A model analysis for dose–response relationship of warfarin in Japanese children: An introduction of the SIZE parameter

Nakamura, Saki; Watanabe, Nao; Yoshimura, Naoki; Ozawa, Sayaka; Hirono, Keiichi; Ichida, Fukiko; Taguchi, Masato

doi:10.1016/j.dmpk.2016.03.007

Cited by 3 publications

(5 citation statements)

References 23 publications

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“…Index for Response to Warfarin In this study, the PT-INR values normalized by daily-dose per SIZE 6) was used as an anticoagulant index for the warfarin effects.…”

Section: Subjects and Data Collection Case Reportmentioning

confidence: 99%

“…Genotyping of CYP2C9 and Vitamin K Epoxide Reductase Complex 1 (VKORC1) Genotypes of CYP2C9 and VKORC1 were determined in this study and our previous study. 6,12) We determined CYP2C9 genotypes by using the PCR-restriction fragment length polymorphism (PCR-RFLP) method and confirmed the VKORC1 1173 C > T variant by direct sequencing. 12) Data Analysis Values were shown as the mean ± standard deviation (S.D.).…”

Section: Anticoagulant Index :Pt-inr /(Dose /Size)mentioning

confidence: 99%

“…We previously demonstrated that the rational pediatric dosage of warfarin can be welldescribed by a body size (SIZE) parameter that includes an allometry exponent of weight. 6,7) The SIZE parameter is useful to describe the response to warfarin in pediatric patients. We encountered the interaction between warfarin and rifampicin via PXR in a pediatric patient with congenital heart disease in whom rifampicin was used for infective endocarditis (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…9) We previously reported that the combined administration of bosentan reversibly reduced the warfarin anticoagulant effects to 87.5% in pediatric patients. 6,7) Thus, we proposed paying attention to the changes in response to warfarin after the withdrawal of bosentan or switching to other drugs. On the other hand, the PXR activation effects of macitentan are thought to be negligible in clinical settings because the EC 50 value for PXR activation is higher than the therapeutic plasma concentrations of macitentan.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Concomitant Administration of PXR Ligand Drugs on the Anticoagulant Effects of Warfarin

Mito

Hirono

Ide

et al. 2022

Biological & Pharmaceutical Bulletin

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We encountered cases in which the anticoagulant effects of warfarin (CYP2C9 substrate) were reversibly attenuated by the concomitant administration of rifampicin or bosentan, which are potent pregnane X receptor (PXR) ligands. The purpose of the present study is to report the previous case with rifampicin, and to evaluate the changes in the warfarin anticoagulant effects when withdrawing or switching bosentan treatment. The former is a case study of a 4-year-old girl undergoing warfarin treatment. The latter is a longitudinal study of 20 pediatric patients receiving stable warfarin treatment. The prothrombin time and international normalized ratio (PT-INR) values were extracted from the medical records and normalized by the daily-dose per body size as an index for the warfarin anticoagulant effects. Rifampicin treatment resulted in a 52.0% decrease in the anticoagulant index. On the other hand, 10 of 20 patients started bosentan and their anticoagulant index was reduced by a median of 2.00. Bosentan was withdrawn in 4 of 20 patients and their anticoagulant index increased by a median of 3.67. Six of 20 patients switched from bosentan to macitentan, which is considered not to activate PXR in clinical settings. However, switching from bosentan to macitentan resulted in a median of 2.25 reduction of the anticoagulant index rather than recovery of the response to warfarin. This study suggests not only the possibility of heterogeneity in the response to PXR activation and deactivation, but also the importance of long-term monitoring of drug-drug interactions when switching from bosentan to macitentan.

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“…Index for Response to Warfarin In this study, the PT-INR values normalized by daily-dose per SIZE 6) was used as an anticoagulant index for the warfarin effects.…”

Section: Subjects and Data Collection Case Reportmentioning

confidence: 99%

Section: Anticoagulant Index :Pt-inr /(Dose /Size)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of Concomitant Administration of PXR Ligand Drugs on the Anticoagulant Effects of Warfarin

Mito

Hirono

Ide

et al. 2022

Biological & Pharmaceutical Bulletin

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“… investigated the possible impact of patient deconditioning and vitamin K intake or fasting upon the INR response to warfarin. Since 2010, 13 original studies and two meta‐analyses focused on warfarin pharmacogenomics have been published, and these were identified with this search strategy. Data synthesis of these studies confirms that the identified vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) and cytochrome P450 2CP ( CYP2CP ) variants probably contribute to a reduction in warfarin dosing requirements as compared with wild‐type alleles; however, all studies were conducted in patients with warfarin steady states, and most studies had small cohorts with limited ethnic diversity.…”

Section: Anticoagulant Therapy: Which Agent Intensity and Duration?mentioning

confidence: 99%

Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues

Newall

Branchford

Male

2018

Journal of Thrombosis and Haemostasis

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This review is aimed at describing the unique challenges of anticoagulant prophylaxis and treatment in children, and highlighting areas for research for improving clinical outcomes of children with thromboembolic disease. The evidence presented demonstrates the challenges of advancing the evidence base informing optimal management of thromboembolic disease in children. Recent observational studies have identified risk factors for venous thromboembolism in children, but there are few interventional studies assessing the benefit-risk balance of using thromboprophylaxis in risk-stratified clinical subgroups. A risk level-based framework is proposed for administering mechanical and pharmacological thromboprophylaxis. More research is required to refine the assignment of risk levels. The anticoagulants currently used predominantly in children are unfractionated heparin, low molecular weight heparin, and vitamin K antagonists. There is a paucity of robust evidence on the age-specific pharmacology of these agents, and their efficacy and safety for prevention and treatment of thrombosis in children. The available literature is heterogeneous, reflecting age-specific differences, and the various clinical settings for anticoagulation in children. Monitoring assays and target ranges are not well established. Nevertheless, weight-based dosing appears to achieve acceptable outcomes in most indications. Given the limitations of the classical anticoagulants for children, there is great interest in the direct oral anticoagulants (DOACs), whose properties appear to be particularly suitable for children. All DOACs currently approved for adults have Pediatric Investigation Plans ongoing or planned. These are generating age-specific formulations and systematic dosing information. The ongoing pediatric studies still have to establish whether DOACs have a positive benefit-risk balance in the various pediatric indications and age groups.

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Evaluation of the effects of ontogenetic or maturation functions and chronic heart failure on the model analysis for the dose-response relationship of warfarin in Japanese children

Tamura

Watanabe

Nakamura

et al. 2019

Eur J Clin Pharmacol

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A model analysis for dose–response relationship of warfarin in Japanese children: An introduction of the SIZE parameter

Cited by 3 publications

References 23 publications

Effects of Concomitant Administration of PXR Ligand Drugs on the Anticoagulant Effects of Warfarin

Effects of Concomitant Administration of PXR Ligand Drugs on the Anticoagulant Effects of Warfarin

Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues

Evaluation of the effects of ontogenetic or maturation functions and chronic heart failure on the model analysis for the dose-response relationship of warfarin in Japanese children

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