Tom Schalekamp

Pharmacogenetics: from bench to byte--an update of guidelines.

Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics‐based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine‐S‐methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA‐B44, HLA‐B*5701, CYP3A5, and factor V Leiden (FVL).

VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation.

Our objective was to assess the effects of VKORC1 and CYP2C9 genotypes on severe overanticoagulation and time to achieve stability and their contributions to dose requirement during the initial phase of acenocoumarol treatment.

VKORC1 and CYP2C9 Genotypes and Phenprocoumon Anticoagulation Status: Interaction Between both Genotypes Affects Dose Requirement

In a prospective follow‐up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T‐1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

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.

Acenocoumarol Stabilization is Delayed in CYP2C9*3 Carriers

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 3 to 6 months of acenocoumarol treatment.

Potential Determinants of Drug-Drug Interaction Associated Dispensing in Community Pharmacies

Although the number of clinically relevant drug-drug interactions (DDIs) is probably low, DDIs may be responsible for a substantial number of hospital admissions. In some countries, the pharmacist is responsible for preventing the use of unsafe or non-effective drug regimens. Specifically they should avoid the dispensing of combinations of drugs that may cause serious DDIs. In order to assess the determinants related to community pharmacies and associated with these dispensings, a systematic literature review was conducted. Medline and International Pharmaceutical Abstracts were searched for articles published in English between 1993 and 2003. Additional relevant articles were identified by screening the reference lists of relevant articles.Seven papers were located. The determinants described in the literature were divided into three groups. The first group focussed on the relationship between the pharmacist and the prescriber. The number of prescribers is of importance as well as the number of dispensing pharmacies. Both a high number of primary care physicians and multiple dispensing pharmacies increased the risk of DDIs. The availability, quality and sensitivity of the medication surveillance software appeared to be a second important determinant. Both too many and too few signals increased the risk of dispensing interacting drugs. The third group of determinants was related to the pharmacist and pharmacy organisation. Signals from the surveillance program are usually judged first by technicians and subsequently managed by the pharmacist. Consequently, knowledge, instructions and supervision are important determinants. A fourth group of determinants was identified in literature assessing interventions by pharmacists, including interventions for DDIs. A higher workload was associated with lower intervention rates, which indicated a higher risk of dispensing interacting drugs.The determinants identified in this review can be used to develop strategies to minimise patient harm resulting from DDIs. Further assessment of the relation between these determinants and the dispensing of DDIs and of the relation between DDI-associated dispensing and patient harm is recommended.

Pharmacogenetics of Oral Anticoagulant Therapy

The identification of the genes encoding CYP2C9, the principal metabolizing enzyme of the coumarins, and VKORC1, the molecular target for coumarins, has strongly stimulated the research on pharmacogenetics of vitamin K antagonists, also designated as coumarins. From 1999 to 2004 a number of observational studies firmly established associations between being carrier of the CYP2C9*2 and especially the CYP2C9*3 allele and reduced coumarin dose requirements and increased risks of overanticoagulation and even major bleeding compared to CYP2C9 wild type patients. The identification of the VKORC1 gene in 2004 gave rise to more observational studies, which mostly indicated a larger contribution of variants of these gene to the interindividual variability in dose requirements. However, whereas overanticoagulation in the initial period of therapy appears to be associated with VKORC1 as well as CYP2C9 genotype, the CYP2C9 genotype could be a more important predictor for major bleeding and retarded stabilisation. The recent discovery that only one single nucleotide polymorphism in the VKORC1 gene, the -1639G>A polymorphism, is representative for VKORC1 activity and the recent conclusion from a genome-wide scan that VKORC1 and CYP2C9 are the only genes with relevant effects on coumarin response, seem to be definitive demarcations of the genetic information which could be needed for improvement of the existing coumarin dosing algorithms. The observational studies from the last decade provided valuable insights into the effects of genetic factors on variability in coumarin response. During the forthcoming years randomized clinical trials are needed to evaluate whether this genetic information will improve the benefit-risk ratio of coumarins.

Effect of oral antiplatelet agents on major bleeding in users of coumarins.

Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data from a Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI). We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2-6.9 and OR 1.6, 95% CI 1.3-1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0-2.3 and OR 1.8, 95 % CI 1.0-3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.

Statin Prescribing in the Elderly in the Netherlands A Pharmacy Database Time Trend Study

AbstractIntroduction There is some evidence that the beneficial effects of HMG-CoA reductase inhibitors (statins) in the elderly are at least comparable to the effects in middle-aged people. However, several studies have shown prescription rates of statins to be significantly lower in the elderly than in younger populations. Objective The aim of the present study was to monitor statin prescribing trends in the elderly in the Netherlands over time in terms of prevalence, incidence, type of statin, dose prescribed and adherence to clinical guidelines. Methods The database of a community pharmacy in Utrecht, which includes prescription data for approximately 11 000 people, was analysed to investigate trends in statin prescriptions from January 1999 to December 2008. The 1-year prevalence and incidence of statin use stratified by age were determined for each calendar year. Rate ratios (RRs) and 95% confidence intervals were calculated with 1999 as the reference year. Furthermore, the following trends of interest were calculated for each calendar year: the percentage of statin users prescribed simvastatin or atorvastatin, the median dose of simvastatin and atorvastatin prescribed, and the percentage of simvastatin users prescribed a dosage of 40 mg/day (which is recommended by the Dutch multidisciplinary guideline). Results The 1-year prevalence of statin use in medication users aged ≥50 years increased from 13.9% in 1999 to 22.8% in 2008 (RR 1.6; 95% CI 1.4, 1.9; p<0.001). Overall, the lowest prevalence (5.1% in 1999 and 15.2% in 2008) and incidence rates (3.2% in 2000 and 4.2% in 2008) were found in patients aged ≥80 years. Before 2006, simvastatin was the most commonly prescribed statin, but the number of users declined as the percentage of patients with new simvastatin prescriptions decreased (from 43.4% in 2000 to 36.5% in 2005) and the percentage of patients treated with new atorvastatin prescriptions increased (from 37.7% in 2000 to 47.3% in 2005). As from 2006, when the Dutch multidisciplinary guideline for Cardiovascular Risk Management was introduced, recommending treatment with a daily simvastatin dose of 40 mg, the number of simvastatin users increased again and most treatment-naive patients were started on simvastatin (62.3% in 2006, increasing to 66.7% in 2008). The median simvastatin dose increased from 10 mg in 1999 to 20 mg in 2001, remaining at the same dose until 2008, and appeared to be related to the patient’s age. From 2006, patients aged ≥80 years were the least likely group to receive the recommended dose of 40 mg simvastatin daily (10.0–20.0% of simvastatin users aged ≥80 years compared with 32.5–36.9% of simvastatin users aged 60–69 years). Conclusion Despite the benefits of statin treatment previously reported in older patients, the prevalence and incidence of statin use were lower in elderly patients compared with younger patients. In addition, lower dosages of statins were prescribed. These findings suggest the beneficial effects of statins in the elderly observed in clinical trials may not be achieved in everyday practice.