Showing papers by "Richard B. Kim published in 2019"

DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report.

Abstract: 5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

Targeted next generation sequencing as a tool for precision medicine

Abstract: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

The Role of Next-Generation Sequencing in Pharmacogenetics and Pharmacogenomics

Abstract: Inherited genetic variations in pharmacogenetic loci are widely acknowledged as important determinants of phenotypic differences in drug response, and may be actionable in the clinic. However, recent studies suggest that a considerable number of novel rare variants in pharmacogenes likely contribute to a still unexplained fraction of the observed interindividual variability. Next-generation sequencing (NGS) represents a rapid, relatively inexpensive, large-scale DNA sequencing technology with potential relevance as a comprehensive pharmacogenetic genotyping platform to identify genetic variation related to drug therapy. However, many obstacles remain before the clinical use of NGS-based test results, including technical challenges, functional interpretation, and strict requirements for diagnostic tests. Advanced computational analyses, high-throughput screening methodologies, and generation of shared resources with cell-based and clinical information will facilitate the integration of NGS data into candidate genotyping approaches, likely enhancing future drug phenotype predictions in patients.

Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1

Abstract: Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. But until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a mouse model with targeted, global disruption of the Slco2b1 gene (KO) for examining the disposition of two confirmed mOATP2B1 substrates, namely fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wildtype (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-last) than WT mice, respectively. In WT mice, co-administration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced Cmax by 80% and 88%, respectively, while the AUC0-last was lower by 35% and 70%, respectively. In KO mice, AJ co-administration reduced oral fexofenadine Cmax and AUC0-last by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of the oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 knockout mice model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation.

Abstract: Author(s): Sukumar, Smrithi; Gulilat, Markus; Linton, Bradley; Gryn, Steven E; Dresser, George K; Alfonsi, Jeffrey E; Schwarz, Ute I; Kim, Richard B; Schwartz, Janice B | Abstract: ObjectivesLower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF.DesignConvenience sample of patients receiving anticoagulation during 2017.SettingAcademic medical center.ParticipantsStable adults older than 65 years with NVAF receiving apixaban on a chronic basis.MeasurementsPatient age, weight, creatinine, co-medications, and apixaban concentrations.ResultsA total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations.ConclusionsApixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

Abstract: The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

Crohn's Disease Is Associated with Decreased CYP3A4 and P-Glycoprotein Protein Expression.

Abstract: Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) have broad substrate overlap and are involved in the metabolism and transport of nearly 50% of currently prescribed medications. In the intestine, CYP3A4 and P-gp are coexpressed in the enterocytes at the intestinal villous tip and act in a coordinated manner to limit drug and xenobiotic oral bioavailability prior to further metabolism and disposition in the liver. Crohn's disease (CD), a form of inflammatory bowel disease, introduces a transmural intestinal insult that disrupts the intestinal barrier function; it therefore has the potential to affect intestinal drug metabolism and transport. We hypothesized that individuals with CD have reduced intestinal expression of CYP3A4 and P-gp. We obtained intestinal biopsy samples from individuals with and without CD and quantified the expression of CYP3A4 and P-gp. When we carried out Western analysis for protein expression, we observed a significant reduction in ileal (45% decrease) and colonic (78% decrease) CYP3A4 protein expression in subjects with CD compared with those without. Similarly, an 85% reduction in colonic P-gp protein expression was seen in the CD patients. Our data highlight important and novel findings pertaining to CD-associated changes to the intestinal expression of CYP3A4 and P-gp that are of relevance to better predict substrate drug dosing for patients with CD.

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations

Abstract: Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 −1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

Precision Medicine: Lessons Learned From Implementation of a Pharmacogenetics-Based Patient Care Program in a Real-World Setting.

Abstract: Despite rapid advances in genomics technologies for a broader adoption of pharmacogenetics as a routine part of patient care, a better understanding of the expectations, needs, and demands faced by our patients, as well as health care providers is essential. We outline some of the insights we have gained from providing pharmacogenetics-based patient care at our tertiary teaching hospital since 2008.

Prospective cohort study of the impact of hospital-wide dihydropyrimidine dehydrogenase (DPYD) genotype testing for fluoropyrimidine-based chemotherapy on adverse events and hospital costs.

Abstract: 3028Background: Fluoropyrimidines remain integral components of modern chemotherapy for solid tumors, and their toxicities can be reduced by pretreatment DPYD genotyping. Our main objective was to ...