ABCC2 c.-24 C&gt;T single-nucleotide polymorphism was associated with the pharmacokinetic variability of deferasirox in Chinese subjects

Cao, Kangna; Ren, Guanghui; Lu, Chengcan; Wang, Yao; Tan, Yanan; Zhou, Jing; Zhang, Yongjie; Lu, Yang; Li, Ning; Chen, Xijing; Zhao, Di

doi:10.1007/s00228-019-02775-1

Cited by 12 publications

(7 citation statements)

References 40 publications

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“…The results of the quality assessment are presented in Supplementary Table S5 . Most of the studies (12 of 13) yielded STREGA scores above 50%, indicating moderate (4 studies ( Chirnomas et al, 2009 ; Cusato et al, 2015 ; Mattioli et al, 2015 ; Chen et al, 2020 )) to high quality studies (8 studies ( Lee et al, 2013 ; Cusato et al, 2016 ; Allegra et al, 2017 ; Allegra et al, 2018a ; Allegra et al, 2018b ; Allegra et al, 2018c ; Allegra et al, 2019 ; Cao et al, 2020 )).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the reduced DFX dispositions were reported in 10 SNPs including ABCC2 rs717620, UGT1A1 rs887829, UGT1A3 rs1983023, CYP24A1 rs2248359 and rs2585428, CYP27B1 rs4646536 and rs10877012, VDR rs7975232 and rs11568820, and VDBP rs7041 ( Cusato et al, 2015 ; Cusato et al, 2016 ; Allegra et al, 2018a ; Allegra et al, 2018b ; Cao et al, 2020 ; Chen et al, 2020 ). Chinese carrying the T allele of ABCC2 rs717620 had lower DFX AUC and clearance concurring with shorter half-life and mean residence time (MRT) ( Cao et al, 2020 ). The Chinese T carriers of UGT1A1 rs887829 ( UGT1A1*80 ) had lower AUC and half-life ( Chen et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

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Genetic polymorphisms influencing deferasirox pharmacokinetics, efficacy, and adverse drug reactions: a systematic review and meta-analysis

et al. 2023

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Objective: Deferasirox is an iron-chelating agent prescribed to patients with iron overload. Due to the interindividual variability of deferasirox responses reported in various populations, this study aims to determine the genetic polymorphisms that influence drug responses.Methods: A systematic search was performed from inception to March 2022 on electronic databases. All studies investigating genetic associations of deferasirox in humans were included, and the outcomes of interest included pharmacokinetics, efficacy, and adverse drug reactions. Fixed- and random-effects model meta-analyses using the ratio of means (ROM) were performed.Results: Seven studies involving 367 participants were included in a meta-analysis. The results showed that subjects carrying the A allele (AG/AA) of ABCC2 rs2273697 had a 1.23-fold increase in deferasirox Cmax (ROM = 1.23; 95% confidence interval [CI]:1.06–1.43; p = 0.007) and a lower Vd (ROM = 0.48; 95% CI: 0.36–0.63; p < 0.00001), compared to those with GG. A significant attenuated area under the curve of deferasirox was observed in the subjects with UGT1A3 rs3806596 AG/GG by 1.28-fold (ROM = 0.78; 95% CI: 0.60–0.99; p = 0.04). In addition, two SNPs of CYP24A1 were also associated with the decreased Ctrough: rs2248359 CC (ROM = 0.50; 95% CI: 0.29–0.87; p = 0.01) and rs2585428 GG (ROM = 0.47; 95% CI: 0.35–0.63; p < 0.00001). Only rs2248359 CC was associated with decreased Cmin (ROM = 0.26; 95% CI: 0.08–0.93; p = 0.04), while rs2585428 GG was associated with a shorter half-life (ROM = 0.44; 95% CI: 0.23–0.83; p = 0.01).Conclusion: This research summarizes the current evidence supporting the influence of variations in genes involved with drug transporters, drug-metabolizing enzymes, and vitamin D metabolism on deferasirox responses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Genetic polymorphisms influencing deferasirox pharmacokinetics, efficacy, and adverse drug reactions: a systematic review and meta-analysis

et al. 2023

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“…The patients suffering from hematological toxicities only had C trough values below the threshold of 7.0 mg/L, hence our results suggest that factors other than the sole drug exposure (i.e., AUC) could be responsible for the onset and the severity of neutropenia or anemia. As a matter of fact, several studies focused on the role of pharmacogenetic determinants (i.e., gene polymorphisms) and pharmacokinetic interindividual variability, including genes coding for both enzymes (CYP and UGT isoforms) and transmembrane transporters [ 20 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Pharmacokinetics and Pharmacodynamics of Deferasirox in Pediatric Patients

Galeotti¹,

Ceccherini²,

Fucile

et al. 2021

Pharmaceutics

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Background: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2–17 years, who underwent an allogeneic hematopoietic stem cell transplantation. Methods: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. Results: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (Ctrough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher’s exact tests) when Ctrough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. Conclusions: The population pharmacokinetic model described the interindividual variability and identified Ctrough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

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“…Some preclinical models may provide insight into a single characteristic of NASH, but none can provide a comprehensive overview of all changes in enzyme and transporter expression or function 15 . A small number of studies have reported drugs that present risk of ADRs in patients with preexisting liver diseases ( Table 1 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , ...…”

Section: Adverse Drug Reactions In Liver Diseasementioning

confidence: 99%

Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients

Marie

Frost²,

Hau³

et al. 2023

Acta Pharmaceutica Sinica B

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ABCC2 c.-24 C>T single-nucleotide polymorphism was associated with the pharmacokinetic variability of deferasirox in Chinese subjects

Cited by 12 publications

References 40 publications

Genetic polymorphisms influencing deferasirox pharmacokinetics, efficacy, and adverse drug reactions: a systematic review and meta-analysis

Genetic polymorphisms influencing deferasirox pharmacokinetics, efficacy, and adverse drug reactions: a systematic review and meta-analysis

Evaluation of Pharmacokinetics and Pharmacodynamics of Deferasirox in Pediatric Patients

Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients

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