Genotype-Guided Prescription of Azathioprine Reduces the Incidence of Adverse Drug Reactions in TPMT Intermediate Metabolizers to a Similar Incidence as Normal Metabolizers

Casajús, Ana; Zubiaur, Pablo; Méndez, Marta; Campodónico, Diana; Gómez, A López; Navares‐Gómez, Marcos; Villapalos‐García, Gonzalo; Soria‐Chacartegui, Paula; Novalbos, Jesús; Román, Manuel; Mejía‐Abril, Gina; Ochoa, Dolores; Abad‐Santos, Francisco

doi:10.1007/s12325-022-02067-8

Cited by 13 publications

(10 citation statements)

References 15 publications

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“…Genotyping routinely in patients with CVS for CYP2C19 and CYP2D6 has the potential to tailor management at the outset and optimize outcomes in CVS. This is akin to testing for the thiopurine S‐methyltransferase (TPMT) in inflammatory bowel disease (IBD) 13,27 . TPMT metabolizes thiopurine drugs, such as azathioprine and 6‐mercaptopurine, which are commonly used in the treatment of IBD.…”

Section: Discussionmentioning

confidence: 99%

“…This contrasts with other areas like IBD where pharmacogenomics is utilized routinely to manage and individualize care such as in testing for TPMT genotype prior to initiating azathioprine. 13 The utility of pharmacogenomics in objectively predicting the risk of ADRs and optimizing treatment with AT can allow for personalized management of patients with CVS.…”

Section: Introductionmentioning

confidence: 99%

“…The Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, 10 but this is not followed in clinical practice in the management of CVS and other DGBI. This contrasts with other areas like IBD where pharmacogenomics is utilized routinely to manage and individualize care such as in testing for TPMT genotype prior to initiating azathioprine 13 . The utility of pharmacogenomics in objectively predicting the risk of ADRs and optimizing treatment with AT can allow for personalized management of patients with CVS.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome

Patel,

Partovi,

Karrento

et al. 2023

Neurogastroenterology Motil

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BackgroundAmitriptyline (AT) is recommended as first‐line prophylactic therapy in patients with cyclic vomiting syndrome (CVS). However, significant side effects limit its use and dosing is based on trial and error. Though the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, this is not followed in clinical practice.MethodsThis pilot study determined CYP2C19 and CYP2D6 genotypes and ascertained its association with adverse drug reactions (ADRs), clinical response, and serum concentration of AT and nortriptyline in a well‐characterized cohort of adults with CVS.Key ResultsOf 46 subjects with CVS, age 33 ± 12 years, 61% female, 85% Caucasian, a third (33%) had normal CYP2C19 metabolizer status, while 4% were poor, and 43% were ultrarapid metabolizers. Most (61%) had normal CYP2D6 genotype while 9% were poor and 2% were ultra‐rapid metabolizers. There was no statistically significant association between genotype and ADRs, clinical response or serum drug concentration. There was a trend towards significance between genotype and clinical response, with 64% of responders having normal CYP2D6 metabolism versus 36% of nonresponders (p = 0.06). ADRs were encountered in 46% of patients with 28% discontinuing the medication as a result.Conclusions and InferencesA subset of patients with CVS have dysfunctional alleles of CYP2C19 and CYP2D6. Larger prospective studies to evaluate the clinical impact of pharmacogenomic testing in CVS are needed. This has the potential to optimize clinical management, predict ADRs and allow for personalized therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome

Patel,

Partovi,

Karrento

et al. 2023

Neurogastroenterology Motil

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show abstract

“…Nevertheless, the latter population needs more doses to resist rapid intermediate metabolite inactivation (Yates et al, 1997). Studies have shown that TPMT genotyping and dose adjustment before using AZA can reduce the incidence of ADR in intermediate metabolites to a level similar to normal metabolism in the Spanish population (Casajus et al, 2022).…”

Section: Mycophenolate Mofetil and Azathioprinementioning

confidence: 99%

Individualized medication based on pharmacogenomics and treatment progress in children with IgAV nephritis

Yang

et al. 2022

Front. Pharmacol.

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Immunoglobulin A vasculitis (IgAV) nephritis, also known as Henoch-Schönlein purpura nephritis (HSPN), is a condition in which small blood vessel inflammation and perivascular IgA deposition in the kidney caused by neutrophil activation, which more often leads to chronic kidney disease and accounts for 1%–2% of children with end-stage renal disease (ESRD). The treatment principles recommended by the current management guidelines include general drug treatment, support measures and prevention of sequelae, among which the therapeutic drugs include corticosteroids, immunosuppressive agents and angiotensin system inhibitors. However, the concentration range of immunosuppressive therapy is narrow and the individualized difference is large, and the use of corticosteroids does not seem to improve the persistent nephropathy and prognosis of children with IgAV. Therefore, individualized maintenance treatment of the disease and stable renal prognosis are still difficult problems. Genetic information helps to predict drug response in advance. It has been proved that most gene polymorphisms of cytochrome oxidase P450 and drug transporter can affect drug efficacy and adverse reactions (ADR). Drug therapy based on genetics and pharmacogenomics is beneficial to providing safer and more effective treatment for children. Based on the pathogenesis of IgAV, this paper summarizes the current therapeutic drugs, explores potential therapeutic drugs, and focuses on the therapeutic significance of corticosteroids and immunosuppressants in children with IgAV nephritis at the level of pharmacogenomics. In addition, the individualized application of corticosteroids and immunosuppressants in children with different genotypes was analyzed, in order to provide a more comprehensive reference for the individualized treatment of IgAV nephritis in children.

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“…However, its therapeutic usage has been limited due to its dose-dependent adverse effects like hepatotoxicity, gastric intolerance, and bone marrow toxicity (Ana Casajús et al 2022). Especially these adverse effects are more pronounced in thiopurine methyltransferase (TPMT) intermediate metabolizers (IMs) (Ana Casajús et al 2022). Drug withdrawal is required in up to 9% of the IBD patients due to hepatotoxicity concerns (Labidi et al 2020).…”

Section: Introductionmentioning

confidence: 99%

L-Ergothioneine protects hepatocytes against azathioprine-Induced toxicity via NIK/NF-ΚB signaling axis

Ramachandraboopathi

Sathanantham

2022

ijhs

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This research study has major implications for the development of ESH as a safe and holistic hepatoprotectant and could be used as an adjuvant in the treatment of IBD to minimize DILI. We demonstrate that ESH regulates oxidative stress, NIK/NF-κB-mediated inflammatory axis, and improves the hepatocellular integrity against AZA-provoked deleterious events in the hepatocytes (Figure 5). However, further research is warranted to elucidate the efficacy, specificity, and safety of ESH in AZA-treated patients with normal genetic makeup and gene polymorphisms.

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Genotype-Guided Prescription of Azathioprine Reduces the Incidence of Adverse Drug Reactions in TPMT Intermediate Metabolizers to a Similar Incidence as Normal Metabolizers

Cited by 13 publications

References 15 publications

Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome

Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome

Individualized medication based on pharmacogenomics and treatment progress in children with IgAV nephritis

L-Ergothioneine protects hepatocytes against azathioprine-Induced toxicity via NIK/NF-ΚB signaling axis

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