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Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

ABSTRACT: OBJECTIVE:To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. METHODS:A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. RESULTS:Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CONCLUSION:CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.

SUBMITTER: Fohner AE

PROVIDER: S-EPMC6989102 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

Fohner Alison E AE Ranatunga Dilrini K DK Thai Khanh K KK Lawson Brian L BL Risch Neil N Oni-Orisan Akinyemi A Jelalian Aline T AT Rettie Allan E AE Liu Vincent X VX Schaefer Catherine A CA

Pharmacogenetics and genomics 20191001 8

<h4>Objective</h4>To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment.<h4>Methods</h4>A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin ...[more]

PMID: 31461080

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Project description:BACKGROUND:The science of measuring and reporting on the performance of healthcare systems is rapidly evolving. In the past decade, across many jurisdictions, organisations tasked with monitoring progress towards reform targets have broadened their purview to take a more system-functioning approach. Their aim is to bring clarity to performance assessment, using relevant and robust concepts - and avoiding reductionist measures - to build a whole-of-system view of performance. Existing performance frameworks are not fully aligned with these developments. METHODS:An eight stage process to develop a conceptual framework incorporated literature review, mapping, categorisation, integration, synthesis and validation of performance constructs that have been used by organisations and researchers in order to assess, reflect and report on healthcare performance. RESULTS:A total of 19 performance frameworks were identified and included in the review. Existing frameworks mostly adopted either a logic model (inputs, outputs and outcomes), a functional, or a goal-achievement approach. The mapping process identified 110 performance terms and concepts. These were integrated, synthesised and resynthesised to produce a framework that features 12 derived constructs reflecting combinations of patients' needs and expectations; healthcare resources and structures; receipt and experience of healthcare services; healthcare processes, functions and context; and healthcare outcomes. The 12 constructs gauge performance in terms of coverage, accessibility, appropriateness, effectiveness, safety, productivity, efficiency, impact, sustainability, resilience, adaptability and equity. They reflect four performance perspectives (patient, population, delivery organisation and system). CONCLUSIONS:Internationally, healthcare systems and researchers have used a variety of terms to categorise indicators of healthcare performance, however few frameworks are based on a theoretically-based conceptual underpinning. The proposed framework incorporates a manageable number of performance domains that together provide a comprehensive assessment, as well as conceptual and operational clarity and coherence that support multifaceted measurement systems for healthcare.

Project description:IntroductionAllelic frequency distribution of drug metabolizing enzyme genes among populations is important to identify risk groups for adverse drug reaction and to select representative populations for clinical trials. Although India emerged as an important hub for clinical trials, information about the pharmacogenetic diversity for this region is still lacking. Here, we investigated genetic diversity of cytochrome-P450-2C9 (CYP2C9) gene which metabolizes wide range of drugs and is highly expressed in the human liver.MethodsIn total, 1278 individuals from 36 diverse Indian populations, 210 individuals from in-house data-repository and 489 other South Asian samples from the 1000 Genomes Project were selected. Variants observed in CYP2C9 gene were subjected to various statistical analyses.ResultsHigh frequency of CYP2C9*3 (~13%) and CYP2C9*3/*3 (~1%) was observed among South Asians, compared to 21 populations living outside the Indian subcontinent. The allelic/genotypic frequency does not correlate with geographical location or linguistic affiliation, except populations speaking Tibeto-Burmans language, who have lower frequency of CYP2C9*3 and CYP2C9*3/*3. Since, South Asians practice strict endogamy, presence of unique mutation and high frequency of homozygous genotypes not surprising. CYP2C9*3 has been associated with therapeutic response.The effect of CYP2C9*3/*3 is more pronounced compared to heterozygous and wild type homozygous genotypes as evident in many in vitro studies. As South Asians have high frequency, it would be interesting to explore potential of CYP2C9*3 as a marker for personalized therapy. Our study revealed several rare functional variants, which form eight novel and rare haplotypes of CYP2C9 (CYP2C9*63-*70). Of which, CYP2C9*64, *65, *66, *68, *69 and *70 haplotypes are South Asian-specific.ConclusionOverall, we find high genetic heterogeneity within South Asians and identified South Asian-specific putative functional CYP2C9 haplotypes. High frequency of CYP2C9*3 and CYP2C9*3/*3 was observed in South Asian populations. Taken together, current study greatly enriches the knowledge of naturally occurring CYP2C9 variants and its diversity in South Asia, which are relevant to further CYP2C9-related functional research and for personalized medicine.

Dataset Information

Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

Publications

Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system.

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