SPECIAL POPULATIONS
`
`Clin Pharmacokinet 2003; 42 (2): 139-151
`0312-5963/03/0002-0139/$30.00/0
`
`© Adis International Limited. All rights reserved.
`
`Pharmacokinetics and
`Pharmacodynamics of Methotrexate
`in Non-Neoplastic Diseases
`∨
`∨
`í Grim, Jaroslav Chládek and Jir
`Jir
`ina Martínková
`Department of Pharmacology, Charles University, Hradec Králové, Czech Republic
`
`Contents
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
`Abstract
`1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
`1.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
`1.1.1 Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
`1.1.2 Parenteral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
`1.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
`1.3 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
`1.3.1 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
`1.3.2 Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`1.4 Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`3. Remission Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
`4. Long-Term Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`5. Supplementation with Folic and Folinic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`
`Abstract
`
`Low dose pulse methotrexate (LDMTX) therapy has become effective in the
`treatment of autoimmune and lymphoproliferative diseases. The pharmacokinet-
`ics of LDMTX is individually highly variable, resulting in a different systemic
`exposure to the drug and a variable therapeutic/toxic effect in patients. The im-
`provements and exacerbations of disease activity in relation to the introductions
`and discontinuations of LDMTX therapy suggest the possible immunosuppresive
`and anti-inflammatory properties of the drug. Because of a strong correlation
`between the drug pharmacokinetics and the therapeutic outcomes (pharmacody-
`namics), it seems to be possible to individualise the LDMTX therapy according
`to the results of pharmacokinetic/pharmacodynamic analysis. In the case of pso-
`riasis, pharmacokinetic/pharmacodynamic analysis in our local study revealed a
`highly significant inverse relationship between PASI (expressed as a percent of
`the initial value) and a steady-state AUCMTX (area under the curve of methotrexate
`plasma concentrations; r8 = –0.65, p < 0.001). The considerable inter-individual
`variability and low intra-individual variability in MTX pharmacokinetics, sup-
`ports a role for therapeutic monitoring and dose individualisation at the start of
`pharmacotherapy. The results of this study suggest that a steady-state AUCMTX
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`Grim et al.
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`value of 700 nmol • h/L and higher are associated with a significantly better
`success rate of antipsoriatic therapy than lower values. The preliminary results
`in our follow-up study suggest the statistically higher incidence of unwanted
`effects depending on maximum plasma concentration of the drug. Moreover,
`statistically significant correlation was found between the toxic effects and expo-
`sure to the drug regarding methotrexate plasma concentrations and intracellular
`storage in erythrocytes. However, the data are still in the process of being com-
`pleted and are not yet published.
`
`Methotrexate is an antifolate, and has been used
`as high-dose pulse therapy (HDMTX) for the treat-
`ment of malignancies since 1947. The favourable
`anti-inflammatory effect of low dose pulse metho-
`trexate (LDMTX), given as 7.5–30mg (approxi-
`mately 0.3 mg/kg) once weekly orally, subcutane-
`ously or intramuscularly, was first reported in the
`1950s in patients with psoriasis and psoriatic ar-
`thritis. The drug has been commonly used in the
`therapy of recalcitrant psoriasis since the 1960s. Its
`use in the treatment of rheumatoid arthritis began
`during the 1980s.[1]
`At present, methotrexate is one of the most fre-
`quently used of the disease-modifying antirheu-
`matic drugs (DMARDs), also called slow-acting or
`symptom-modifying drugs. In the treatment of
`rheumatoid arthritis, methotrexate has proved to be
