Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low‐dose methotrexate in patients recently diagnosed with rheumatoid arthritis

Rodríguez-Báez, Ana Socorro; Huerta-García, Ana Patricia; Medellín‐Garibay, Susanna Edith; Rodríguez-Pinal, Cristian Jazmín; Martínez‐Martínez, Marco Ulises; Oostdam, David Herrera-Van; Abud‐Mendoza, Carlos; Romano‐Moreno, Silvia; Milán‐Segovia, Rosa del Carmen

doi:10.1111/bcpt.13728

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…Recently, a randomized controlled study showed that daily therapy is as effective as weekly therapy when the polyglutamate-3 levels are similar. This study also showed that obese patients achieve a lower concentration of Mtx-PG3 ( 125 ). Clinical response in several other diseases like juvenile rheumatoid arthritis, juvenile dermatomyositis, and inflammatory bowel disease was also reported to be affected by the Mtx-PG concentrations.…”

Section: Methotrexatesupporting

confidence: 61%

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

et al. 2022

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Cytotoxic drugs are highly efficacious and also have low therapeutic index. A great degree of caution needs to be exercised in their usage. To optimize the efficacy these drugs need to be given at maximum tolerated dose which leads to significant amount of toxicity to the patient. The fine balance between efficacy and safety is the key to the success of cytotoxic chemotherapeutics. However, it is possibly more rewarding to obtain that balance for this class drugs as the frequency of drug related toxicities are higher compared to the other therapeutic class and are potentially life threatening and may cause prolonged morbidity. Significant efforts have been invested in last three to four decades in therapeutic drug monitoring (TDM) research to understand the relationship between the drug concentration and the response achieved for therapeutic efficacy as well as drug toxicity for cytotoxic drugs. TDM evolved over this period and the evidence gathered favored its routine use for certain drugs. Since, TDM is an expensive endeavor both from economic and logistic point of view, to justify its use it is necessary to demonstrate that the implementation leads to perceivable improvement in the patient outcomes. It is indeed challenging to prove the utility of TDM in randomized controlled trials and at times may be nearly impossible to generate such data in view of the obvious findings and concern of compromising patient safety. Therefore, good quality data from well-designed observational study do add immense value to the scientific knowledge base, when they are examined in totality, despite the heterogeneity amongst them. This article compiles the summary of the evidence and the best practices for TDM for the three cytotoxic drug, busulfan, 5-FU and methotrexate. Traditional use of TDM or drug concentration data for dose modification has been witnessing a sea change and model informed precision dosing is the future of cytotoxic drug therapeutic management.

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Section: Methotrexatesupporting

confidence: 61%

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

et al. 2022

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“…In those patients with low MTX‐PG 3 levels (mostly younger patients in our cohort (data not shown)) despite treatment with a maximal dosage of 25 mg/week MTX SC, alternative approaches to MTX administration are currently being explored. These include daily rather than weekly dosing schemes (5 days per week, divided weekly dose), 28 pH‐sensitive and colon‐specific nanoparticles loaded with MTX to target the gut specifically, 29 and addition of PK enhancers to MTX, such as efflux transporter blockers (MTX Forte, Amplio Pharma, Sweden). Further research is necessary to evaluate the added value of these new MTX administration strategies.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic drug monitoring of methotrexate in patients with Crohn's disease

van de Meeberg,

Fidder,

Oldenburg

et al. 2023

Aliment Pharmacol Ther

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SummaryBackgroundTherapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate‐polyglutamate (MTX‐PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD).AimTo investigate the relationship between MTX‐PGs and methotrexate drug survival, efficacy and toxicityMethodsIn a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step‐up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX‐PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation.ResultsWe included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 μg/g (IQR 73–480). After the 12‐month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty‐one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX‐PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75–0.99), lower FCP (β −3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 μg/g; OR 1.1, 95% CI 1.0–1.3). Higher MTX‐PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX‐PGs and HBI or hepatotoxicity.ConclusionsHigher MTX‐PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX‐PG3 could be used for TDM if a target concentration can be established.

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“…1 finden sich Angaben zu bDMARD, bei denen dies beschrieben wurde. Auch bei MTX ist ein therapeutisches "Drug-Monitoring" möglich [54]. Unzureichende (und auch deutlich zu hohe) Medikamentenspiegel können durch interagierende Medikamente, neutralisierende Antikörper, v. a. aber durch "Non-Compliance", verursacht werden.…”

Section: Ursachen Eines Therapierefraktären Verlaufesunclassified

Behandlung therapierefraktärer Verläufe der polyartikulären JIA

Haas

2023

Arthritis und Rheuma

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ZUSAMMENFASSUNGAls juvenile idiopathische Arthritis (JIA) wird eine Arthritis mit einer Dauer von mehr als 6 Wochen bezeichnet, wenn: (i) sie vor dem 16. Lebensjahr erstmalig auftritt und (ii) keine anderen Ursachen gefunden werden können. Aus heutiger Sicht lassen sich mindestens 4 Gruppen kindlicher rheumatischer Polyarthritis differenzieren: (a) die zumeist ANA-positiven, Rheumafaktor-negativen kindlichen Formen (eo-JIA und RF– pJIA), (b) die Rheumafaktor-positive Form mit Beginn im Kindes- und Jugendalter (RF+ pJIA), (c) eine polyartikuläre Verlaufsform der sJIA ohne Symptome systemischer Inflammation, (d) die monogenetisch bedingte Polyarthritis aufgrund einer LACC1/FAMIN-Mutation. Letztere ist damit eigentlich keine rheumatische, sondern eine hereditäre Polyarthritis. Ausgehend von den ProKind-Protokollen zur Therapie der polyartikulären JIA wird das Vorgehen bei Nichterreichen der angestrebten Therapieziele erarbeitet. Dies sind neben ausführlicher Diagnostik und Dokumentation der Aktivität die Einschätzung von Komorbiditäten (z. B. Infektionen), Medikamenteninteraktionen und Problemen der „Non-Compliance“ bzw. „Non-Adherence“. Neben Maßnahmen zur Therapie einer fortbestehenden lokalen therapierefraktären Aktivität werden systemische Therapieoptionen, insbesondere die neu verfügbaren Januskinase-Inhibitoren (JAKi), diskutiert.

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Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low‐dose methotrexate in patients recently diagnosed with rheumatoid arthritis

Cited by 4 publications

References 47 publications

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices

Therapeutic drug monitoring of methotrexate in patients with Crohn's disease

Behandlung therapierefraktärer Verläufe der polyartikulären JIA

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