Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

Ren, Yirong; Yang, Chenguang; Chen, Hao; Dai, Da‐Peng; Wang, Yan; Zhu, Huolan; Wang, Fang

doi:10.3389/fphar.2020.01014

Cited by 6 publications

(10 citation statements)

References 28 publications

(39 reference statements)

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“…The estimated initial therapeutic dose of warfarin was 3.0 mg/day for the hypothetical patient, according to the algorithm based on clinical factors and the CYP2C9 and VKORC1 genotypes ( Gage et al, 2008 ). The mean stable dosage required for the elderly Chinese patients identified in Ren’s study ( Ren et al, 2020 ) were similar to the estimated initial dose shown above. However, this dose was far lower than the actual dosage of warfarin used for the patient possessing the I213V mutation.…”

Section: Discussionsupporting

confidence: 73%

“…The mean stabilized warfarin dose for this population that was applied in the project ranged from 2.39 to 4.06 mg/day. We found that the CYP2C9 wild-type *1*1 and VKORC1 (AA) were most common group (275 cases, 76.39%); the mean stabilized dose of warfarin was 3.0 mg/day ( Ren et al, 2020 ). In addition, we used a prediction model ( www.warfarindosing.org ) to estimate the initial therapeutic dose of warfarin in a hypothetical patient possessing CYP2C9*1/*1 and VKORC1 A/A genotype.…”

Section: Discussionmentioning

confidence: 94%

“…The patient had been taking 6.0 mg/day warfarin, achieving a good therapeutic effect, after weekly dose adjustment based on the INR. This study represented a continuation of an earlier project in which we enrolled several hundred elder patients taking warfarin to establish a new prediction algorithm for stable warfarin dose for the elderly Han-Chinese population under the guidance of pharmacogenetics ( Ren et al, 2020 ). The mean stabilized warfarin dose for this population that was applied in the project ranged from 2.39 to 4.06 mg/day.…”

Section: Discussionmentioning

confidence: 99%

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Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient

Zhou

et al. 2021

Front. Pharmacol.

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Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes among 120 patients taking warfarin. A new coding variant was identified by sequencing CYP2C9. The novel A > G mutation at nucleotide position 14,277 led to an amino acid substitution of isoleucine with valine at position 213 (I213V). The functional consequence of the variant was subsequently evaluated in vitro. cDNA of the novel variant was constructed by site-directed mutagenesis and the recombinant protein was expressed in vitro using a baculovirus–insect cell expression system. The recombinant protein expression was quantified at apoprotein and holoprotein levels. Its enzymatic activities toward tolbutamide, warfarin and losartan were then assessed. It exhibited changed apparent Km values and increases of 148%, 84% and 67% in the intrinsic clearance of tolbutamide, warfarin and losartan, respectively, compared to wild-type CYP2C9*1, indicating dramatically enhanced in vitro enzymatic activity. Our study suggests that the amino acid at position 213 in wild-type CYP2C9*1 may be important for the enzymatic activity of CYP2C9 toward tolbutamide, warfarin and losartan. In summary, a patient taking high-dose warfarin (6.0 mg/day) in order to achieve the target international normalized ratio was found to have a mutation in the CYP2C9 gene.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient

Zhou

et al. 2021

Front. Pharmacol.

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“…Operational definitions (adapted from references). 7,8,11,12,14,15 Actual warfarin dose: is the maintenance dosing that is taken by the patient. 11,12,14 Warfarin 5 mg fixed standard dose: it is the strategy to initiate warfarin therapy by given 5 mg dose then after 3 days can be adjusted according to INR.…”

Section: Discussionmentioning

confidence: 99%

“…7,8,11,12,14,15 Actual warfarin dose: is the maintenance dosing that is taken by the patient. 11,12,14 Warfarin 5 mg fixed standard dose: it is the strategy to initiate warfarin therapy by given 5 mg dose then after 3 days can be adjusted according to INR. The warfarin fixed dose was defined as the average daily dose of warfarin (mg/day, weekly dose/7 days) when the INR was in the target range (2.0 to 3.0) for at least 3 consecutives (at least 7 to 14 days) days after warfarin treatment.…”

Section: Discussionmentioning

confidence: 99%

Validation and comparison between two warfarin dosing clinical algorithms and warfarin fixed dosing in specialized heart center: cross-sectional study