`more effective and less toxic than auranofin and
`azathioprine, and as effective as but less toxic than
`sulfasalazine.[1,2] The continuation rate of LDMTX
`therapy in patients with rheumatoid arthritis has
`been reported as 70% after 1 year of therapy,
`54% after 3 years and 50% after 6 years.[3] These
`percentages compare favourably with the overall
`probability of less than 20% for three other
`DMARDs after 5 years: 19% for sulfasalazine,
`17% for penicillamine and 8% for parenteral
`gold.[4]
`LDMTX therapy was also shown in placebo-
`controlled randomised trials to be efficacious in
`children with juvenile rheumatoid arthritis (espe-
`cially the polyarticular form) and systemic onset
`juvenile rheumatoid arthritis (Still’s disease). Gen-
`erally, children tolerate higher doses of the drug
`than adults, up to 0.6 mg/kg. Long-term LDMTX
`therapy does not induce osteopenia in children,
`which has been described after HDMTX.[5] Paren-
`
`teral LDMTX therapy also has a beneficial effect
`on numerous other inflammatory disorders, in-
`cluding corticosteroid-dependent chronic active
`Crohn’s disease,[6-8] antimalarial-resistant lupus
`arthritis, cutaneous lupus erythematosus,[9] sys-
`temic lupus erythematosus,[10] polymyositis, poly-
`myalgia rheumatica, Reiter’s syndrome, sarcoido-
`sis, primary biliary cirrhosis, primary sclerosing
`cholangitis, scleroderma, graft-versus-host disease
`and organ allograft rejection.[7,11]
`From many clinical studies it is evident that
`LDMTX treatment is associated with great interin-
`dividual variability in the therapeutic response.
`Regardless of the different immunological charac-
`teristics of patients, a significant relationship be-
`tween pharmacokinetics and pharmacodynamics
`(i.e. efficacy and toxicity) has been reported.[12-15]
`
`1. Pharmacokinetics
`
`1.1 Absorption
`
`1.1.1 Oral Administration
`Methotrexate is a weak dicarboxylic organic
`acid with a molecular weight of 454 daltons. The
`molecule is negatively charged at neutral pH (pKa1
`= 4.84, pKa2 = 5.51), resulting in limited lipid sol-
`ubility. After oral administration, active absorp-
`tion of the drug occurs in the proximal jejunum.
`The process is capacity-limited and decreases non-
`proportionally with increased oral doses.[16-18] Ear-
`lier studies indicated that methotrexate absorption
`was rapid and complete after oral doses of less than
`30 mg/m2.[16,19] More recent investigations with
`larger numbers of patients demonstrated that the
`rate and extent of absorption are highly variable
`between patients, and that the absolute bioavaila-
`bility may be less than 50% for doses as low as
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`Low-Dose Methotrexate
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`10–15 mg/m2.[15,20,21] The mean absolute bioavail-
`ability is about 70–80% and a large interindividual
`variation from 30–90% has been observed.[15,20,22-24]
`Conversely, only a moderate intra-individual vari-
`ability in LDMTX pharmacokinetics was noticed
`during intermediate-term (13 weeks[15]) and long-
`term (2 years[21]) treatment in patients with psori-
`asis and rheumatoid arthritis receiving a single
`weekly dose of methotrexate 15mg.
`Under fasting conditions, maximum plasma
`concentrations of methotrexate (Cmax) range be-
`tween 0.3 and 1.6 μmol/L, and occur at a tmax of
`0.75–2 hours after administration.[15,21,22,24] Food
`did not significantly influence the bioavailability
`of methotrexate, but slightly reduced Cmax and pro-
`longed tmax by about 0.4–0.7 hours as a result of
`delayed gastric emptying.[24]
`
`1.1.2 Parenteral Administration
`LDMTX is given parenterally to ensure effec-
`tive compliance and, presumably, uniform bio-
`availability.[25] The drug is absorbed more rapidly
`and reaches higher serum concentrations after in-
`tramuscular or subcutaneous administration com-
`pared with the oral route.[26,27] Nevertheless, the
`mean absolute bioavailability is very similar,[28,29]
`suggesting that the routes of LDMTX administra-
`tion are interchangeable.[30,31]
`LDMTX may also be injected intra-articularly.
