Michael B. Ward

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

Summary.  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.

Cytochrome P450 Part 1: Multiplicity and Function

While new cytochrome P450 (CYP450) enzymes continue to be identified, it is now possible to predict with some confidence the total number of human CYP450 enzymes. This review is an update of the CYP450 superfamily of drug metabolising enzymes. It comprises a brief history of CYP450 research, outlines the standard P450 nomenclature system, and describes CYP450 multiplicity, structure and function.

Investigation of HTR3C mutations for association with 5HT3 receptor antagonist anti-emetic efficacy

OBJECTIVE Chemotherapy-induced nausea and vomiting is a significant clinical problem. The 5HT(3) receptor antagonists are effective anti-emetic medications but approximately 30% of patients do not respond. METHOD We examined the HTR3C gene, which is believed to encode a subunit of the 5HT(3) receptor, for genetic variation and association with anti-emetic efficacy in a group of 70 patients receiving cancer chemotherapy. RESULTS Seven novel mutations were identified; three mutations resulted in amino acid substitutions, two were synonymous and two were intronic. No statistically significant associations between either isolated mutations or estimated haplotypes and anti-emetic efficacy were detected. CONCLUSION The results of this investigation indicate that the genetic variants that have been identified within HTR3C do not predict response to 5HT(3) antagonists, necessitating further investigation of possible genetic determinants of 5HT(3) antagonist efficacy.

Current Challenges and Potential Opportunities for the Pharmaceutical Sciences to Make Global Impact: An FIP Perspective

The chairs of each of the 8 Special Interest Groups of the Board of Pharmaceutical Sciences of the International Pharmaceutical Federation have compiled opinions with regard to major challenges for the pharmaceutical sciences over the next 5-10 years. Areas covered are drug design and discovery, natural products, formulation design and pharmaceutical technology, pharmacokinetics/pharmacodynamics and systems pharmacology, translational and personalized medicine, biotechnology, analytical sciences and quality control, and regulatory science.

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.

Effect of Garlic, Gingko, and St. John's Wort Extracts on the Pharmacokinetics of Fexofenadine: A Mechanistic Study.

The aim of this study was to determine the effects of garlic and ginkgo herbal extracts on the pharmacokinetics of the P-glycoprotein (P-gp)/organic anion-transporting polypeptides (Oatps) substrate fexofenadine. Male rats were dosed orally with garlic (120 mg/kg), ginkgo (17 mg/kg), St. John’s wort (SJW; 1000 mg/kg; positive control), or Milli-Q water for 14 days. On day 15, rats either were administered fexofenadine (orally or i.v.), had their livers isolated and perfused with fexofenadine, or had their small intestines divided into four segments (SI–SIV) and analyzed for P-gp and Oatp1a5. In vivo, SJW increased the clearance of i.v. administered fexofenadine by 28%. Garlic increased the area under the curve0–∞ and maximum plasma concentration of orally administered fexofenadine by 47% and 85%, respectively. Ginkgo and SJW had no effect on the oral absorption of fexofenadine. In the perfused liver, garlic, ginkgo, and SJW increased the biliary clearance of fexofenadine with respect to perfusate by 71%, 121%, and 234%, respectively. SJW increased the biliary clearance relative to the liver concentration by 64%. The ratio of liver to perfusate concentrations significantly increased in all treated groups. The expression of Oatp1a5 in SI was increased by garlic (88%) and SJW (63%). There were no significant changes in the expression of P-gp. Induction of intestinal Oatp1a5 by garlic may explain the increased absorption of orally administered fexofenadine. Ginkgo had no effect on the expression of intestinal P-gp or Oatp1a5. A dual inductive effect by SJW on opposing intestinal epithelial transport by Oatp1a5 and P-gp remains a possibility.

The use of antipsychotics among people treated with medications for dementia in residential aged care facilities.

BACKGROUND Antipsychotic agents have limited efficacy for Behavioral and Psychological Symptoms of Dementia (BPSD) and there are concerns about their safety. Despite this, they are frequently used for the management of BPSD. This study aimed to assess the use of antipsychotics among people on anti-dementia medicines in Australian residential aged care facilities. METHODS Data were obtained from an individual patient unit dose packaging database covering 40 residential aged care facilities in New South Wales, Australia. Residents supplied an anti-dementia medicine between July 2008 and June 2013 were included. Prevalence of concurrent antipsychotic use was established. Incident antipsychotic users between January 2009 and December 2011 were identified. We examined initial antipsychotic dose, maximum titrated doses, type and duration of antipsychotic use, and compared use with Australian guidelines. RESULTS There were 291 residents treated with anti-dementia medicines, 129 (44%) of whom received antipsychotics concomitantly with an anti-dementia medicine. Among the 59 incident antipsychotic users, risperidone (73%) was the most commonly used antipsychotic agent. Amongst the risperidone initiators, 43% of patients had initial doses greater than 0.5 mg/day and 6% of patients exceeded 2.0 mg/day for their maximum dose. 53% of concomitant users received daily treatment for greater than six months. CONCLUSIONS Our study using records of individual patient unit dose supply, which represents the intended medication consumption schedule, shows high rates of concurrent use of antipsychotics and anti-dementia medicines and long durations of use. The use of antipsychotics in patients with dementia needs to be carefully monitored to improve patient outcomes.

Reforming Pharmaceutical Education to Enhance the Global Uptake of Pharmacogenomics and Personalized Medicine

Mafalda M. Dias, Krupa Depala, Helena M. Ward, Michael B. Ward, Michael J. Sorich, Claire Anderson and Ross A. McKinnon

The Emergence of Pharmacogenomics

The role of heredity in modifying individual response to drugs and other chemicals has been known for more than six decades. More recently, the Human Genome Project, and various technical innovations emerging from it, have dramatically accelerated the depth of this knowledge. The collective term now given to this field is ‘pharmacogenomics’. The rapid emergence of pharmacogenomics provides many exciting opportunities for achieving better health outcomes and, in particular, offers enormous potential for markedly improving drug therapy, through rational drug selection and prediction of susceptibility to adverse events or toxicity. It is envisaged that the implementation of pharmacogenomic programs will provide clinicians with greater certainty of a desired outcome, including the avoidance of underdosing, overdosing, misdosing and adverse drug reactions. Importantly, pharmacogenomics also offers the pharmaceutical industry potential economic advantages through improved drug selection and streamlined clinical trial protocols. This review provides a background to the development and conduct of pharmacogenomic research and highlights examples where pharmacogenomics is likely to have a significant clinical impact on the pharmacokinetics of drugs.

Pharmacogenomics and Personalised Medicine: Consumer Perspectives, Lessons Learned in Australia and Beyond

Claire Anderson, Helena Ward, David Corkindale, Michael B. Ward, Michael J. Sorich and Ross A. McKinnon