Multicentric Case–Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease

Stocco, Gabriele; Martelossi, Stefano; Arrigo, S.; Barabino, A.; Aloi, Marina; Martinelli, Massimo; Miele, Erasmo; Knafelz, D.; Romano, Claudio; Naviglio, Samuele; Favretto, Diego; Cuzzoni, Eva; Franca, Raffaella; Decorti, Giuliana; Ventura, Alessandro

doi:10.1097/mib.0000000000001051

Cited by 13 publications

(8 citation statements)

References 35 publications

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“…Azathioprine dose is strongly associated with patients’ age in the present study, an observation consistent with our previous results in children with IBD, showing that these patients require higher doses of azathioprine to achieve similar therapeutic efficacy and TGN concentration [25]. TPMT activity indeed is significantly higher in children than in adults [26]; interestingly, in pediatric patients (age less than 18 years), we could observe a lower ratio of TGN/azathioprine dose, as in our previous report.…”

Section: Discussionsupporting

confidence: 93%

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

Lucafò

Stocco

Martelossi

et al. 2019

Genes

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The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.

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Section: Discussionsupporting

confidence: 93%

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

Lucafò

Stocco

Martelossi

et al. 2019

Genes

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“…Another planned RCT aims to assess the need for different protocols of personalized therapy in early onset IBD (children under 6 years of age) because these patients are less responsive and have higher rates of azathioprine and infliximab failure and adverse events than older children. 105–107…”

Section: Discussion Gap Analysis and Outlookmentioning

confidence: 99%

Challenges in Therapeutic Drug Monitoring: Optimizing Biological Treatments in Patients With Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases

Papamichael

Stocco

Agua

2023

Therapeutic Drug Monitoring

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Background: Therapeutic drug monitoring (TDM) is a decision-making tool for optimizing the use of certain therapies. In this article, the authors review the role of proactive TDM of biological agents in patients with inflammatory bowel disease (IBD) and other immune-mediated inflammatory diseases (IMID). They also discuss the future of TDM as a component of personalized medicine from the clinical laboratory perspective. Methods: This narrative review originated from proceedings of the fifth biannual Challenges in Therapeutic Drug Monitoring seminar and was supplemented by additional literature identified at various stages of critical review. Results: Proactive TDM aims to achieve adequate concentrations of biological drugs, such that patients attain and maintain an optimal treatment response. Proactive TDM may also have a role in de-escalating anti–tumor necrosis factor therapy in patients in clinical remission and in optimizing infliximab monotherapy as an alternative to combination therapy with an immunomodulator. A major proactive TDM application is in pediatric patients with IBD. Achieving mucosal healing in children with IBD requires that infliximab or adalimumab concentrations are monitored early during induction therapy, with dose modifications guided by the timing (week) of measurement. Recent innovations in biological therapy include international standards for infliximab and adalimumab for the global harmonization of bioactivity and monotest devices with an accuracy equivalent to that of conventional enzyme-linked immunosorbent assays and quicker turnaround times. Conclusions: Despite several knowledge gaps regarding proactive TDM of anti–tumor necrosis factor therapy in patients with IMID, growing evidence suggests that it is associated with better outcomes than empiric optimization and/or reactive TDM in IBD. Enhanced pharmacokinetic modeling to predict drug exposure and patient genotyping for the precise application of proactive TDM are considered key elements to optimize biological therapy in the future.

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“…Therefore, these patients would benefit from changing their therapy to another class of medication, such as methotrexate or biologicals. It has been suggested that metabolite testing might be especially useful in younger children (< 6 years), who typically need higher dosages (up to 3 mg/kg/day) to have a sustained clinical effect and in order to have metabolite levels within the therapeutic range [86,87]. This is at least partially explained Fig.…”

Section: Monitoring Of Thiopurine Metabolite Levelsmentioning

confidence: 99%

Thiopurines in Pediatric Inflammatory Bowel Disease: Current and Future Place

Hoeve

Vermeire

2020

Pediatr Drugs

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Thiopurines have been widely used to maintain steroid-free remission in children with inflammatory bowel disease (IBD). However, within the expanding treatment armamentarium, the role of these non-selective immunomodulators has been questioned, especially in pediatric patients, who often present with a more aggressive disease course, which can impact growth and development. The less favorable safety but also inferior efficacy profile associated with thiopurines, in contrast to the newer biological therapies, has interfered with their use. The future place of thiopurines in the management of childhood IBD, therefore, needs revisiting. This review provides a practical overview on the historical and current use of thiopurines in pediatric IBD with specific attention for thiopurine S-methyltransferase testing and monitoring of thiopurine metabolite levels as an approach to improve outcomes. We also give a personal expert opinion on the future role of these drugs in childhood IBD.

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Multicentric Case–Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease

Abstract: This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.

Cited by 13 publications

References 35 publications

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

Challenges in Therapeutic Drug Monitoring: Optimizing Biological Treatments in Patients With Inflammatory Bowel Disease and Other Immune-Mediated Inflammatory Diseases

Thiopurines in Pediatric Inflammatory Bowel Disease: Current and Future Place

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