`The mean synovial methotrexate concentration ex-
`ceeds the serum concentration by a minimum of
`10-fold throughout the whole 24-hour post-dose
`period and ensures the therapeutic effect.[32] The
`topical application of LDMTX in cream results in
`drug absorption and accumulation in keratinocytes
`of psoriatic plaques, but without any histological
`change.[33]
`
`1.2 Distribution
`
`The volume of distribution of methotrexate is
`0.87–1.43 L/kg, which corresponds to the intracel-
`lular distribution of the drug.[26,34] In blood, 30–
`70% of methotrexate is bound to proteins, almost
`exclusively to albumin.[23,26,27,34-36] Edno et al. dem-
`onstrated a significantly increased drug plasma
`concentration for 8 hours following methotrexate
`
`administration,[34] reflecting the possible entero-
`hepatic cycling of the drug. The concentrations of
`methotrexate in the synovial fluid are approxi-
`mately equal to plasma concentrations at 4 and 24
`hours after oral or intramuscular administration.[23]
`With regard to the intracellular mechanism of
`action, it is believed that the most important pro-
`cess is transport of methotrexate into cells and its
`accumulation within cells in the form of poly-
`glutamates. Transport of methotrexate occurs both
`by passive transmembrane diffusion and by a
`carrier-mediated active transport system that meth-
`otrexate shares with folates.[18,25] A folate surface
`receptor responsible for the intracellular transport
`of both reduced folates and methotrexate has
`been well described in various in vitro studies.[37]
`Once inside the cell, up to six glutamate residues
`may be progressively added to the drug molecule
`by the folyl-polyglutamate synthetase enzyme.
`Polyglutamyl derivatives of methotrexate cannot
`be transported extracellularly unless they are
`hydrolysed back to the monoglutamate.[16,18] Intra-
`cellular accumulation of methotrexate poly-
`glutamates allows drug administration once
`weekly as a bolus or divided into three equal sub-
`doses.[38] It was found that the pool of folate poly-
`glutamates in liver cells and erythrocytes is grad-
`ually replaced by methotrexate polyglutamates
`during long-term LDMTX therapy.[39,40]
`The pharmacokinetics of methotrexate in eryth-
`rocytes have been studied extensively.[39] After a
`single dose, methotrexate concentrations in
`plasma and erythrocytes change simultaneously as
`a consequence of a rapid equilibrium between
`these compartments. The concentrations of meth-
`otrexate both in plasma and erythrocytes usually
`fall below 10 nmol/L within 24 hours after
`LDMTX administration. At 3–4 days later, the
`drug reappears in erythrocytes despite its negli-
`gible plasma concentration.[39] Methotrexate poly-
`glutamates in erythrocytes accumulate until a
`steady-state level is reached after 4–6 weeks of
`intermittent administration.[15,41] This is a much
`shorter time than that required for medullar matu-
`ration of erythroblasts into erythrocytes (14–18
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`Grim et al.
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`weeks). The probable explanation is that metho-
`trexate polyglutamates are synthesised mainly in
`the circulating erythrocytes.[41] The steady-state
`erythrocyte methotrexate concentration is also
`highly variable among patients undergoing long-
`term LDMTX therapy. A range of 10–170 nmol/L
`erythrocytes was observed following the admin-
`istration of 7.5–15mg methotrexate once a
`week.[15,40] No correlation was found between the
`total cumulative dose of methotrexate and erythro-
`cyte methotrexate concentration.[42]
`Although no close relationship was found be-
`tween folate status and intracellular accumulation
`of methotrexate, the highest methotrexate concen-
`trations were found in erythrocytes with the lowest
`folate concentration.[40] Moreover, erythrocyte
`methotrexate concentration seems to be indicative
`of hepatic changes that occur during LDMTX ther-
`apy. Significantly higher erythrocyte methotrexate
`concentrations were found in patients with pro-
`gressive hepatic changes than in patients with no
`progression. Nevertheless, a critical erythrocyte
`concentration was not established because of its
`very large interindividual variability.
