Effect of Sex, Use of Pantoprazole and Polymorphisms in SLC22A1, ABCB1, CES1, CYP3A5 and CYP2D6 on the Pharmacokinetics and Safety of Dabigatran

Zubiaur, Pablo; Saiz‐Rodríguez, Miriam; Ochoa, Dolores; Navares‐Gómez, Marcos; Mejía, Gina; Román, Manuel; Koller, Dóra; Soria‐Chacartegui, Paula; Almenara, Susana; Abad‐Santos, Francisco

doi:10.1007/s12325-020-01414-x

Cited by 20 publications

(32 citation statements)

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“…This was contrary to the conclusion that gender did not affect the exposure of dabigatran in a previous study. 15 The genotypes of 104 healthy Chinese subjects were obtained in this study, CES1 rs2244613 allele C accounted for 61.1%, CES1 rs8192935 allele G accounted for 24%. ABCB1 rs1045642 allele A accounted for 43.8% and ABCB1 rs414738 allele C accounted for 43.8%.…”

Section: Discussionmentioning

confidence: 95%

“…This flexibility in dabigatran metabolism suggested that the deficiency of CES1 might be compensated by the activation of the intestinal CES2. 15,20 It may explain the divergence between the conclusions of the different studies. More clinical trials are still needed to confirm further the role of the CES1 gene in the metabolism of Dabigatran.…”

Section: Discussionmentioning

confidence: 98%

“…The relationship between ABCB1 rs2032582 and the pharmacokinetics of dabigatran had only been reported in haplotype-based studies. 15,22 Haplotype 2677-3435 was inferred by exclusively considering ABCB1 rs2032582, rs1045642 variants, and haplotype 1236-2677-34355 was inferred by exclusively considering ABCB1 rs1128503, rs2032582 and rs1045642. The two haplotypes were not significantly associated with variability on dabigatran exposure.…”

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confidence: 99%

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

Liu¹,

Yang²,

Wei³

et al. 2021

PGPM

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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 dabigatranrelated 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-∞ .

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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

Liu¹,

Yang²,

Wei³

et al. 2021

PGPM

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“…46 SNPs in 14 genes were analyzed: CYP1A2 *1C (rs2069514), *1F (rs762551), *1B (rs2470890), CYP2A6 *9 (rs28399433), CYP2B6 *9 (rs3745274), *5 (rs3211371), rs4803419, rs2279345, rs2279343, CYP2C8 *2 (rs11572103), *3 (rs10509681), *4 (rs1058930), CYP2C9 *2 (rs1799853), *3 (rs1057910), CYP2C19 *2 (rs4244285), *3 (rs4986893), *4 (rs28399504), *17 (rs12248560), CYP2D6 *3 (rs35742686), *4 (rs3892097), *6 (rs5030655), *7 (rs5030867), *8 (rs5030865), *9 (rs5030656), *10 (rs1065852), *14 (rs5030865), *17 (rs28371706), *41 (rs28371725), CYP3A4 *22 (rs35599367), rs55785340, rs4646438, CYP3A5 *3 (rs776746), *6 (rs10264272), ABCB1 C3435T (rs1045642), G2677 T/A (rs2032582), C1236T (rs1128503), ABCC2 c.1247G>A (rs2273697), rs717620, SLCO1B1 *1B (rs2306283), *5 (rs4149056), c.-910G > A (rs4149015), rs11045879, SLC22A1 *2 (rs72552763), *3 (rs12208357), *5 (rs34059508), and UGT1A1 *80 (rs887829). A CYP2D6 copy number variation assay (CNV) was performed following the methodology previously reported ( Zubiaur et al, 2020 ). For the genotyping, a QuantStudio 12 k flex was used with two thermal blocks: the OpenArray for the genotyping of variants and the 96-well fast thermal-block for CNV determination ( Zubiaur et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…A CYP2D6 copy number variation assay (CNV) was performed following the methodology previously reported ( Zubiaur et al, 2020 ). For the genotyping, a QuantStudio 12 k flex was used with two thermal blocks: the OpenArray for the genotyping of variants and the 96-well fast thermal-block for CNV determination ( Zubiaur et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

et al. 2021

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Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

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Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics

Thompson

Davis

Narayan

et al. 2022

Clin Pharma and Therapeutics

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Oral anticoagulants (OACs) are commonly used to reduce the risk of venous thromboembolism and the risk of stroke in patients with atrial fibrillation. Endorsed by the American Heart Association, American College of Cardiology, and the European Society of Cardiology, direct oral anticoagulants (DOACs) have displaced warfarin as the OAC of choice for both conditions, due to improved safety profiles, fewer drug-drug and drug-diet interactions, and lack of monitoring requirements. Despite their widespread use and improved safety over warfarin, DOAC-related bleeding remains a major concern for patients. DOACs have stable pharmacokinetics and pharmacodynamics; however, variability in DOAC response is common and may be attributed to numerous factors, including patient-specific factors, concomitant medications, comorbid conditions, and genetics. Although DOAC randomized controlled trials included patients of varying ages and levels of kidney function, they failed to include patients of diverse ancestries. Additionally, current evidence to support DOAC pharmacogenetic associations have primarily been derived from European and Asian individuals. Given differences in genotype frequencies and disease burden among patients of different biogeographic groups, future research must engage diverse populations to assess and quantify the impact of predictors on DOAC response. Current under-representation of patients from diverse racial groups does not allow for proper generalization of the influence of clinical and genetic factors in relation to DOAC variability. Herein, we discuss factors affecting DOAC response, such as age, sex, weight, kidney function, drug interactions, and pharmacogenetics, while offering a new perspective on the need for further research including frequently excluded groups.

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Effect of Sex, Use of Pantoprazole and Polymorphisms in SLC22A1, ABCB1, CES1, CYP3A5 and CYP2D6 on the Pharmacokinetics and Safety of Dabigatran

Cited by 20 publications

References 29 publications

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

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

Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics

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