Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

Tom Schalekamp; Mirjam Oosterhof; Erik van Meegen; Felix J M van Der Meer; Jean Conemans; Mirjam Hermans; Irma Meijerman; Anthonius de Boer

doi:10.1016/j.clpt.2004.08.006

Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

Tom Schalekamp, Mirjam Oosterhof, Erik van Meegen, Felix J M van Der Meer, Jean Conemans, Mirjam Hermans, Irma Meijerman, Anthonius de Boer

Dept of Pharmaceutical Sciences

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVE: Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment.

METHODS: A prospective follow-up study was performed at 2 anticoagulation clinics in The Netherlands. Included subjects started phenprocoumon during the study period, had their first check of the international normalized ratio (INR) on the third or fourth day of therapy, and had an indication for the low therapeutic range (INR, 2.0-3.5). CYP2C9 genotypes ( CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 ) were assessed, and data on indication, INR checks, comedication, and comorbidity were collected.

RESULTS: After genotyping, 284 subjects were available for analysis. Of these, 186 (65.5%) were homozygous carriers of the CYP2C9 wild-type allele ( CYP2C9*1/*1 ), 61 (21.5%) were carriers of the CYP2C9*2 allele, and 37 (13.0%) were carriers of the CYP2C9*3 allele. Compared with homozygous CYP2C9*1/*1 subjects, carriers of CYP2C9*2 or *3 had an increased risk of severe overanticoagulation (INR >6.0). The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 3.09 (95% confidence interval [CI], 1.56 to 6.13; P=.001), and the hazard ratio for CYP2C9*3 versus CYP2C9*1/*1 was 2.40 (95% CI, 1.03 to 5.57; P=.042). Carriers of CYP2C9*2 also had a lower chance to achieve stability in the follow-up period. The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 0.61 (95% CI, 0.43 to 0.85; P=.003). Carriers of the CYP2C9*2 or *3 allele needed a significantly lower phenprocoumon dosage compared with homozygous CYP2C9*1/*1 subjects.

CONCLUSION: The presence of at least 1 CYP2C9*2 or *3 allele in phenprocoumon users is associated with an increased risk of severe overanticoagulation. Similar to warfarin and acenocoumarol, phenprocoumon had a lower dosage requirement in carriers of CYP2C9*2 or *3 compared with that in CYP2C9 wild-type subjects.

Original language	English
Pages (from-to)	409-417
Number of pages	9
Journal	Clinical Pharmacology and Therapeutics
Volume	76
Issue number	5
DOIs	https://doi.org/10.1016/j.clpt.2004.08.006
Publication status	Published - Nov 2004

Keywords

Aged
Alleles
Anticoagulants
Aryl Hydrocarbon Hydroxylases
Blood Coagulation
Cytochrome P-450 CYP2C9
Dose-Response Relationship, Drug
Endpoint Determination
Female
Follow-Up Studies
Gene Frequency
Genotype
Heterozygote
Humans
Male
Middle Aged
Netherlands
Phenprocoumon
Polymorphism, Genetic
Proportional Hazards Models
Prospective Studies

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10.1016/j.clpt.2004.08.006

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@article{5811e75318b64eabb421c0c2eab8e6af,

title = "Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status",

abstract = "OBJECTIVE: Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment.METHODS: A prospective follow-up study was performed at 2 anticoagulation clinics in The Netherlands. Included subjects started phenprocoumon during the study period, had their first check of the international normalized ratio (INR) on the third or fourth day of therapy, and had an indication for the low therapeutic range (INR, 2.0-3.5). CYP2C9 genotypes ( CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 ) were assessed, and data on indication, INR checks, comedication, and comorbidity were collected.RESULTS: After genotyping, 284 subjects were available for analysis. Of these, 186 (65.5%) were homozygous carriers of the CYP2C9 wild-type allele ( CYP2C9*1/*1 ), 61 (21.5%) were carriers of the CYP2C9*2 allele, and 37 (13.0%) were carriers of the CYP2C9*3 allele. Compared with homozygous CYP2C9*1/*1 subjects, carriers of CYP2C9*2 or *3 had an increased risk of severe overanticoagulation (INR >6.0). The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 3.09 (95% confidence interval [CI], 1.56 to 6.13; P=.001), and the hazard ratio for CYP2C9*3 versus CYP2C9*1/*1 was 2.40 (95% CI, 1.03 to 5.57; P=.042). Carriers of CYP2C9*2 also had a lower chance to achieve stability in the follow-up period. The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 0.61 (95% CI, 0.43 to 0.85; P=.003). Carriers of the CYP2C9*2 or *3 allele needed a significantly lower phenprocoumon dosage compared with homozygous CYP2C9*1/*1 subjects.CONCLUSION: The presence of at least 1 CYP2C9*2 or *3 allele in phenprocoumon users is associated with an increased risk of severe overanticoagulation. Similar to warfarin and acenocoumarol, phenprocoumon had a lower dosage requirement in carriers of CYP2C9*2 or *3 compared with that in CYP2C9 wild-type subjects.",

keywords = "Aged, Alleles, Anticoagulants, Aryl Hydrocarbon Hydroxylases, Blood Coagulation, Cytochrome P-450 CYP2C9, Dose-Response Relationship, Drug, Endpoint Determination, Female, Follow-Up Studies, Gene Frequency, Genotype, Heterozygote, Humans, Male, Middle Aged, Netherlands, Phenprocoumon, Polymorphism, Genetic, Proportional Hazards Models, Prospective Studies",

