Download Potential for methotrexate exposure through contamination during

Internal Medicine Journal 39 (2009) 379–383
O R I G I N A L A RT I C L E
Potential for methotrexate exposure through contamination
during parenteral use as an immunosuppressant
imj_1716
379..383
L. S. Wong,1,2 K. E. Tymms2,3 and N. A. Buckley1,3
Departments of 1Clinical Pharmacology and Toxicology and 2Rheumatology, Canberra Hospital and 3Medical School, Australian National University,
Canberra, Australian Capital Territory, Australia
Key words
methotrexate, skin contamination, handling
precautions, rheumatoid arthritis, toxicity.
Correspondence
Ling S. Wong, GPO Box 1194, Canberra,
ACT 2601, Australia.
Email: [email protected]
Received 22 January 2008; accepted
31 March 2008.
doi:10.1111/j.1445-5994.2008.01716.x
Abstract
Background: To evaluate whether the risk of methotrexate (MTX) exposure
through skin contamination using parenteral doses of 25 mg warrants special
oncology handling precautions during administration.
Methods: We conducted a study with six human volunteers deliberately
exposed to an entire dose of 25 mg MTX solution on their skin for 30 min.
Serum levels of MTX were measured at baseline, 2, 4, 8, 12 and 24 h as well
as serum homocysteine at baseline and 24 h after clinical exposure. Twentyfour-hour urinary excretion of MTX and possible local or systemic signs of
toxicity were also recorded.
Results: All MTX serum concentrations were less than 0.02 mmol/L within
the 24-h period. This is 500 times below the recommended serum concentration for which folinic acid supplementation is recommended. There was also
no significant increase in homocysteine level to suggest MTX toxicity. The only
adverse effects were mild local dermal reactions in three female volunteers.
Conclusion: Deliberate skin contamination and possible inhalation of a
25 mg MTX solution failed to show significant or quantifiable serum and urine
concentrations to suggest MTX toxicity. Precautions to prevent contact with
MTX designed for oncology protocols are unnecessary for our rheumatology
patients or their carers using these much lower immunosuppressant doses for
autoimmune diseases.
Introduction
Methotrexate (MTX) was initially introduced as a cytotoxic drug in high doses (1000–5000 mg/day) as chemotherapy treatment for various malignancies. MTX is also
the most commonly used disease-modifying drug in
rheumatoid arthritis, but at much lower dosage (25 mg
once weekly) with similar use for psoriasis, Crohn
disease, polymyositis and other diseases that require the
immune system to be suppressed for treatment effect.
It has often been assumed that, as MTX is a cytotoxic
drug, an accidental exposure to MTX through spillage
Funding: None
Potential conflicts of interest: None
© 2009 The Authors
Journal compilation © 2009 Royal Australasian College of Physicians
with skin contamination and inhalation is potentially
hazardous. Therefore, similar handling precautions as for
oncology chemotherapy protocols have been applied for
autoimmune disease use (Fig. 1). For rheumatoid arthritis outpatients, this could mean a weekly nurse or physician visit rather than patients’ relatives being able to
assist those with disability who require help with
parenteral low-dose weekly MTX administration.
Although the dose of MTX that is used for an autoimmune disease such as rheumatoid arthritis is many-fold
lower than that used in neoplasia, the potential risk posed
by the preparation of usual MTX dose has not been
studied. There is also no live human data on how much
MTX is absorbed systemically through skin contamination
(and possible inhalation). The primary aim of this study
was to determine in the event of gross skin contamination
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Wong et al.
Figure 1 Relevant methotrexate product information accessed through Monthly Index of Medical Specialties (MIMS).13
with a 25 mg MTX solution whether there is any significant absorption of MTX by measuring the blood and urine
concentrations of MTX for 24 h and thus any potential
toxicity by observable clinical or biological effects.
Methods
Subjects
The study was carried out in March 2007 at Canberra
Hospital, Australian Capital Territory (ACT), Australia,
after approval by the ACT Human Research Ethics Committee. Eight healthy subjects volunteered. Exclusion criteria consisted of any significant medical history or
abnormal laboratory studies, including liver or renal
impairment, potential pregnancy, known hypersensitivity to MTX, subjects taking folic acid or other medications
except contraceptive pill, concurrent infection, alcohol
intake >60 g/day or extensive skin lesions, which could
interfere with the study. Two volunteers had exclusion
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criteria following their initial screening; hence six volunteers were enrolled into the study after informed consent.