`Peripheral blood T-lymphocytes also inten-
`sively convert methotrexate to polyglutamyl deriv-
`atives (tetra- and penta-glutamates). Similarly,
`methotrexate is highly accumulated in fibroblasts,
`myeloid precursors in bone marrow and kera-
`tinocytes.[1,20,33] Relatively high and equal metho-
`trexate concentrations were found in the synovial
`membrane, cortical bone and trabecular bone.[43]
`The intracellular accumulation results in drug-in-
`duced apoptosis of T-lymphocytes.[44] On the con-
`trary, the activity of intracellular hydrolases in in-
`testinal epithelium cells is very high, and therefore
`the accumulation of methotrexate in small intestine
`mucosa is not significant.[18]
`
`1.3 Elimination
`
`Elimination of methotrexate from plasma was
`shown to be biphasic or triphasic (dependent on
`the length of sample collection period) with a
`mean terminal biological half-life (t1⁄2β) of 6–15
`hours.[15,18,22-24,26,27,29,34] Thus, accumulation of
`
`methotrexate in plasma cannot occur after inter-
`mittent administration once a week. Extensive
`sampling of plasma over 1 week after methotrexate
`administration in nine patients with rheumatoid
`arthritis allowed estimation of a t1⁄2β of 55 hours,
`reflecting slow release of methotrexate from its in-
`tracellular forms.[29] The longer the sampling, the
`longer the reported t1⁄2β of the drug, probably due
`to intracellular methotrexate storage, polyglutamy-
`lation and slow release back to plasma.[16,18] Accu-
`mulation of methotrexate in pleural effusion and
`ascitic fluid is the reason for its slowed elimination
`in cancer patients receiving HDMTX therapy, but
`seems to be of no importance after LDMTX.[18]
`
`1.3.1 Metabolism
`Three metabolic pathways of methotrexate have
`been described in humans. First, the drug is meta-
`bolised by intestinal bacteria to 4-amino-deoxy-
`N10-methylpteroic acid. The metabolite usually ac-
`counts for less than 5% of the administered dose,
`and is rarely detectable in human plasma and
`urine.[18]
`Secondly, in the liver, methotrexate is con-
`verted to 7-hydroxy-methotrexate. 7-Hydroxy-
`methotrexate is less water soluble than metho-
`trexate, and it may therefore contribute to acute
`nephrotoxicity because of its precipitation in
`acidic urine. The metabolite is a 10-fold less potent
`inhibitor of dihydrofolate reductase (DHFR), one
`of the intracellular target enzymes for methotrex-
`ate.[16,18,45] The hepatic first-pass effect of metho-
`trexate is low (about 10%), as is its metabolic clear-
`ance to 7-hydroxy-methotrexate: 5–7% of the dose
`was recovered as 7-hydroxy-methotrexate in urine
`after a broad range of methotrexate doses.[3,15,29]
`However, due to its slower rate of urinary excre-
`tion, plasma concentrations of 7-hydroxy-metho-
`trexate usually exceed those of methotrexate within
`8–10 hours after drug administration.[15,29,35]
`Despite its extensive binding to serum albumin
`(91–93%), 7-hydroxy-methotrexate does not alter
`the protein binding of methotrexate.[18,23,26,27,34-36]
`Both compounds compete for the same membrane
`carriers, intracellular transporters and, subsequently,
`for folyl-polyglutamate synthetase.[46]
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`Low-Dose Methotrexate
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`143
`
`Thirdly, the intracellular conversion of metho-
`trexate to polyglutamates represents the most
`important metabolic pathway regarding effi-
`cacy.[16,18] Polyglutamyl derivatives of metho-
`trexate also exhibit more efficient inhibitory
`properties towards intracellular metabolism of
`pyrimidines and purines than does the parent
`drug.[18,25] Alteration of the intracellular folate cy-
`cle results in intracellular accumulation of homo-
