
concentration was reached was 27.5 weeks (range 6.6–
62.0 weeks). The mean rates of accumulation and final
MTXGlun concentrations were no different in those
patients receiving sulfasalazine compared with those
who were not receiving sulfasalazine.
Effect of age and renal function on accumulation
of RBC MTXGlun. Increasing age and impaired renal
function did not correlate significantly with higher final
concentrations for individual RBC MTXGlun or MTXGlutotal in RBCs. This analysis was undertaken using
concentrations corrected for the individual participant’s
final dose and weight, to help eliminate confounding
factors.
Variability and proportions of RBC MTXGlu1–5
in patients starting MTX. At the last visit, the range of
RBC MTXtotal concentrations in patients starting MTX
treatment was ⬃4-fold (90.9–351.5 nmoles/8 ⫻ 1012
RBCs). At the final visit, mean concentrations of MTXGlu1 accounted for 25% of MTXtotal, with MTXGlu2
accounting for 21%, MTXGlu3 accounting for 37%,
MTXGlu4 accounting for 11%, and MTXGlu5 account-
MTX PHARMACOKINETICS
3303
Figure 2. Concentration-time profiles of RBC MTXGlun and MTXtotal for a patient who commenced MTX treatment at a dosage of 10
mg/week (week 0), with an increase in the dosage to 15 mg/week at week 8 and 20 mg/week at week 12 (dose changes are indicated by the
dotted lines). The line is fitted to a nonlinear exponential accumulation (first-order) model as calculated using GraphPad Prism 4 software
from the time at which the patient received the final stable dose. See Figure 1 for definitions.
ing for 6%. These proportions are similar to those
reported in other studies described in the literature
(23,26).
RBC MTXGlun elimination in patients stopping
MTX treatment. At the time of discontinuing MTX, the
median dosage was 12.5 mg/week (range 7.5–20 mg/
week). Patients had been receiving a stable dosage of
MTX for a median of 17 months (range 1.5–120
months). MTX was discontinued for a variety of reasons,
Table 2. Estimated accumulation half-life and time to reach steady
state after the final stable dose of MTX*
MTXGlu1
MTXGlu2
MTXGlu3
MTXGlu4
MTXGlu5
No. of
patients
Accumulation
half-life, weeks
7†
10
10
6‡
4§
1.9 (0.0–4.2)
3.2 (2.1–23.4)
12.5 (6.0–20.2)
45.2 (4.9–252.1)
42.4 (4.7–80)
Time to reach
steady state, weeks
6.2 (0.0–13.9)
10.6 (7.0–77.2)
41.2 (19.8–66.7)
149 (16.2–831.6)
139.8 (15.5–264.0)
* Values are the median (range). Steady state was defined as 90% of
the maximum concentration. MTXGlu ⫽ methotrexate polyglutamate.
† Three patients were excluded because R2 ⬍ 0.7.
‡ Four patients were excluded because R2 ⬍ 0.7.
§ Four patients were excluded because R2 ⬍ 0.7, 1 was excluded
because MTXGlu5 was undetectable, and 1 was excluded because the
data did not fit a first-order exponential model.
including adverse effects, lack of efficacy, quiescent
disease, and concurrent infection.
A representative concentration-time profile from
1 patient stopping MTX is shown in Figure 3. In all 10
patients, MTXGlu 1 became undetectable before
MTXGlu2–5 became undetectable. With the exception of
MTXGlu1, there was generally a lag time before a steady
decline was observed in the MTXGlun concentrations.
This lag time generally increased as the number of
glutamate moieties increased. Although there was variation in the pattern of MTXGlu2–5 loss from RBCs,
MTXGlu3–5 persisted in circulating RBCs longer than
MTXGlu1–2.
Time for RBC MTXGlun to become undetectable and half-life of elimination. The median times
until each RBC MTXGlun became undetectable in
patients stopping MTX are shown in Table 3. The first
time point used for modeling to calculate the half-life
of elimination for each patient was taken as the time
when a consistent decrease in the MTXGlun concentration was observed. This terminal elimination halflife was then calculated using the first-order exponential model in GraphPad Prism 4. Some of the data fit
this model poorly. Where GraphPad Prism 4 calculated an R2 value ⬍0.7, these results were excluded
3304
DALRYMPLE ET AL
Figure 3. RBC MTXGlun and MTXtotal concentration-time profiles for a participant stopping MTX. The line is fitted to a nonlinear
elimination (first-order) model as calculated using GraphPad Prism 4 software. Broken lines indicate the limit of quantification. See Figure
1 for definitions.
from the calculation of the median elimination halflife for the individual MTXGlun concentration, because it was considered that the fitted model results
were too inaccurate for meaningful further analysis.