Study protocols
The subjects had baseline blood tests to confirm a normal
full blood count (FBC), electrolytes, urea, creatinine, estimated glomerular filtration rate (eGFR), homocysteine
and liver function tests (LFT). Subjects were then exposed
to a 25 mg/mL MTX solution with 1 mL spilled onto
subjects’ ventral forearm, soaking a 10 cm ¥ 10 cm gauze
cloth, all then wrapped with aluminium foil and left on the
arm for 30 min before being washed off with soap and
water. The surface area in contact with MTX was measured from the gauze. The area of exposure was covered
with aluminium foil to protect MTX from possible deactivation by light. Subjects were in a small room with no
special ventilation and thus in addition to skin contamination may also have been exposed to MTX by inhalation.
Blood samples were collected at baseline, 2, 4, 8, 12
and 24 h from the time of exposure to measure serum
© 2009 The Authors
Journal compilation © 2009 Royal Australasian College of Physicians
Methotrexate skin contamination
Table 1 Baseline characteristics of the six volunteers
Mean ⫾ SD
Characteristics
Sex, female : male (%)
Age (years)
Weight (kg)
Height (cm)
Creatinine clearance (mL/min)
Estimated area of exposure (cm2)
50:50
45 ⫾ 8.1
60.5 ⫾ 14.4
170.5 ⫾ 8.0
96.2 ⫾ 33.0
68 ⫾ 10.2
SD, standard deviation.
MTX concentration. All six subjects were asked to empty
their bladder just before MTX exposure followed by 24-h
urine sample collection using two separate 12-h urine
bottles. MTX has 90% renal elimination within 24 h, so it
is possible to estimate the total absorbed dose from the
urine volume and concentration. Baseline and 24-h
serum homocysteine levels were also measured because
increased level of homocysteine can also correlate to
MTX toxicity when MTX reduces demethylation of
homocysteine.1,2
Safety of exposure was evaluated using clinical questionnaires, laboratory haematological and biochemistry
tests. Any local or systemic effects were also documented
at the times of blood collection, including documentation
of any skin irritation (such as redness, burning, itch or
pain) or any suggestion of systemic toxicity (such as
nausea, vomiting or breathing difficulty). If the level of
MTX in any individual was >0.02 mmol/L at 24 h, then
repeat blood tests (FBC, eGFR and LFT) were to be
carried out to monitor for toxicity with a formal consideration to give antidote therapy with folinic acid.
Assay methods
MTX concentrations were measured using an Abbott TDX
analyser (Abbott Laboratories, Abbott Park, IL, USA)
using the MTX II assay with the level reported in micromoles per litre. Sensitivity was defined as the lowest
measurable concentration that can be distinguished
from 0 with 95% confidence interval and this was
0.02 mmol/L. Therefore, any results less than or equal to
0.02 mmol/L would be reported as not detectable for this
Figure 2 Homocysteine concentration changes at 24 h following dermal
exposure to 25 mg of methotrexate solution in six human volunteers.
study. Two consecutive 12-h urine samples were chosen
to test the excretion of MTX in urine.
Results
All six volunteers had normal baseline FBC, homocysteine, electrolytes, renal function and LFT. Table 1
summarizes the characteristics of the subjects. The estimated area of forearm skin exposure to the MTX solution
was 68 cm2.
The minimum reliable serum MTX detectable level
(0.02 mmol/L for the assay) was not detected at any time
of the study (2, 4, 8, 12 and 24 h) in all six volunteer
samples. The subjects’ 24-h urine MTX levels were
exceedingly low (Table 2). All subjects’ homocysteine
measures were found to be within the normal range and
there was no significant change after MTX exposure
(Fig. 2). The three female subjects reported short-lived
local dermal irritation in the form of a mild erythema that
resolved within 24 h in each case.
Table 2 Urine MTX levels and estimated MTX absorption following dermal exposure to 25 mg of MTX solution
Subject
Urine MTX (mmol/L), 24 h
Estimated MTX absorbed (Vol ¥ Conc)
1
2
3
4
5
6
<0.01
<0.016
0.01
0.038
<0.01
<0.063
<0.01
<0.018
<0.01
<0.05
0.02
<0.015
MTX, methotrexate; Vol ¥ Conc, Volume ¥ Concentration.
© 2009 The Authors
Journal compilation © 2009 Royal Australasian College of Physicians
381
Wong et al.
Discussion
MTX is a folic acid antagonist interfering with cell tissue
production that has also been widely used as an immunosuppressant drug since the 1980s. It competitively
inhibits the enzyme dihydrofolate reductase and thereby
inhibits DNA synthesis. It is a relatively polar drug
because of the presence of glutamic acid and is watersoluble at physiological pH. It has pKa of 4.7 and its
solubility in pH 4.0 buffer is low (0.32 g/L).3 The
25 mg/mL MTX solution also contains other inactive constituents, such as Sodium Hydroxide BP, which may contribute to irritation.