`cysteine and depletion of polyamines such as
`spermine and spermidine. Polyamines have pro-
`inflammatory properties.[47]
`
`1.3.2 Excretion
`Renal excretion constitutes the major elimina-
`tion route for methotrexate. The drug is filtered in
`renal glomeruli and, additionally, undergoes bidi-
`rectional transport across the renal tubules, i.e. ac-
`tive secretion, utilising the general transport mech-
`anism for organic acids, and active reabsorption
`unaffected by acidic compounds from the distal
`tubule. At serum concentrations from 0.1–0.4
`μmol/L, tubular secretion prevails over reabsorp-
`tion, which reaches saturation.[16,41] Accordingly,
`renal clearance (CLR) of LDMTX usually exceeds
`creatinine clearance (CLCR) by about 2–28%.[26,48]
`At methotrexate plasma concentrations of 0.6–1
`μmol/L, CLR equals CLCR (i.e. 80–120 ml/min),
`reflecting the saturation of methotrexate active tu-
`bular secretion. There is a considerable interindi-
`vidual variation in the saturation point of both se-
`cretion and reabsorption in tubules. Both kinetic
`processes can occasionally be saturated even at
`low methotrexate plasma concentrations within
`the range of 0.1–1 μmol/L. Thus, nonlinear elimi-
`nation may result following the administration of
`7.5–30mg of methotrexate and contribute to the
`interindividual variability in methotrexate con-
`centrations.[40]
`After 6 months of LDMTX therapy, CLR of
`methotrexate decreased by a mean of 23.8 ml/min
`and CLCR by 8.6 ml/min.[48] A decrease in glomer-
`ular filtration rate has also been reported in rheu-
`matoid arthritis patients taking LDMTX, usually
`over a period of 2–4 weeks.[29] This important
`effect of methotrexate has also been observed in
`
`HDMTX.[48] It could be explained by an increase
`in plasma adenosine concentration in extracellular
`fluid and by subsequent activation of A1 receptors
`in renal parenchyma, diminishing renal blood flow
`and salt and water excretion.[47]
`In addition, a variable amount of methotrexate
`is eliminated by active biliary excretion, responsi-
`ble for 10–30% of methotrexate clearance.[26,36,41,48]
`However, only about 1–2% of the drug is excreted
`in faeces, suggesting extensive enterohepatic cir-
`culation of methotrexate.[40,45] Biliary excretion
`can become more important in patients with renal
`insufficiency.[17,20] Enterohepatic cycling can be
`interrupted by cholestyramine or charcoal, which
`can be administered to attenuate potentially life-
`threatening toxicity of LDMTX in patients with
`renal insufficiency or after methotrexate poison-
`ing.[49]
`
`1.4 Therapeutic Drug Monitoring
`
`Recently, to provide therapeutic drug moni-
`toring effectively and more practically, limited
`sampling methods to estimate methotrexate phar-
`macokinetics using a Bayesian approach and pop-
`ulation data modelling programs have been imple-
`mented.[50-52]
`
`2. Pharmacodynamics
`
`Methotrexate is an analogue of folic acid that
`was originally designed to inhibit the activity of
`the enzyme DHFR. This enzyme converts dihydro-
`folates to tetrahydrofolates, which are involved in
`single carbon atom transfers in crucial intracellular
`metabolic pathways such as de novo synthesis of
`purines, pyrimidines and polyamines and trans-
`methylation of phospholipids and proteins. In on-
`cology, the rationale for the use of HDMTX is that
`malignant cells become starved of the purine and
`pyrimidine precursors required for DNA and RNA
`synthesis, proliferation and cell division. As a re-
`sult of their inability to synthesise DNA and RNA,
`the number of malignant cells rapidly falls under
`such therapeutic conditions.[53]
`LDMTX has immunosuppressive and anti-
`inflammatory properties. Concerning immuno-
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`Grim et al.