There were 6 such sets of concentration-time data
among a total of 50.
The estimated median half-life of elimination of
RBC MTXtotal was 3.1 weeks (range 0.94–4.1 weeks).
Table 3. Time until each RBC MTXGlu concentration was undetectable, and elimination half-life*
MTXGlu1
MTXGlu2
MTXGlu3
MTXGlu4
MTXGlu5
Time until
undetectable,
weeks
No. of
patients
Elimination
half-life,
weeks
No. of
patients
4.5 (2–14)
5.5 (3–32)
10 (2–⬎21)
6 (2–⬎21)
4 (2–10)
10
10
10
9‡
5¶
1.2
2.3
4.3
2.7
2.1
9†
9†
10
6§
4#
* Values are the median (range).
† One patient was excluded because R2 ⬍ 0.7.
‡ One patient was excluded because no red blood cell methotrexate
polyglutamate 4 (RBC MTXGlu4) was detectable.
§ Three patients were excluded because R2 ⬍ 0.7, and 1 was excluded
because no RBC MTXGlu4 was detectable.
¶ Five patients were excluded because no RBC MTXGlu5 was detectable.
# One patient was excluded because R2 ⬍ 0.7, and 5 were excluded
because no MTXGlu5 was detectable.
The median time until RBC MTXtotal was undetectable
was 15 weeks (range 3–⬎32 weeks) from the time MTX
treatment was ceased.
Effect of age and renal function on MTXGlun.
Increasing age did not correlate significantly with higher
initial concentrations of each MTXGlun or MTXtotal in
RBCs. However, impaired renal function did correlate
with higher initial concentrations of RBC MTXGlu2,
RBC MTXGlu3, and RBC MTXGlutotal. This analysis
was undertaken using concentrations corrected for the
individual participant’s final dose and weight, to reduce
confounding factors.
Variability and proportions of RBC MTXGlu1–5
in patients stopping MTX treatment. The range of RBC
MTXtotal concentrations at the first visit in patients
stopping MTX was ⬃5-fold (48.5–242.3 nmoles/8 ⫻ 1012
RBCs). At the initial visit, the mean concentration of
MTXGlu1 accounted for 26% of the MTXtotal, with
MTXGlu2 accounting for 28%, MTXGlu3 accounting
for 30%, MTXGlu4 accounting for 11%, and MTXGlu5
accounting for 5%.
DISCUSSION
Weekly oral administration of low-dose MTX is
the mainstay of treatment for RA. Despite the wide-
MTX PHARMACOKINETICS
spread use of MTX, the understanding of its mechanism
of action and pharmacokinetics remains limited. After
ingestion, MTX is rapidly taken up into a variety of cells,
including RBCs. Within the cell, MTXGlun bind to and
inhibit several important enzymes, including dihydrofolate reductase (which leads to decreased DNA methylation), thymidylate synthase (which interferes with DNA
synthesis), and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (which increases adenosine
release into the circulation, ultimately inhibiting tumor
necrosis factor ␣ and interleukin-1␤). Thus, MTX has
several important antiinflammatory actions mediated
through a variety of different pathways. The rapid
intracellular uptake of MTX and short plasma half-life
of the parent drug mean that plasma concentrations
are unable to be used for therapeutic drug monitoring.
However, RBCs are a readily accessible source for
measuring intracellular MTXGlun concentrations.
To date, there are limited data regarding the
accumulation and elimination of MTXGlun. We have
shown that after oral ingestion, the parent drug MTXGlu1 is detectable in circulating RBCs 1–2 weeks after
administration of the first dose. The data presented
herein suggest a progressive accumulation of MTXGlu2–5,
starting with MTXGlu2 (which generally is present after
2 weeks), and subsequently MTXGlu3 (which is present
after 3 weeks), MTXGlu4 (present after a median of 8
weeks), and finally MTXGlu5 (present after a median of
7 weeks). This sequential accumulation occurs at least in
part because RBC MTXGlu2–5 are produced intracellularly and therefore require MTXGlu1 to be present
before MTXGlu2 and the other polyglutamates can be
produced. Our observation that production of MTXGlu2–5
is delayed and progressive may be explained partly by
the fact that glutamation of MTXGlun is a slow reaction.
