Azathioprine Therapy in a Pediatric TPMT-Deficient Patient—Still an Option

Moorsel, Sofia A. W. van; Bevers, Nanja; Meurs, Marjan van; Rossum, L. K. van; Hooymans, P. M.; Wong, Dennis R.

doi:10.1097/ftd.0000000000000366

Cited by 5 publications

(2 citation statements)

References 11 publications

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“…A recent study suggested that enzyme-inducing antiepileptic drugs such as carbamazepine and oxcarbazepine might increase the apparent clearance of LEV by more than 40%. 27 In our cohort, only five women were treated with enzyme-inducing antiepileptic drugs. However, these women were already on stable polytherapy before pregnancy and no dose change was made during the pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic levetiracetam monitoring during pregnancy: “mind the gap”

Berlin

Barchel

Gandelman-Marton

et al. 2019

Therapeutic Advances in Chronic Disease

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Background: Epilepsy is one of the most common chronic neurological conditions and its treatment during pregnancy is challenging. Levetiracetam (LEV) is an antiepileptic medication frequently used during pregnancy. Only a few small studies have been published on LEV monitoring during pregnancy, demonstrating decreased serum LEV levels during the first and second trimester; however, the most significant decrease was observed during the third trimester of pregnancy. In this study we aimed to evaluate LEV pharmacokinetics during different stages of pregnancy. Methods: We followed up and monitored serum levels of pregnant women treated with LEV for epilepsy. Results: Fifty-nine women with 66 pregnancies during the study period were included. The lowest raw LEV serum concentrations were observed during the first trimester. Compared with the pre-pregnancy period, raw serum concentration was lower by 5.76 mg/L [95% confidence interval (CI) (2.78, 8.75), p = 0.039] during the first trimester. Comparing the decrease in the first trimester with either the second or the third, no significant changes were observed ( p = 0.945, p = 0.866). Compared with pre-pregnancy measurements, apparent clearance was increased by 71.08 L/day [95%CI (16.34, 125.83), p = 0.011] during the first trimester. About 30% of LEV serum levels during pregnancy were below the laboratory quoted reference range. Conclusions: Raw LEV serum levels tend to decrease during pregnancy, mainly during the first trimester contrary to previous reports. Monitoring of LEV serum levels is essential upon planning pregnancy and thereafter if pre-pregnancy LEV levels are to be maintained. However, more studies are needed to assess the correlation with clinical outcome.

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Section: Discussionmentioning

confidence: 99%

Therapeutic levetiracetam monitoring during pregnancy: “mind the gap”

Berlin

Barchel

Gandelman-Marton

et al. 2019

Therapeutic Advances in Chronic Disease

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“…Especially patients with a homozygous genetic variant in TPMT (~0.3% of the population), and to a lesser degree patients with a heterozygous variant in TPMT (~10% of the population) are at increased risk for severe, life‐threatening, myelosuppression when treated with the standard recommended dose of azathioprine (AZA) or mercaptopurine (MP) . Leucopenia can be prevented by genotyping for these variants prior to initiation of thiopurine treatment and subsequently taper the thiopurine dose to 50% of the original dose in those heterozygous for a variant in TPMT and 0%‐10% of the original dose in patients with a homozygous variant . However, only up to 25% of the leucopenia cases can be explained by variants in TPMT , which makes that leucopenia is frequently observed in patients without a TPMT variant .…”

Section: Introductionmentioning

confidence: 99%

Risk factors for thiopurine‐induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype

Broekman

Coenen²,

Wanten

et al. 2017

Aliment Pharmacol Ther

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SummaryBackgroundLeucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S‐methyltransferase (TPMT) gene are the best‐known risk factor, but only explain up to 25% of leucopenia cases.AimTo identify the clinical risk factors for thiopurine‐induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections.MethodsPost hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni‐ and multivariate Cox‐proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 × 109/L and infections were classified according to the Common Terminology Criteria for Adverse Events.ResultsSixty hundred and ninety‐five patients (90.6%) included in the TOPIC‐trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29‐112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39‐4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71‐0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18‐3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14‐4.07; P = .02]).ConclusionsLow baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine‐induced leucopenia in patients without a TPMT variant.

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