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`suppressive activity, the assumption for the intro-
`duction of LDMTX was that the drug would inhibit
`proliferation of lymphocytes (notably the CD3 and
`CD4 subtypes) and other immunocompetent cells
`(e.g. monocytes-macrophages and polymorphonu-
`clear neutrophils). At concentrations of 0.1–10
`μmol/L, methotrexate induces apoptosis of in vitro
`activated T cells from human peripheral blood.[54]
`The ability to undergo apoptosis may reflect the
`capacity of lymphocytes to convert methotrexate
`to methotrexate polyglutamates, containing four or
`five glutamyl groups, which were reported to be
`retained up to 24 hours in breast cancer cells.[6]
`According to several lines of evidence, LDMTX
`does not seem to act only as a cytotoxic agent
`against immunocompetent cells.[55] In vitro, mod-
`ulation of the cytokine network by LDMTX in-
`creased T helper 2 cytokines, e.g. interleukin-4
`(IL-4) and interleukin-10 (IL-10), and decreased T
`helper 1 cytokines, e.g. interferon-γ (IFNγ) and
`interleukin-2 (IL-2). This observation could ex-
`plain the methotrexate-induced anti-inflammatory
`and immunoregulatory actions in vivo. Once intra-
`cellular, methotrexate-polyglutamates bind com-
`petitively, and with higher affinity than dihydro-
`folate and methotrexate, to several enzymes and
`inhibit their function: DHFR, thymidylate synthe-
`tase (TMS) and 5-amino-imidazole-4-carboxamide
`ribosyl-5-phosphate formyltransferase (AICAR-
`formyltransferase).[1]
`Inhibition of AICAR-formyltransferase leads to
`intracellular accumulation of 5-amino-imidazole-
`4-carboxamide ribosyl-5-phosphate (AICAR),
`even if the enzymatic block is only partial.[21,56]
`High concentrations of AICAR lead to enhanced
`release of adenosine into the blood.[57] Addition-
`ally, adenosine is synthesised in plasma under con-
`ditions of LDMTX therapy.[58] This mediator acti-
`vates A2a, A2b and A3 extracellular receptors on
`monocytes-macrophages,[47,59] inhibiting produc-
`tion of tumour necrosis factor α (TNFα), IL-6 and
`IL-8, promoting transcription of mRNA for an IL-1
`receptor antagonist[60,61] and increasing secretion
`of the potent anti-inflammatory cytokine IL-10.[62]
`It was also reported that activation of adenosine
`
`receptors on human endothelial cells inhibits their
`production of IL-6 and IL-8 and diminishes expres-
`sion of E-selectin on the cell surface.[47,60] These
`observations indicate that adenosine plays a major
`role in the anti-inflammatory response.
`Recent data confirm that enhanced adenosine
`release may be also responsible for some of the
`toxicity of LDMTX therapy. Adenosine release in
`the CNS and its activation of A1 receptors in the
`brain can be responsible for induction of fatigue
`and lethargy.[63] A1 receptors are also present in
`endothelial cells and their activation provokes va-
`sodilatation. This could explain the headache that
`appears in many patients a few hours after intake
`of LDMTX and the decrease of CLCR (section
`1.3.2).[55]
`
`3. Remission Induction
`
`The maximum effect of LDMTX therapy of
`rheumatoid arthritis and psoriasis is usually
`achieved from 4–6 months after the beginning of
`intermittent drug administration.[7,57,64] To induce
`and maintain remission of the disease, it is neces-
`sary to start intermittent LDMTX therapy at an ap-
`propriate dose and mode of administration and to
`individualise maintenance therapy to preserve the
`effect under conditions of minimal toxicity.
