Race, ethnicity, ancestry, and pharmacogenetics.
ABSTRACT Pharmacogenetics is the study of how genetic variation influences the response to drugs. The concepts of race, ethnicity, and ancestry have long had a strong influence on pharmacogenetic discovery and on our understanding of population-level differences in drug response. The primary goal of pharmacogenetics, however, is to identify the individual genetic determinants of drug activity so that therapy can be tailored to the individual patient. This article describes the relationship between the concepts of race, ethnicity, and ancestry and how these concepts have been applied to pharmacogenetics, and it provides examples of the benefits and pitfalls associated with the use of racial or ethnic labels in genetic studies. The future of pharmacogenetics, including the study of rare genetic variation and what this means for racial or ethnic disparities in pharmacogenetic discovery, is also discussed.
SourceAvailable from: Thiago Torres[Show abstract] [Hide abstract]
ABSTRACT: Lopinavir/ritonavir (LPV/r) based regimen is recommended during pregnancy to reduce the risk of HIV mother-to-child transmission, but the appropriate dose is controversial. We compared the pharmacokinetics of standard and increased LPV/r doses during pregnancy. This randomized, open-label prospective study enrolled 60 HIV-infected pregnant women between gestational weeks 14 and 30. Participants received either the standard (400/100 mg BID) or increased dose (600/150 mg BID) of LPV/r tablets during pregnancy and the standard dose for six weeks after childbirth. Pharmacokinetic analysis was performed using a high-performance liquid chromatography-tandem mass spectrometry method. Adherent participants who received the standard dose presented minimum LPV concentrations of 4.4, 4.3 and 6.1μg/mL in the second and the third trimesters and postpartum, respectively. The increased dose group exhibited values of 7.9, 6.9 and 9.2 μg/mL at the same timepoints. Although LPV exposure was significantly higher in the increased dose group, the standard dose produced therapeutic levels of LPV against wild-type virus in all adherent participants, except one patient in the third trimester; 50%, 37.5%, 25% and 0%, 15%, 0% of the participants in the standard and increased dose groups, respectively, failed to achieve therapeutic levels against resistant viruses during the second and third trimesters and after childbirth. After 12 weeks of treatment and after childbirth, all adherent participants achieved undetectable HIV viral loads, and their babies (49/54) were uninfected. No serious drug-related adverse events were observed. We conclude that the standard dose is appropriate for use during pregnancy and an increased dose may be necessary for women harboring resistant HIV (clinicaltrials.gov identifier NCT00605098).Antimicrobial Agents and Chemotherapy 03/2014; DOI:10.1128/AAC.02599-13 · 4.45 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Introduction: Large-scale whole genome and exome resequencing studies have revealed that humans have a high level of deleterious rare variation, which has important implications for the design of future pharmacogenetics studies. Areas covered: Current pharmacogenetic guidelines focus on the implementation of common variation into dosing guidelines. However, it is becoming apparent that rare variation may also play an important role in differential drug response. Current sequencing technologies offer the opportunity to examine rare variation, but there are many challenges associated with such analyses. Nonetheless, if a comprehensive picture of the role that genetic variants play in treatment outcomes is to be obtained, it will be necessary to include the entire spectrum of variation, including rare variants, into pharmacogenetic research. Expert opinion: In order to implement pharmacogenetics in the clinic, patients should be genotyped for clinically actionable pharmacogenetic variants and patients responding unfavourably to treatment after pharmacogenetics-based dosing should be identified and resequenced to identify additional functionally relevant variants, including rare variants. All derived information should be added to a central database to allow for the updating of existing dosing guidelines. By routinely implementing such strategies, pharmacogenetics-based treatment guidelines will continue to improve.Expert Opinion on Drug Metabolism & Toxicology 03/2014; DOI:10.1517/17425255.2014.903239 · 2.93 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The neurotransmitter dopamine (DA) plays a central role in addictive disorders, including nicotine addiction. Specific DA-related gene variants have been studied to identify responsiveness to treatment for nicotine addiction. Genetic variants in DRD2, DRD4, ANKK1, DAT1, COMT and DBH genes show some promise in informing personalized prescribing of smoking cessation pharmacotherapies. However, many trials studying these variants had small samples, used retrospective design or were composed of mainly self-identified Caucasian individuals. Furthermore, many of these studies lacked a comprehensive measurement of nicotine metabolism rate, did not assess the roles of sex or the menstrual cycle, and did not investigate the role of rare variants and/or epigenetic factors. Future work should be conducted addressing these limitations to more effectively utilize DA genetic information to unlock the potential of smoking cessation pharmacogenetics.Pharmacogenomics 02/2014; 15(2):221-34. DOI:10.2217/pgs.13.246 · 3.43 Impact Factor