Cost-effectiveness of using CYP2C19 genotype to guide selection of clopidogrel or ticagrelor in Australia

Conclusion: Ticagrelor is likely to be cost-effective even for individuals not carrying a CYP2C19 LoF allele.

Challenges and limitations in the interpretation of systematic reviews : making sense of clopidogrel and CYP2C19 pharmacogenetics

From 2010 to 2012, nine systematic reviews reported highly variable conclusions regarding the association between carriage of a cytochrome P450 2C19 loss-of-function allele and the risk of adverse cardiovascular (CV) events in individuals using clopidogrel. Possible contributors to the variable findings include differences in patient populations, CV end points, and statistical models utilized by the systematic reviews, as well as unexplained heterogeneity, inconsistent/incomplete reporting, and risk of publication bias with respect to the primary studies.

Review of the cost effectiveness of pharmacogenetic-guided treatment of hypercholesterolaemia

Hypercholesterolaemia is a highly prevalent condition that has major health and cost implications for society. Pharmacotherapy is an important and effective treatment modality for hypercholesterolaemia, with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (‘statins’) the most commonly used class of drugs. Over the past decade, there has been intensive research to identify pharmacogenetic markers to guide treatment of hypercholesterolaemia. This study aimed to review the evidence of incremental cost, effect and cost effectiveness of pharmacogenetic-guided treatment of hypercholesterolaemia. Three cost-effectiveness analyses (CEAs) were identified that studied the value of screening for genotypes of angiotensin I converting enzyme (ACE), cholesteryl ester transfer protein (CETP), and kinesin family member 6 (KIF6) prior to initiating statin therapy. For all three CEAs, a major limitation identified was the reproducibility of the evidence supporting the clinical effect of screening for the pharmacogenetic marker. Associated issues included the uncertain value of pharmacogenetic markers over or in addition to existing approaches for monitoring lipid levels, and the lack of evidence to assess the effectiveness of alternative therapeutic options for individuals identified as poor responders to statin therapy. Finally, the economic context of the market for diagnostic tests (is it competitive or is there market power?) and the practicality of large-scale screening programmes to inform prescribing in a complex and varied market may limit the generalizability of the results of the specific CEAs to policy outcomes. The genotype of solute carrier organic anion transporter family member 1B1 (SLCO1B1) has recently been associated with increased risk of muscle toxicity with statin therapy and the review identified that exploration of cost effectiveness of this pharmacogenetic marker is likely warranted.

Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis

Expert opinion: While teriflunomide is no more effective than a number of other agents that are used in the treatment of MS, it has a favorable side-effect profile and the convenience of once a day oral administration. As such, it is likely to be a popular agent in the treatment of MS over the next 5 years.

Cytochrome P450 part 3: Impact of drug-drug interactions

The role of individual hepatic cytochrome P450 (CYP) enzymes in drug metabolism and the factors that modulate CYP activity are becoming increasingly well understood. These advances have resulted in a better understanding of drug-drug and drug-food interactions and an enhanced capacity to predict drug interactions that may occur with new drugs. This final article in the series describes the issues and principles that are important in identifying and assessing drug interactions that involve CYP enzymes.

Partial charge calculation method affects CoMFA QSAR prediction accuracy

The 3D-QSAR method comparative molecular field analysis (CoMFA) involves the estimation of atomic partial charges as part of the process of calculating molecular electrostatic fields. Using 30 data sets from the literature the effect of using different common partial charge calculation methods on the predictivity (cross-validated R2) of CoMFA was studied. The partial charge methods ranged from the popular Gasteiger and the newer MMFF94 electronegativity equalization methods, to the more complex and computationally expensive semiempirical charges AM1, MNDO, and PM3. The MMFF94 and semiempirical MNDO, AM1, and PM3 methods for computing charges were found to result in statistically significantly more predictive CoMFA models than the Gasteiger charges. Although there was a trend toward the semiempirical charges performing better than the MMFF94 charges, the difference was not statistically significant. Thus, semiempirical partial charge calculation methods are suggested for the most predictive CoMFA models, but the MMFF94 charge calculation method is a very good alternative if semiempirical methods are not available or faster calculation speed is important.

Prasugrel vs. clopidogrel for cytochrome P450 2C19-genotyped subgroups : integration of the TRITON-TIMI 38 trial data

Background: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON-TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced-function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non-ST segment elevation myocardial infarction is currently uncertain. Methods and Results: An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON-TIMI 38 trial. Individuals with a CYP2C19 reduced-metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39–0.83]. For CYP2C19 extensive metabolizers (∼ 70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80–1.20). Conclusions: Integration of the TRITON-TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.

Pharmacists' role in targeted cancer therapy in Australia and implications for pharmacy education

Objectives. To investigate the pharmacists’ role in providing targeted therapies to patients and its implications for pharmacy education. Methods. Nine pharmacy faculty members, 12 clinical pharmacists, and 4 oncologists from across Australia and New Zealand participated in semistructured interviews, which were analysed using the framework method. Results. Education about targeted therapies was seen as being important, although content about pharmacodiagnostic tests was taught inconsistently among 7 universities. Issues including funding, clinical and diagnostic validity of tests, and time taken for turnaround of tests were perceived as impediments to the acceptance by clinicians of the utility of pharmacodiagnostic tests. Conclusions. Pharmacists may be the ideal professionals to interpret test results and provide counselling for patients to assist them in compliance with targeted cancer therapies. Pharmacy education in cancer therapies is critical to training pharmacists who can assist patients in the correct use of these therapies.

Is there a role for routinely screening children with autism spectrum disorder for creatine deficiency syndrome?

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that presents in the first three years of life. Currently, diagnosis of ASD is based on its behavioural manifestations, as laboratory diagnostic tests do not exist. Creatine deficiency syndrome (CDS) is one form of inborn error of metabolism where affected individuals have similar clinical features to individuals with ASD. Abnormal urinary creatine (CR) and guanidinoacetate (GAA) levels have been reported as biomarkers of CDS. We hypothesized that screening for abnormal levels of urinary CR and GAA in children with ASD may assist in identifying a subgroup of ASD individuals who can be managed with dietary interventions. Morning urine samples were collected from children with and without autism and analyzed for CR and GAA levels. Results showed there was no statistically significant difference in urinary CR:creatinine and GAA:creatinine between the children with ASD and sibling or unrelated controls. In conclusion, routine screening for abnormal urinary CR and GAA could be considered in ASD diagnostic protocols; however, individuals positive for CDS are likely to be rare in an ASD cohort.