`Increasing information on the severe, progres-
`sive and debilitating nature of rheumatoid arthritis
`and its negative influence on lifespan has prompted
`the development of improved treatment courses
`aimed at slowing disease progression. A major
`change in approach has taken place in that rheuma-
`tologists are starting treatment with DMARDs
`(LDMTX, cyclosporin, hydroxychloroquine, gold
`salts, penicillamine, sulfasalazine, azathioprine,
`etanercept and infliximab) as early as possible, be-
`fore joint damage and loss of function can occur.
`The American College of Rheumatology recom-
`mends that DMARD therapy should be initiated no
`later than 3 months after diagnosis if a patient has
`ongoing joint pain, morning stiffness, fatigue, syn-
`ovitis or persistent elevation of erythrocyte sedi-
`mentation rate and C-reactive protein.[65] LDMTX
`
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`Low-Dose Methotrexate
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`
`is currently considered to be the most efficacious
`therapy.
`LDMTX therapy is generally started with inter-
`mittent oral administration of the drug. The weekly
`starting dosage is generally 5–7.5mg of methotrex-
`ate in adults and 0.3 mg/kg in children.[4] If the
`response is inadequate and no adverse effects are
`present, the dose can be increased at 6- to 8-week
`intervals up to 25mg or 0.6 mg/kg, respectively.
`Self-administered subcutaneous injections have
`been recommended in those patients whose ab-
`sorption of oral methotrexate is insufficient or in
`those with low tolerance to the tablets.
`A split-dose regimen consisting of three divided
`doses given at 12-hour intervals may be useful in
`patients with gastrointestinal complaints, head-
`ache and fatigue early after drug ingestion, i.e.
`smaller doses result in the decrease of acute toxic-
`ity of LDMTX therapy.[25,66] The rationale seems
`to be prevention of excessive release of adenosine
`in the CNS. Conversely, a fortnightly maintenance
`schedule may be used once the disease is well con-
`trolled, or even in clinical remission. This every-
`other-week regimen may result in a flare of disease
`activity.[67] The mode of administration is based on
`the dose-dependent relationship to clinical out-
`comes. Indeed, the clinical efficacy of the drug is
`dose related,[29] although a definitive dose-concen-
`tration-effect relationship has not been elucidated
`and the predictive value of the administered dose
`for effect is rather poor.[15,68]
`With regard to the pharmacokinetics of
`LDMTX, considerable interindividual variability
`of drug bioavailability seems to be the most impor-
`tant problem in reaching a significant clinical
`effect in terms of immunosuppressive and anti-
`inflammatory therapy. A significant correlation was
`recently reported between the AUC of methotrex-
`ate and both morning stiffness and the Ritchie ar-
`ticular index.[14] However, such correlation was
`not found with other parameters, including joint
`pain count, join swelling count, erythrocyte sedi-
`mentation rate, liver and renal function tests, and
`haemoglobin levels. Significant correlation was
`also found between AUC and decrease in Psoriasis
`
`Activity and Severity Index (PASI) score during 3
`months of treatment (r2 = –0.91, p < 0.002).[15] This
`outcome may be significant for individualising
`LDMTX therapy. Others did not find any correla-
`tion between pharmacokinetics and efficacy of
`LDMTX in patients with rheumatoid arthritis.[69]
`Capone et al.[70] did not show any difference in
`LDMTX pharmacokinetics between patients with
`rheumatoid arthritis who did or did not respond to
`systemic therapy. However, during the 8-week
`study, all pharmacokinetic values obtained in re-
`sponders were higher than those in nonresponders,
`even if the differences did not reach statistical sig-
`nificance.
`The rationale for therapeutic drug monitoring
`of any drug is based on several prerequisites.
