Effect of Genetic Polymorphisms on the Pharmacokinetics of Deferasirox in Healthy Chinese Subjects and an Artificial Neu
- PDF / 1,800,998 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 14 Downloads / 216 Views
ORIGINAL RESEARCH ARTICLE
Effect of Genetic Polymorphisms on the Pharmacokinetics of Deferasirox in Healthy Chinese Subjects and an Artificial Neural Networks Model for Pharmacokinetic Prediction Jinliang Chen1 · Yichao Xu1 · Honggang Lou1 · Bo Jiang1 · Rong Shao1 · Dandan Yang1 · Yin Hu1 · Zourong Ruan1
© Springer Nature Switzerland AG 2020
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 backpropagation 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
1 Introduction Deferasirox is an oral iron chelator used to reduce iron levels in iron-overloaded patients with transfusion-dependent anemia or non-transfusion-dependent thalassemia. It is a tridentate ligand with high specificity and affinity for ferric ion. The absolute oral bioavailability of deferasirox is approximately 70%, and the maximum plasma concentration (Cmax) is reached at 1.5–4 h after oral administration [1]. An approximately linear, dose-dependent relationship between Cmax and the area under the plasma concentration-time * Zourong Ruan [email protected] 1
Key Points The relationships between gene polymorphisms and deferasirox pharmacokinetics in the Chinese population are unclear This study revealed that metabolic enzyme-related gene polymor
Data Loading...
