A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives.

Anticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy. This article describes the findings of a systematic review of published cost-effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost-effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice.

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design.

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.

CYP2D6 genotyping for psychiatric patients treated with risperidone: considerations for cost-effectiveness studies.

In order to ascertain data availability and feasibility for conducting cost-effectiveness studies in pharmacogenetics, and as part of a European Commission Joint Research Center, Institute for Prospective Technological Studies (JRC-IPTS) study, data concerning risperidone use and cytochrome P450 (CYP2D6) genotyping in medical care was collected in Germany, Spain and the USA, and are summarized in this perspective. The gene coding for CYP2D6 is highly polymorphic, resulting in a significant part of the population being poor metabolizers and ultrarapid metabolizers. Individuals who are CYP2D6 poor metabolizers, have an increased risk of adverse drug reactions (ADRs) when treated with CYP2D6-metabolized drugs, suggesting that CYP2D6 genotyping might be beneficial for patient care. This might be especially important in psychiatry, where approximately 50% of the patients use at least one drug primarily metabolized by CYP2D6. In particular, ADRs and poor response to treatment are major problems for some antipsychotics, including risperidone. However, there are no published cost-effectiveness studies on CYP2D6 genotyping, and the benefit that pharmacogenetic testing might represent by identifying problematic patients is still unclear. The present European Commission study found that current clinical and economical data concerning the frequency and direct healthcare costs of risperidone-related ADRs, the relation of such ADRs with the patients CYP2D6 genotypes, and costs for CYP2D6 genotyping, are not sufficient for determining if routine CYP2D6 genotyping might be cost beneficial for patients treated with risperidone. Therefore, efforts should be put on performing prospective cost-benefit studies with randomized treatment according to the CYP2D6 genotype to establish the utility of CYP2D6 genotyping for personalizing antipsychotic treatment.

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity.

OBJECTIVES: (S)-Mephenytoin is selectively metabolised to (S)-4'-hydroxymephenytoin by CYP2C19. The urinary excretion of 4'-hydroxymephenytoin reflects the activity of individual enzymes. We evaluated fractioned urinary collection and beta-glucuronidase pre-treatment in order to determine the optimal CYP2C19 metrics. We also assessed whether urinary excretion of N-desmethylmephenytoin (nirvanol) might be a useful CYP2B6 metric in in vivo studies. METHODS: A 50-mg dose of mephenytoin was administered to 52 volunteers as a component of phenotyping cocktails in four separate studies. Urine was collected up to 166 h post-dose. Urinary excretion of 4'-hydroxymephenytoin and nirvanol was quantified by liquid chromatography-tandem mass spectrometry, and common CYP2C19 and CYP2B6 genotypes were determined. RESULTS: Cumulative excretion of 4'-hydroxymephenytoin in urine with beta-glucuronidase treatment collected from before mephenytoin administration up to 12-16 h thereafter showed the greatest difference between CYP2C19 genotypes and the lowest intra-individual variability (7%). Renal elimination of nirvanol was highest for a *4/*4 individual and lowest for individuals carrying the *5/*5 and *1/*7 genotype, but lasted for several weeks, thus making its use in cross-over studies difficult. CONCLUSION: Cumulative urinary excretion of 4'-hydroxymephenytoin 0-12 h post-administration is a sensitive and reproducible metric of CYP2C19 activity, enabling the effect of a drug on CYP2C19 to be assessed in a small sample size of n=6 volunteers. While nirvanol excretion may reflect CYP2B6 activity in vivo, it is not useful for CYP2B6 phenotyping.

Translating pharmacogenomics: challenges on the road to the clinic.

Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years, commercially available pharmacogenomic tests have been approved by the Food and Drug Administration (FDA), but their application in patient care remains very limited. More generally, the implementation of pharmacogenomics in routine clinical practice presents significant challenges. This article presents specific clinical examples of such challenges and discusses how obstacles to implementation of pharmacogenomic testing can be addressed.

Pharmacogenetics-based therapeutic recommendations--ready for clinical practice?

Although considerable progress has been made in basic pharmacogenetic research, less has been demonstrated in the application of pharmacogenetics (PGx)-based diagnostics to drug development and in clinical practice. There are drugs that are currently used in the clinic for which individualized therapy could be beneficial based on PGx data. However, specific, actionable recommendations on how to implement individualized therapy--particularly with respect to dosage--still have to be developed. Moreover, to apply PGx efficiently in clinical drug development, and later in drug therapy, study designs and the generation and handling of PGx data need to become more standardized. Here, we argue for the development of concise guidelines for implementation of PGx analyses in drug development and therapy.