Elnour¹,

Ahmed²,

Khalid³

et al. 2022

PHARMPRACT

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Background: Warfarin is well known as a narrow therapeutic index that has prodigious variability in response which challenges dosing adjustment for the maintenance of therapeutic international normalized ratio. However, an appreciated population not on new oral anticoagulants may still need to be stabilized with warfarin dosing. Objective: The current study's main objective was to validate and compare two models of warfarin clinical algorithm models namely the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) with warfarin 5 mg fixed standard dosing strategy in a sample of Sudanese subjects. Method: We have conducted a cross-sectional study recruited from the out-patient clinic at a tertiary specialized heart center. We included subjects with unchanged warfarin dose (stabilized), and with therapeutic international normalized ratio. The predicted doses of warfarin in the two models were calculated by three different methods (accuracy, clinical practicality, and the clinical safety of the clinical algorithms). Main outcome measure: The primary outcomes were the measurements of the clinical (accuracy, practicality, and safety) in each of the two clinical algorithms models compared to warfarin 5 mg fixed standard dose strategy. Results: We have enrolled 71 Sudanese subjects with mean age (51.7 ± 14 years), of which (49, 69.0%) were females. There was no significant difference between the warfarin 5 mg fixed standard dose strategy and the predicted doses of the two clinical algorithm models (MAE 1.44, 1.45, and 1.49 mg/day [P =0.4]) respectively. In the clinical practicality, all of the three models had a high percent of subjects (95.0%, 51.9%, and 66.7%) in the ideal dose range in middle dose group (3-7 mg/ day) for warfarin 5 mg fixed standard dosing strategy, Gage, and IWPC clinical algorithm models respectively. However, a small percent of subjects was exhibited in the warfarin low dose group ≤ 3 mg/day (0.0%, 15.0%, and 10.0%) and warfarin high dose group ≥ 7 mg/day (0.0%, 33.3%, and 33.3%) for warfarin 5 mg fixed standard dosing strategy, Gage, and IWPC clinical algorithms respectively. In terms of clinical safety, the percent of subjects with severely over-prediction were 28.2%, 22.5%, and 22.5% for warfarin 5 mg fixed standard dosing, Gage, and IWPC, respectively. While the percent of severely under-prediction was 12.7%, 7.0%, and 5.6% for the warfarin 5 mg fixed standard dosing, Gage, and IWPC, respectively. Conclusion: The Gage and IWPC clinical algorithm models were accurate, more clinically practical, and clinically safe than warfarin 5 mg standard dosing in the study population. The cardiologist can use either models (Gage and IWPC) to stratify subjects for accurate, practical, and clinically safe warfarin dosing..

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Warfarin dosing prediction algorithm assessments in Asian patients after aortic surgery

Peng

Shi

Zhang

et al. 2022

Preprint

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Background: To evaluate the accuracy and predictive performance of multiple linear regression algorithms, Gage algorithm and International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, and Bayesian algorithm for the maintenance dose of warfarin in Asian patients after aortic surgery. Methods:The predictive performance of Gage, IWPC and Bayesian algorithm were compared by calculating mean prediction error (MPE), mean squared error (MSE), root-mean-squared error (RMSE), and the percentage of patients whose predicted warfarin dose fell within 20% of the maintenance dose. Then the predictive performance of each algorithm was calculated separately in conventional dose group (dose of warfarin between 3mg and 3.75mg) and unconventional dose group (dose less than 3mg or more than 3.75mg). Results: Among three algorithms, the Gage algorithm predicted the warfarin dose with the highest percentage within 20% (58.1%). Bayesian-priori (dose estimation before starting therapy) algorithm had the highest RMSE (1.45 mg/day) and the lowest percentage within 20% (40.9%). The algorithm of Gage method tended to perform better in the conventional dose group (percentage within 20%: 70.0%), and Bayesian-priori method performed better in the unconventional dose group (percentage within 20%: 38.5%). And as the number of international normalized ratio (INR) observations increases, the predictive performance of Bayesian-posteriori (dose estimation after initiating therapy) algorithm showed an increasing trend in both groups and a significantly higher advantage, especially in the unconventional dose group. Conclusion: For Asian patients after aortic surgery, the Gage algorithm was appropriate for patients requiring conventional dose (2.25-3.75mg). Bayesian-posteriori algorithm might be more appropriate for patients requiring high dose or low dose (＜2.25mg or＞3.75mg).

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Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

Cited by 6 publications

References 28 publications

Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient

Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient

Validation and comparison between two warfarin dosing clinical algorithms and warfarin fixed dosing in specialized heart center: cross-sectional study

Warfarin dosing prediction algorithm assessments in Asian patients after aortic surgery

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