Although MTX is used in much smaller dosage for
rheumatoid arthritis and other autoimmune disease
versus chemotherapy dosage in oncology, the product
information focuses on use as an antineoplastic drug in
terms of instructions on handling precautions. Therefore,
in some centres, the administration of MTX in patients
with rheumatoid arthritis whether given through p.o.,
s.c. or i.m. route has followed the same precautions for
administration as for oncology patients causing considerable inconvenience and financial cost.
MTX is not lipophilic and therefore is not readily transported through stratum corneum by passive diffusion.
Experiments have shown that MTX is bound in the epidermis.4 In vitro studies show that the penetration of MTX
through cadaver or animal skin ranges from 0 to 24%,
with most studies ranging from just 0.05 to 4.0%.5–8 For
example, with dermal application of dilute MTX to
cadaver skin, a study showed only 0.05% of the applied
dose penetrated completely through the dermis, whereas
0.07% was recovered in the epidermis. Following
removal of the stratum corneum, still only 25% of the
applied MTX penetrated through the skin. Increased
duration of exposure or temperature did not increase the
drug absorption in this model.6 There also did not appear
to be a linear increase in absorption with increasing
concentrations.5
In fact, most formulations of MTX designed for topical
use have been formulated to enhance penetration or
solubility. A variety of techniques have been used,
including electroporation, iontophoresis, alteration of
vehicle or increasing the lipophilicity by changing the pH
or esterification of the carboxyl groups.3,9 In a human
study reporting therapeutic use of topical 1% MTX combined with enhancer on a large skin area of patients with
psoriasis, there was no clinically significant systemic toxicity (but 70% reported local irritation).10
Studies have concluded that duration of exposure to
MTX in concentrations that exceed threshold levels necessary for cellular cytotoxicity are more important than
the actual concentration of MTX itself. From these
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reports and experience in oncology, it has been determined that concentrations of >5 mmol/L at 24 h after a
single large dose results in cytotoxic effects. In patients
with rheumatoid arthritis, it has been shown that generally with weekly dosing of 7.5–15 mg of MTX, the peak
concentration is approximately 0.3–0.8 mmol or slightly
higher with the value falling to <0.05 mmol by 24 h after
each single dose of MTX.11
A contamination study has been carried out on the
technical preparation of very large doses of MTX used in
chemotherapy where 50- to 100-fold higher doses are
routinely used in chemotherapy. Interestingly, no MTX
was found in air samples or masks of the technician. This
suggests that exposure through inhalation is unlikely.12
In our study, none of the six live human volunteers had
significant absorption of MTX, as indicated by their serum
or urine concentrations, nor were there any other significant adverse effects from a large spill that was not washed
off for 30 min. This with the limited published work
suggests that elaborate precautions as outlined for oncology chemotherapeutic use (Fig. 1) are not justified by
scientific evidence for rheumatological dose use. Rather
issues of governance in Australian workplace safety and
health service matters have become the barrier to the
relatively recent usual clinical practice for administration
of parenteral MTX, which was identical to other parenteral
drugs given for rheumatological conditions in the community. It remains to be seen whether current lack of
scientific evidence also results in oncology chemotherapeutic precautions for staff involved with p.o. use of MTX
in rheumatological dose on the hospital ward.
Our study involved just six volunteers. It may be
speculated that some other individuals may get greater
exposure, such as a rheumatology specialist nurse who
regularly gives s.c. injections to patients with rheumatoid
arthritis. Similarly, we believe that our study findings in
six normal volunteers are generalizable to patients, carers
and clinical staff with perhaps underlying medical conditions, such as renal impairment, because following skin
contamination there was no significant systemic absorption of MTX. We reiterate our study results indicating the
typical extent of absorption, suggesting that the safety
margin is very high for MTX rheumatological dose use in
autoimmune disease, with concentrations 500 times
below the recommended blood concentration, which
warrants use of folinic acid (>10 mmol/L at 24 h).
This was a small pharmacokinetic safety study and
formal sample size calculations were not carried out.
However, based on these results and other published
work available on MTX, it seems unlikely that further
volunteer studies would record significantly greater
absorption in any individual or suggest that there is a
significant hazard.
© 2009 The Authors
Journal compilation © 2009 Royal Australasian College of Physicians
Methotrexate skin contamination
Conclusions
This study has shown that even with deliberate dermal
contamination with a 25 mg MTX solution as used for
rheumatoid arthritis, there was no significant quantifiable serum and urine concentration or toxicity. This confirmed poor dermal MTX penetrance as reported in the
published work. Hence, this suggests that expensive,
inconvenient precautions to prevent contact with MTX
designed for oncology protocols are unnecessary for
our rheumatology patients or their carers using these
much lower immunosuppressant doses for autoimmune
diseases.
Acknowledgement
The authors acknowledge the help with blood samples
analysis by Emma Southcott, ACT Pathology, Canberra
Hospital, ACT, Australia.
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