author = "Tom Schalekamp and Mirjam Oosterhof and {van Meegen}, Erik and {van Der Meer}, {Felix J M} and Jean Conemans and Mirjam Hermans and Irma Meijerman and {de Boer}, Anthonius",

year = "2004",

month = nov,

doi = "10.1016/j.clpt.2004.08.006",

language = "English",

volume = "76",

pages = "409--417",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

publisher = "Wiley-Blackwell",

number = "5",

}

TY - JOUR

T1 - Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

AU - Schalekamp, Tom

AU - Oosterhof, Mirjam

AU - van Meegen, Erik

AU - van Der Meer, Felix J M

AU - Conemans, Jean

AU - Hermans, Mirjam

AU - Meijerman, Irma

AU - de Boer, Anthonius

PY - 2004/11

Y1 - 2004/11

N2 - OBJECTIVE: Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment.METHODS: A prospective follow-up study was performed at 2 anticoagulation clinics in The Netherlands. Included subjects started phenprocoumon during the study period, had their first check of the international normalized ratio (INR) on the third or fourth day of therapy, and had an indication for the low therapeutic range (INR, 2.0-3.5). CYP2C9 genotypes ( CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 ) were assessed, and data on indication, INR checks, comedication, and comorbidity were collected.RESULTS: After genotyping, 284 subjects were available for analysis. Of these, 186 (65.5%) were homozygous carriers of the CYP2C9 wild-type allele ( CYP2C9*1/*1 ), 61 (21.5%) were carriers of the CYP2C9*2 allele, and 37 (13.0%) were carriers of the CYP2C9*3 allele. Compared with homozygous CYP2C9*1/*1 subjects, carriers of CYP2C9*2 or *3 had an increased risk of severe overanticoagulation (INR >6.0). The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 3.09 (95% confidence interval [CI], 1.56 to 6.13; P=.001), and the hazard ratio for CYP2C9*3 versus CYP2C9*1/*1 was 2.40 (95% CI, 1.03 to 5.57; P=.042). Carriers of CYP2C9*2 also had a lower chance to achieve stability in the follow-up period. The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 0.61 (95% CI, 0.43 to 0.85; P=.003). Carriers of the CYP2C9*2 or *3 allele needed a significantly lower phenprocoumon dosage compared with homozygous CYP2C9*1/*1 subjects.CONCLUSION: The presence of at least 1 CYP2C9*2 or *3 allele in phenprocoumon users is associated with an increased risk of severe overanticoagulation. Similar to warfarin and acenocoumarol, phenprocoumon had a lower dosage requirement in carriers of CYP2C9*2 or *3 compared with that in CYP2C9 wild-type subjects.

AB - OBJECTIVE: Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment.METHODS: A prospective follow-up study was performed at 2 anticoagulation clinics in The Netherlands. Included subjects started phenprocoumon during the study period, had their first check of the international normalized ratio (INR) on the third or fourth day of therapy, and had an indication for the low therapeutic range (INR, 2.0-3.5). CYP2C9 genotypes ( CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 ) were assessed, and data on indication, INR checks, comedication, and comorbidity were collected.RESULTS: After genotyping, 284 subjects were available for analysis. Of these, 186 (65.5%) were homozygous carriers of the CYP2C9 wild-type allele ( CYP2C9*1/*1 ), 61 (21.5%) were carriers of the CYP2C9*2 allele, and 37 (13.0%) were carriers of the CYP2C9*3 allele. Compared with homozygous CYP2C9*1/*1 subjects, carriers of CYP2C9*2 or *3 had an increased risk of severe overanticoagulation (INR >6.0). The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 3.09 (95% confidence interval [CI], 1.56 to 6.13; P=.001), and the hazard ratio for CYP2C9*3 versus CYP2C9*1/*1 was 2.40 (95% CI, 1.03 to 5.57; P=.042). Carriers of CYP2C9*2 also had a lower chance to achieve stability in the follow-up period. The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 0.61 (95% CI, 0.43 to 0.85; P=.003). Carriers of the CYP2C9*2 or *3 allele needed a significantly lower phenprocoumon dosage compared with homozygous CYP2C9*1/*1 subjects.CONCLUSION: The presence of at least 1 CYP2C9*2 or *3 allele in phenprocoumon users is associated with an increased risk of severe overanticoagulation. Similar to warfarin and acenocoumarol, phenprocoumon had a lower dosage requirement in carriers of CYP2C9*2 or *3 compared with that in CYP2C9 wild-type subjects.

KW - Aged

KW - Alleles

KW - Anticoagulants

KW - Aryl Hydrocarbon Hydroxylases

KW - Blood Coagulation

KW - Cytochrome P-450 CYP2C9

KW - Dose-Response Relationship, Drug

KW - Endpoint Determination

KW - Female

KW - Follow-Up Studies

KW - Gene Frequency

KW - Genotype

KW - Heterozygote

KW - Humans

KW - Male

KW - Middle Aged

KW - Netherlands

KW - Phenprocoumon

KW - Polymorphism, Genetic

KW - Proportional Hazards Models

KW - Prospective Studies

U2 - 10.1016/j.clpt.2004.08.006

DO - 10.1016/j.clpt.2004.08.006

M3 - Article

C2 - 15536456

SN - 0009-9236

VL - 76

SP - 409

EP - 417

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 5

ER -

Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

Abstract

Keywords

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