Although the longer-chain polyglutamates
(MTXGlu3–5) were detectable within 3–8 weeks, the
period of time until steady state was achieved was
significantly longer. From a clinical perspective, a response to MTX usually occurs within the first 6–12
weeks after initiation of therapy, with a maximal response observed at 6 months (28,29). This suggests that
the longer-chain polyglutamates, which take longer to
become detectable and reach steady state, may have a
more important role in the clinical response compared
with the shorter-chain polyglutamates.
These data beg the question as to whether a more
rapid attainment of steady state MTXGlun concentrations and a clinical response could be achieved with
alternative dosing strategies. Such a strategy might include more rapid dose escalation or starting therapy with
3305
higher doses. However, high doses have lower associated
oral availability (30). In addition, starting with higher
oral doses may result in discontinuation due to adverse
events such as nausea. Alternatively, MTX can be administered by the subcutaneous or intramuscular route,
resulting in improved bioavailability (30). In a recent
study, subcutaneous administration of MTX was associated with a significantly improved response at 24 weeks
as compared with oral administration (31). It would be
of interest to know whether the observed improved
clinical response seen with subcutaneous administration
occurred at an earlier time point compared with oral
administration.
The proportion of individual RBC MTXGlu concentrations at steady state in this study is similar to that
in other studies, with MTXGlu3 accounting for the
largest portion (30% of MTXGlutotal) and MTXGlu5
accounting for the smallest proportion (⬃5% of MTXGlutotal) (23,26,32). Interestingly, some patients starting
MTX had no detectable RBC MTXGlu5 at any time
during the study. Further larger studies are required to
determine whether this lack of MTXGlu5 has any effect
on the clinical response.
Upon discontinuation of oral MTX, the loss of
MTXGlu1 from RBCs is relatively rapid. In contrast,
there is a lag time before initiation of the loss of the
other MTXGlun (MTXGlu2–5). This is similar to the
pattern of elimination observed in children with acute
lymphoblastic leukemia who discontinued oral MTX
(16.8–21.4 mg/m2/week) after 3 years of therapy (23).
This delay before loss of MTXGlu2–5 may have 2
contributing factors. First, each MTXGlun may be
present in immature RBCs (reticulocytes) that continue
to enter the circulation after MTX dosing has ceased.
Second, progressive metabolism from the parent drug to
MTXGlu2, then MTXGlu3, then MTXGlu4, and finally
MTXGlu5 may continue intracellularly even after MTX
dosing has ceased. This predisposes to earlier loss of
shorter-chain MTXGlu1–2 in comparison with MTXGlu3–5.
It has been suggested that once MTX enters the
RBC, a proportion does not efflux and persists for the
life of the RBC. The human RBC has a lifespan in adults
of ⬃110–120 days. Two studies of RBC MTXGlu1–5
concentrations suggest that the portion that persists in
the RBC consists of MTXGlu3–5 (32,33). The initial
elimination appears predominantly due to RBC loss of
MTXGlu1 and MTXGlu2. This is followed by a slower
elimination of MTXGlu3–5, suggesting that this phase
in elimination is determined by the lifespan of RBCs
plus the dilutional effect of new RBCs that do not
contain MTX being released into the circulation (32,33).
3306
Schroder suggests that the concentrations of MTXGlu3–5
did not change in more mature RBCs, because the
activity of intraerythrocytic enzymes declines as the cells
age. However, there is no direct evidence showing that
mature RBCs lack the enzyme FPGS or ␥-glutamyl
hydrolase.
RBC MTXGlu3 was often the last MTXGlun to
be eliminated from RBCs. This may simply be because it
starts at the highest concentration compared with the
other MTXGlun rather than having different elimination
kinetics. It may also be attributable to the rate of
conversion from RBC MTXGlu3 to the longer-chain
polyglutamates being slower than the rate of transformation from RBC MTXGlu1 to MTXGlu2 and subsequently to MTXGlu3.
When MTXGlu1, MTXGlu2, and MTXGlu3 are
compared, the estimated half-life of elimination of each
increased with the greater number of glutamate residues. However, this pattern did not extend to MTXGlu4
and MTXGlu5. The sensitivity of the assay may have
been a limiting factor in calculating an accurate elimination half-life for MTXGlu4 and MTXGlu5, which were
not present in high concentrations in the majority of
patients.
