- Title
- Assessment of potential drug and gene interactions for cardiovascular and antidepressant drugs from high-throughput genotyping data in a community cohort of older Australians
- Creator
- Biswas, Mohitosh
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The safety and efficacy of drugs may be affected by drug-drug interactions (DDIs), drug-gene interactions (DGIs) and multifactorial combinations involving both kinds of interactions. This PhD thesis hypothesises that older people, who are often exposed to polypharmacy, may be at risk of drug and gene interactions that have clinically significant consequences for medication safety and efficacy. This hypothesis was tested by investigating the prevalence of predicted drug and gene interactions for cardiovascular drugs of interest (clopidogrel, statins or warfarin) in a community cohort of older Australians from the Hunter Community Study. These drugs were chosen because they are widely used by older people in the community and because both adverse effects and therapeutic failure of these drugs can be life-threatening. To investigate whether the findings also applied to other drug classes, the prevalence of predicted drug and gene interactions for antidepressant drugs of interest (TCAs or SSRIs) was also determined. The project used self-reported medication data of 2,642 study participants (55 years of age or greater), predominantly of European ancestry. Potential interacting medications were identified from a composite list derived from the Monthly Index of Medical Specialties (MIMS) list of evidence-based clinically significant interactions and relevant clinical tables of CYP and OATP1B1 inhibitors, inducers or substrates from the U.S. Food and Drug Administration (FDA) and elsewhere. To determine the prevalence of potential clinically significant DDIs, co-prescribed drugs potentially interacting with the cardiovascular or antidepressant drugs of interest were identified from this composite list and the prevalence of study participants exposed to the interacting drugs determined. To determine the prevalence of potential clinically significant DGIs, genotype data were obtained from Affymetrix Kaiser Axiom human microarrays and imputed data from the 1000 Genomes and HapMap Phase II European reference panels. Clinically significant pharmacogenotypes were identified using the Clinical Pharmacogenetics Implementation Consortium (CPIC) pharmacogenomics based dosing guidelines. Participants were considered at risk of simple DGIs if they had a clinically significant genotype potentially affecting the safety or efficacy of the main drug under investigation but were not taking any interacting drugs. Participants were considered to be at risk of multifactorial DGIs if they had one or more clinically significant genotypes for the main drug under investigation and were also taking other interacting drugs potentially affecting medication safety or efficacy. Of the 1062 participants on cardiovascular drugs of interest (clopidogrel, statins or warfarin), 351 participants (33.1%; 95% CI 30%-36%) were at risk of clinically significant DDIs, with a mean of 1.8±1.2 possible interactions per participant. Relevant genotype data were available for 307 participants taking clopidogrel, simvastatin or warfarin, of whom 53 (17.3%; 95% CI 13%-21%) were identified as being at risk of clinically significant simple DGIs and 37 (12.1%; 95% CI 8%-16%) at risk of clinically significant multifactorial DGIs. Approximately 3% of cardiovascular drug users were at risk of severe DDIs and in total 0.5% were at risk of severe DDIs and also had risk genotypes i.e. at risk of severe multifactorial DGIs. Targeting this restricted group for special clinical attention may be an effective way to improve drug safety. There was high prevalence (42.4%) of co-prescription of proton pump inhibitors in clopidogrel users, predicted to increase risk of serious adverse DDIs such as myocardial infarction, stroke or death, with ~15% (6/39) also having genotypes placing them at risk of serious multifactorial DGIs causing therapeutic inefficiency. Approximately 15-20% of simvastatin users were co-prescribed OATP1B1 or CYP3A4/5 inhibitors that can cause fatal rhabdomyolysis, with 1.5% being at risk of serious multifactorial DGIs causing severe toxicities. The project hypothesis was further tested by investigating predicted drug and gene interactions for selected antidepressant drugs (TCAs or SSRIs). Of the 270 participants on TCAs or SSRIs, 174 (64.4%; 95% CI 59%-70%) were at risk of clinically significant DDIs, with a mean of 1.6±0.8 possible interactions per participant. Genotype data were available for 128 of the 270 participants, of whom 15 (11.7%; 95% CI 6%-17%) were identified as being at risk of clinically significant simple DGIs and 20 (15.6%; 95% CI 9%-22%) at risk of clinically significant multifactorial DGIs. Approximately 14% of antidepressant drug users were at risk of severe DDIs. In total ~1% were at risk of severe DDIs and also had genotypes placing them at risk of severe multifactorial DGIs that could cause toxicities such as gastrointestinal bleeding. The overall findings of this thesis provide evidence to support the PhD hypothesis that older Australians in the community are at considerable risk of clinically significant drug and gene interactions affecting the safety or efficacy of important drugs such as cardiovascular drugs and anti-depressants. This PhD thesis is believed to be the first study to provide evidence that there may be considerable numbers of older people in the community who are at risk of experiencing clinically significant health problems due to combined effects of DDIs and DGIs. The findings highlight the importance of taking such effects into consideration for optimal medication safety and efficacy. Large scale randomised longitudinal studies collecting medication and genetic data for different ethnicities should also be undertaken to examine the clinical utility of considering pharmacogenomics factors in real world scenarios. This study will make a substantial contribution to the current literature by facilitating the identification of a restricted subset of older people in the community who may be at particularly high risk of severe clinical sequelae from drug and gene interactions and benefit from additional practitioner awareness and monitoring to achieve optimal treatment safety and effectiveness. It is hoped that this PhD thesis will also contribute to the future of this area by providing new knowledge and analytical frameworks to inform practitioner education and further research including clinical trials.
- Subject
- DDIs; DGIs; gene interactions; drug interactions; Hunter Community Study; clopidogrel; warfarin; statins
- Identifier
- http://hdl.handle.net/1959.13/1393461
- Identifier
- uon:33547
- Rights
- Copyright 2018 Mohitosh Biswas
- Language
- eng
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