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The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects.

ABSTRACT: Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on C_max and AUC_0-∞.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8081719 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods:A total of 60 patients, aged 37-81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results:Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p<0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. Conclusion:Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations.

Project description:BACKGROUND AND OBJECTIVE:Dabigatran etexilate is a non-vitamin K antagonist oral anticoagulant (NOAC) that is used to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation (NVAF) and one or more risk factors. Pharmacokinetic data on this anticoagulant in Chinese subjects are limited. This study aimed to provide further information on the pharmacokinetic profile of dabigatran in healthy Chinese subjects, together with its safety profile. METHODS:This was an open-label, single-centre, phase I study. Subjects were randomized into 110 and 150 mg dabigatran etexilate treatment groups. Each subject received 7 days of treatment: a single dose on day 1, no dose on days 2-3, and then multiple doses on days 4-10. Blood samples were collected to analyze the pharmacokinetic profile of dabigatran. All adverse events (AEs) were recorded. Routine clinical laboratory tests, a physical examination, vital signs, and 12-lead electrocardiogram (ECG) measurements were performed. RESULTS:A total of 28 subjects (14 males and 14 females) were randomized in this trial. The plasma concentration of total dabigatran reached its maximum measured concentration at a median time of 3-4 h from the dose of interest (either the initial single dose on day 1 or the final dose on day 10) under fed conditions, and declined with an elimination half-life of 10.7-10.9 h following the dose of interest. There was a modest difference in pharmacokinetic profile between male and female subjects. None of the subjects experienced a serious adverse event (SAE) or an AE of moderate or severe intensity. The investigator reported that 17 of the 28 subjects had mild treatment-emergent AEs that resolved without any concomitant treatment or intervention. No clinically significant changes in vital signs or ECG parameters were observed. CONCLUSIONS:This study revealed the pharmacokinetic characteristics and good safety profile of dabigatran in healthy Chinese subjects.

Project description:STUDY OBJECTIVE:To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting ?2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects. DESIGN:Double-blind, placebo-controlled, single-site, randomized, four-way crossover study. SETTING:The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China. SUBJECTS:Sixteen healthy, nonsmoking Chinese adults. INTERVENTION:Subjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 ?g, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period. MEASUREMENTS AND MAIN RESULTS:The co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting ?2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 ?g, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 ?g but not with 200/25 ?g. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 ?g on day 1 and FF/VI 50/25 and 200/25 ?g on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 ?g ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects. CONCLUSION:In healthy Chinese subjects, minimal and non-clinically relevant ?-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 ?g. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 ?g. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 ?g.

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The Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects.

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