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Effect of Genetic Polymorphisms on the Pharmacokinetics of Deferasirox in Healthy Chinese Subjects and an Artificial Neural Networks Model for Pharmacokinetic Prediction

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Deferasirox is an oral iron chelator used to reduce iron levels in iron-overloaded patients with transfusion-dependent anemia or non-transfusion-dependent thalassemia. This study investigated the effects of genetic polymorphisms on the pharmacokinetics of deferasirox in healthy Chinese subjects and constructed a pharmacokinetic prediction model based on physiologic factors and genetic polymorphism data.

Methods

Twenty-eight subjects were enrolled in a randomized, open-label, two-period crossover study, and they received a single dose of one of two formulations of deferasirox (20 mg/kg) with a 7-day washout interval between the two periods. The plasma defersirox concentration was determined using a validated liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were calculated using the noncompartmental method. The polymorphisms of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), UGT1A3, multidrug resistance protein 2 (MRP2), cytochrome P450 1A1 (CYP1A1), and breast cancer resistance protein 1 (BCRP1) were genotyped using Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was used to predict the pharmacokinetics.

Results

The UGT1A1 rs887829 C > T single-nucleotide polymorphism (SNP) significantly influenced the area under the plasma concentration-time curve and the terminal half-life. Neither the MRP2 rs2273697 G > A SNP nor BCRP1 rs2231142 G > T SNP altered the absorption, disposition, and excretion of the drug. The BP-ANN model had a high goodness-of-fit index and good coherence between the predicted and measured concentrations (R2 = 0.921).

Conclusion

Metabolic enzyme-related genetic polymorphisms were more strongly associated with the pharmacokinetics of deferasirox than membrane transporter-related genetic polymorphisms in the Chinese population.

Trial registration: www.Chinadrugtrials.org.cn CTR20191164

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Acknowledgements

We would like to thank participating subjects and to acknowledge all clinical center personnel who contributed to conduct of this study. We thank Joe Barber Jr., PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English test of a draft of this manuscript.

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Authors and Affiliations

  1. Center of Clinical Pharmacology, School of Medicine, The Second Affiliated Hospital of Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China

    Jinliang Chen, Yichao Xu, Honggang Lou, Bo Jiang, Rong Shao, Dandan Yang, Yin Hu & Zourong Ruan

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  1. Jinliang Chen
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  2. Yichao Xu
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  3. Honggang Lou
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Corresponding author

Correspondence to Zourong Ruan.

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Author Contributions

JC: designed and conceived the study, analyzed the data, and wrote the original version; YX: conceived the study and developed the BP-ANN model; ZR: designed and conceived the study and performed the pharmacokinetics analysis; HL, BJ, RS, DY, and YH conceived the study. All authors were involved in reviewing the manuscript and approved the final version.

Funding

This study was supported by the National Major Science and Technology projects of China (No. 2020ZX09201022). This study was funded by Jiangsu Aosaikang Pharmaceutical Co., Ltd.

Conflict of Interest

All authors (JC, YX, HL, BJ, RS, DY, YH, and ZR) report no conflicts of interest in this work.

Ethics Approval

The protocol and amendment of the study were reviewed and approved by the Human Subject Research Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine (Hangzhou, Zhejiang, China). The ethics approval number is 2018–672. This study was registered at www.Chinadrugtrials.org.cn (CTR20191164). The study was conducted at the Phase I Clinical Trials Unit (the Second Affiliated Hospital of Zhejiang University School of Medicine) in accordance with Good Clinical Practices and the ethical principles enunciated in the amended Declaration of Helsinki (revised version of Fortaleza, 2013). Documented written informed consent was obtained from each subject before any protocol-related investigations or procedures.

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Documented written informed consent was obtained from each subject before any protocol-related investigations or procedures.

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Chen, J., Xu, Y., Lou, H. et al. Effect of Genetic Polymorphisms on the Pharmacokinetics of Deferasirox in Healthy Chinese Subjects and an Artificial Neural Networks Model for Pharmacokinetic Prediction. Eur J Drug Metab Pharmacokinet 45, 761–770 (2020). https://doi.org/10.1007/s13318-020-00647-z

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  • DOI: https://doi.org/10.1007/s13318-020-00647-z

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