Potential for methotrexate exposure through contamination during parenteral use as an immunosuppressantimj_

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1 Internal Medicine Journal 39 (2009) ORIGINAL ARTICLE Potential for methotrexate exposure through contamination during parenteral use as an immunosuppressantimj_ L. S. Wong, 1,2 K. E. Tymms 2,3 and N. A. Buckley 1,3 Departments of 1 Clinical Pharmacology and Toxicology and 2 Rheumatology, Canberra Hospital and 3 Medical 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. wlsan@yahoo.com Received 22 January 2008; accepted 31 March doi: /j 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 ( 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 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 Journal compilation 2009 Royal Australasian College of Physicians 379

2 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 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 380 Journal compilation 2009 Royal Australasian College of Physicians

3 Methotrexate skin contamination Table 1 Baseline characteristics of the six volunteers Characteristics Mean SD Sex, female : male (%) 50:50 Age (years) Weight (kg) Height (cm) Creatinine clearance (ml/min) Estimated area of exposure (cm 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 cm 2. 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 < <0.01 <0.01 < Estimated MTX absorbed (Vol Conc) < <0.063 <0.018 <0.05 <0.015 MTX, methotrexate; Vol Conc, Volume Concentration. Journal compilation 2009 Royal Australasian College of Physicians 381

4 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 pk a 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 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 mg of MTX, the peak concentration is approximately 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. 382 Journal compilation 2009 Royal Australasian College of Physicians

5 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. References 1 Valik D, Radina M, Sterba J, Vojtesek B. Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics 2004; 5: Hoekstra M, Haagsma CJ, Doelman CJ, Van de Laar MA. Intermittent rises in plasma homocysteine in patients with rheumatoid arthritis treated with higher dose methotrexate. Ann Rheum Dis 2005; 64: Chatterjee DJ, Li WY, Koda RT. Effect of vehicles and penetration enhancers on the in vitro and in vivo percutaneous absorptions of methotrexate and edatrexate through hairless mouse skin. Pharm Res 1997; 14: Lu G, Won Jun H, Suh H. Percutaneous absorption and disposition studies of methotrexate in rabbits and rats. Biopharm Drug Dispos 1997; 18: Newbold PCH, Stoughton RB. Percutaneous absorption of methotrexate. J Invest Dermatol 1972; 58: McCulloch JL, Snyder DS, Weinstein GD, Friedland A, Stein B. Factor affecting human percutaneous penetration of methotrexate and its analogues in vitro. J Invest Dermatol 1976; 66: Alvarez-Figueroa MJ, Delgado-Charro MB, Blanco-Mendez J. Passive and iontophoretic transdermal penetration of methotrexate. Int J Pharm 2001; 212: Stewart WD, Wallace SM, Runikis JO. Absorption and local action of methotrexate in human and mouse skin. Arch Dermatol 1972; 106: Wong TW, Zhao YL, Sen A, Hui SW. Pilot study of topical delivery of methotrexate by electroporation. Br J Dermatol 2005; 152: Sutton L, Swinehart JW, Allen C, Kaplan AS. A clinical study to determine the efficacy and safety of 1% methotrexate/azone (MAZ) gel applied topically once daily with patients with psoriasis vulgaris. Int J Dermatol 2001; 40: Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004; 50: Sessink PJM, Van De Kerkhof MCA, Anzion RBM, Noordhoek J, Bos RP. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of expose pharmacy technicians: is skin absorption and important exposure route? Archives of Environmental Health 1994; 49: Monthly Index of Medical Specialties. Relevant Methotrexate product information. MIMS [online] [cited 16 Aug 2005] Available from: URL: Journal compilation 2009 Royal Australasian College of Physicians 383

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