Current Pharmacogenomics and Personalized Medicine - Volume 12, Issue 1, 2014

With growing information on antiretroviral drug pharmacogenetics, several studies have been conducted in African countries. One unique strand of knowledge that is currently emerging is the use of dried plasma spot devices in rural communities in Africa with a view to individualizying drugs employed against HIV infection. The results are encouraging as a relatively inexpensive test could inform on the probability of adverse reactions or treatment failure, thus helping to select the best regimen for a given patient in different African populations. This could have an important impact in African countries where anti-viral therapy failures (whether related to low adherence/intolerance or to resistance/insufficient drugs exposure) have huge associated costs, both in terms of disease progression and money expenditure. Data on the available information on pharmacogenetics in African patients as well as patients of African descendant are reviewed. Nevertheless no randomized controlled study evaluating the impact of pharmacogenetics in Africa has so far been conducted, particularly with a view to employing novel diagnostic platforms such as dried plasma/blood spot devices in rural communities. Following the discussed data a few candidate genes are suggested as potential candidates for prospective studies taking into account two pitfalls in the path towards individualized antiretroviral regimens in Africa: the reliance on non-African based laboratories that signal the need for local capacity building as well as international collaborations, and finally the need to better understand genetic diversity of different ethnic groups in the African continent.

For more than 60 years, genetic variation had been recognized as an important determinant of inter-individual variability in drug efficacy and drug safety. Pharmacogenomics, studying the variations of DNA sequence and gene expression related to drug responses, is the whole genome application of pharmacogenetics. The aim of PGt/PGx is to elucidate functionally relevant genomic determinants for drug metabolism, transport and response in order to optimize drug therapy including therapy response prediction, appropriate drug selection and individualization based on the patient's genomic profile. This article describes and surveys the international landscape on recent PGt/PGx applications in clinical practice. A topline list of drugs in personalized medicine is highlighted together with the cutting edge initiatives such as the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group.

Pharmacogenomics as a science aims at individualizing the treatment based on the genetic makeup, to mitigate the chances of adverse drug events and/or to maximize the efficacy in a sub-population. Pharmacometrics is the science of quantifying disease, drug and trial characteristics with the goal to influence key drug development, regulatory and therapeutic decisions. Pharmacometric analysis as a tool has revolutionized the way dose/dosing regimens or clinical trials are being designed prospectively to answer key drug development questions. Exposure-response relationships established in adult patients have made it possible to make dosing recommendations in special populations (pediatrics and organ function impaired patients), leading to approval of doses/dosing regimen that were not studied in registration trials. Until now, pharmacogenomics is predominantly used retrospectively to understand the between subject variability of drug’s pharmacokinetic and pharmacodynamic properties. In this article we discuss how the advent of advanced pharmacometric tools can leverage prior pharmacogenomic information to prospectively design late stage clinical trials. In addition, selected case studies are presented that demonstrates the application of modeling and simulation in supporting dose selection in patients with allelic variants across different therapeutic areas.

Personalized medicine will play an important role in the treatment of infectious diseases. Molecular microbiology diagnostics have the potential to identify pathogens with great accuracy and rapidity. The speed of identification is particularly crucial to effective clinical management of many infections. An important complement to precision diagnostic techniques is moving towards point-of-care application, to avoid the costly diagnostic delays associated with transport and laboratory analysis. Point-of-care molecular diagnostics are expected to have a significant impact in combatting hospital acquired infections (‘HAIs’). HAIs are a major cause of increased morbidity and death among patients in health care settings globally. These infections are often antibiotic resistant, and affect already weakened patients. It is hoped that molecular diagnostics will eventually allow for the rapid identification of a particular strain of pathogen(s), even for unculturable and polymicrobial infections. This article considers how the existing legal and normative framework governing hospitals’ responses to HAIs may affect the introduction of rapid, point-of-care molecular diagnostics. To this end, we carried out a review of international, national, and institutional guidelines addressing hospital duties to prevent, control, and rapidly diagnose HAIs. We also reviewed relevant legislation and case law in Canada and the United States. In particular, we consider if the complex normative framework governing hospitals helps or hinders the adoption and implementation of precision diagnostic tools. We conclude that health-care institutions are likely to come under increasing pressure – both ethical and legal – to adopt rapid molecular diagnostics as part of their response to HAIs.

The inter-patient differences in drug response is documented to be attributable to heritable genetic variations in the nucleotide sequence of drug-metabolizing enzymes. The identification of variant allele frequencies in specific ethnic groups is important to individualize drug dosing and improve therapeutics. This study aimed to detect single-nucleotide polymorphism (SNP) in CYP3A4 and the homozygous deletion (0/0) of GSTM1 and GSTT1 in a Filipino population. Onehundred and forty-two Filipino subjects were genotyped for the CYP3A4*18 SNP using PCR-RFLP and the GSTM1 0/0 and GSTT1 0/0 by basic PCR followed by agarose gel electrophoresis. In the study population, the frequency of the CYP3A4*18 variant allele was found to be 2.11%. The percentage of GSTM1 0/0 observed was 64.08 while that of GSTT1 0/0 was 48.59. These frequencies complement studies in other Asian populations highlighting the importance of the screening for future prospects of individualized medicines.

Concerns about genetic discrimination (GD) have been reported since the 1980s. The potential chilling effects of GD both in the clinical and research settings have prompted the adoption of a myriad of laws and moratoria on access to genetic data in Europe and the United States. Recent studies in Canada, Australia and Germany concerning patients and family members at-risk for Huntington’s disease have raised concerns about GD and life insurance. However, broader empirical evidence on the occurrence of GD (ex. involving complex genetic disorders in the context of personalized medicine) remains scarce. This study identifies the information that Canadian life insurers request in their primary proposal forms. 21 forms from different insurers, available online, were assessed to determine 1) whether insurers are explicitly or specifically requesting genetic information from applicants, 2) whether insurers are using open-ended questions in a way that may compel the broad disclosure of personal information, and 3) what type of authorization is requested from applicants to enable insurers to verify the accuracy and completeness of the information submitted on the form. Our findings show that Canadian life insurers do not explicitly request that applicants disclose their genetic test results on insurance questionnaires. However, their use of broad terminology and open questions, provide them access to a wealth of medical information (including genetic test results) in addition to family history of diseases. Both the breadth of information currently being collected through their proposal forms and the lack of standardization across insurance groups raise concerns about the equity, transparency and overall coherence of the process. Although the findings have to be interpreted in the context of the inherent limitations of this type of study, they carry important consequences for the translation of personalized medicine which requires and generates a wealth of genomic information for patients.