`LDMTX meets at least three of these: (i) large in-
`terindividual variability in kinetics; (ii) concentra-
`tion-effect relationship; and (iii) a considerable
`time period for the clinical effect to develop. Our
`finding of a low intra-individual variability and
`no effect of the duration of therapy on methotrex-
`ate pharmacokinetics in plasma agrees with pre-
`vious reports from studies over intermediate (13
`weeks[15]) and long (6 months to 2 years[21,48]) pe-
`riods. This suggests that therapeutic drug monitor-
`ing and dose individualisation need only be per-
`formed at the start of therapy, with a possible
`additional examination of methotrexate pharmaco-
`kinetics in patients showing an unsatisfactory re-
`sponse. According to the individually determined
`pharmacokinetic parameter values, it might be
`possible to assure effective exposure of the patient
`to the drug by changing the route of administration
`in case of inadequate absorption from the gastro-
`intestinal tract.
`The other important issue for the effect of
`LDMTX seems to be the ability of peripheral blood
`lymphocytes to convert methotrexate to poly-
`glutamates. It is possible to measure the capacity
`of intracellular conversion and estimate the clini-
`cal outcome. Uptake and intracellular accumula-
`tion of methotrexate, along with the irreversibility
`of its effect on activated lymphocytes, provide a
`rationale for the intermittent weekly administra-
`
`© Adis International Limited. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (2)
`
`Page 00007
`
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`146
`
`Grim et al.
`
`tion of the drug, in contrast to other anti-inflamma-
`tory and immunosuppressive agents that must be
`administered daily because of their short half-life
`and/or reversible activity.[44]
`Decreased formation of methotrexate long-
`chain polyglutamates is associated with metho-
`trexate resistance, whereas high levels of metho-
`trexate polyglutamate accumulation are found in
`the blasts of leukaemia patients who respond to
`the therapy and have improved outcome.[71] The
`steady-state concentration of long-chain metho-
`trexate polyglutamates depends on the balance of
`activities of two enzymes: folylpolyglutamyl syn-
`thetase (FPGS), which adds glutamate residues to
`methotrexate with γ-carboxyl linkages, and γ-glut-
`amyl hydrolase (GGH) or conjugase, which se-
`quentially removes the terminal glutamate residue
`of methotrexate polyglutamates. The ratio of GGH
`and FPGS activities could be used as a predictor
`of methotrexate polyglutamylation, response to
`methotrexate therapy and outcome.
`
`4. Long-Term Maintenance Therapy
`
`Patients usually receive LDMTX therapy for
`several months or years, which requires strategies
`to maintain efficacy, increase drug tolerability and
`prevent chronic toxicity. The most important goal
`is the prevention of excessive accumulation of
`
`methotrexate in tissues and the depletion of endog-
`enous folates.
`Nausea and fatigue are symptoms of the acute
`toxicity of LDMTX; however, they become more
`prominent with the duration of therapy. The inci-
`dence (about 30% of patients on LDMTX therapy)
`and significance of these clinical symptoms are
`probably related to intracellular depletion of fo-
`lates, resulting in increased adenosine production
`and hyperhomocysteinaemia during long-term
`LDMTX administration.[1,55] Folic/folinic acid
`substitution therapy and division of the weekly
`dose of methotrexate into three equal doses given
`at 12-hour intervals is considered to alleviate the
`clinical significance of such symptoms.[1,38,72]
`Hepatotoxicity is the major problem of LDMTX
`therapy, mainly in patients with psoriasis.[38] Ele-
`vation of hepatic enzymes, especially transami-
`nases, occurs in about 20% of patients shortly after
`initiation of LDMTX therapy, but generally re-
`solves within 1–3 weeks of treatment. However,
`the risk of developing severe hepatotoxicity (grade
`III or IV) occurs later and has been reported in
`approximately 3–25% of psoriatic patients. Hepa-
`totoxicity is related to the dose given each week
`and to the cumulative dose of methotrexate (table
`I).[50,73-81] Patients with rheumatoid arthritis on
`LDMTX pulse therapy rarely develop severe hep-
`atotoxicity.[38,45]
`
`Table I. Liver biopsy findings during methotrexate therapy of psoriasis with a sing