Drugs that accumulate and are eliminated by
simple first-order pharmacokinetic mechanisms usually
accumulate and are eliminated at approximately the
same rate. The data from this study suggest that the
median rate of elimination of each RBC MTXGlun is
more rapid than the median rate of accumulation. This
may be related to the RBC lifespan. The gradual loss of
RBCs from the circulation, combined with the ongoing
production of new RBCs, provides a “dilutional effect”
when MTX dosing is ceased. The RBC lifespan may also
contribute to the delay in achieving steady state, although this is less clear from the data presented here. If
it were only “young” RBCs that have intact mechanisms
for metabolizing MTXGlu1 to MTXGlu2–5, this might
explain the delay to steady state while waiting for the
generations of young cells to move through to maturity.
Previous studies have demonstrated an approximate half-life of elimination of RBC MTXtotal of 2
weeks to 11.3 weeks (23,32,34). In comparison, the
half-life of elimination in our population ranged from
0.9 week to 13.3 weeks. The time for RBC MTXtotal
concentrations to become undetectable has been reported to be within 15 weeks of stopping MTX (23,35).
In comparison, we have shown that RBC MTXtotal
concentrations became undetectable after anywhere
from 3 weeks to more than 32 weeks. At least some of
this difference might be attributable to differences in the
DALRYMPLE ET AL
populations studied. The previous studies involved either children, in whom one can expect pharmacokinetic
differences due to age, or adults with solid tumors, in
whom much higher dosing regimens are utilized.
The long elimination period appears to be inconsistent with the period of time until a disease flare occurs
after stopping MTX (frequently within 1 month) (36).
The long duration of elimination has implications for
discontinuation of MTX prior to surgery, conception,
and in the face of concomitant infection. Although newly
produced cells will not be exposed to MTX, existing cells
will clearly continue to be affected by MTX for a
considerable length of time.
There was significant interpatient variability in
the measured concentrations of RBC MTXGlun. This
variation was not explained by age. A correlation between
renal impairment and an increased RBC MTXGlun concentration is suggested, but further study in a larger
population is required to substantiate this finding.
There are some limitations of our study design,
including the small sample size. The low number of
participants means that these results cannot be extrapolated to all patients taking MTX, particularly given the
variability displayed. The results also suggest that participants stopping MTX should have been included only
after receiving a stable dosage of MTX for at least 6
months. Three of the participants included in this study
had been receiving their current MTX dosage for fewer
than 6 months. Furthermore, 2 patients had been receiving MTX therapy for fewer than 6 months in total. This
limited our ability to calculate the rate of elimination
and observe the time to undetectable concentrations of
each RBC MTXGlun in some patients, because it is
unlikely that concentrations were at steady state before
ceasing MTX. The planned analysis was based on the
expectation that first-order pharmacokinetics were likely
to explain the accumulation and elimination of RBC
MTXGlun. This appears reasonable for MTXGlu1.
However, the concentration-time profiles for MTXGlu2–5
accumulation and elimination suggest that a more complex analysis is required.
Although we acknowledge the limitations of this
analysis, these data provide a substantial increase in our
understanding of RBC MTXGlun accumulation and
elimination. However, the variability in time until RBC
MTXGlu3–5 concentrations reach steady state after initiation and dose adjustment may limit the clinical usefulness of RBC MTXGlu1–5 as a therapeutic monitoring
tool in clinical practice. If RBC MTXGlun concentrations correlate with MTX efficacy, consideration of
subcutaneous administration from the onset of treat-
MTX PHARMACOKINETICS
ment or rapid oral dose escalation to reduce the length
of time to steady state may be required.
3307
11.
ACKNOWLEDGMENTS
We gratefully acknowledge the assistance of Jill James,
Rheumatology Research Nurse, and Jan Ipenburg, Rheumatology Clinical Nurse Specialist, in assisting with patient data
collection.
AUTHOR CONTRIBUTIONS
Dr. Stamp had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Dalrymple, Stamp, O’Donnell, Chapman, Barclay.
Acquisition of data. Dalrymple, Stamp, O’Donnell.
Analysis and interpretation of data. Dalrymple, Stamp, Chapman,
Zhang, Barclay.
Manuscript preparation. Dalrymple, Stamp, O’Donnell, Chapman,
Zhang, Barclay.
Statistical analysis. Dalrymple, Barclay.
Development and validation of HPLC assay. Zhang.
12.
13.
14.
15.
16.
17.
18.
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