Publications by authors named "Richard B Kim"

191 Publications

Digoxin Dosing and the Risk of Toxicity in Older Adults With CKD.

Am J Kidney Dis 2021 Nov 19. Epub 2021 Nov 19.

ICES, London ON, Canada; Department of Epidemiology & Biostatistics, Western University, London ON, Canada; Division of Nephrology, Department of Medicine, Western University, London ON, Canada.

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http://dx.doi.org/10.1053/j.ajkd.2021.09.024DOI Listing
November 2021

In-vitro characterization of coding variants with predicted functional implications in the efflux transporter multidrug resistance protein 4 (MRP4, ABCC4).

Pharmacogenet Genomics 2021 Oct 22. Epub 2021 Oct 22.

Department of Physiology and Pharmacology Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada.

MRP4 (gene ABCC4) is a polymorphic efflux transporter that has been implicated in drug-induced toxicity. We selected ten commonly observed MRP4 coding variants among Europeans for experimental characterization including nine variants predicted to be deleterious or functional (combined annotation-dependent depletion score >15). We assessed protein localization and activity by quantifying intracellular accumulation of two prototypic substrates, taurocholic acid (TCA) and estradiol 17-β-glucuronide (E217βG), in HEK293T over-expressing MRP4 wildtype or variant where cellular substrate loading was optimized through co-transfection with an uptake transporter. V458M, a novel variant not previously studied, and T1142M, showed reduced activity compared to MRP4 wildtype for E217βG and TCA (P < 0.01), while L18I, G187W, K293E, and R531Q moderately increased activity in a substrate-dependent manner. Protein expression analysis indicated reduced cell surface expression for V458M (P < 0.01) but not T1142M compared to wildtype. Reduced activity may result from altered surface expression (V458M) or intrinsic activity as both variants map within the nucleotide-binding domains of MRP4. G187W showed a trend for reduced surface expression (P = 0.054) despite transport comparable or increased to wildtype suggesting enhanced intrinsic activity. Our findings suggest moderately altered MRP4 activity in six out of nine predicted functional variants with likely different mechanisms and substrate-specific effects. Cell-based studies using multiple known substrates are warranted to more accurately predict functional variants in this clinically important transporter.
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http://dx.doi.org/10.1097/FPC.0000000000000459DOI Listing
October 2021

Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates.

Front Pharmacol 2021 14;12:713567. Epub 2021 Sep 14.

Department of Physiology & Pharmacology, University of Western Ontario, London, ON, Canada.

Organic anion transporting polypeptide 2B1 (OATP2B1, gene ) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) . Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and genotypes. No association was observed between variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities were not fully aligned with their associations to plasma concentrations of endogenous substrates . Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity.
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http://dx.doi.org/10.3389/fphar.2021.713567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476882PMC
September 2021

Novel variant in glycophorin c gene protects against ribavirin-induced anemia during chronic hepatitis C treatment.

Biomed Pharmacother 2021 Nov 22;143:112195. Epub 2021 Sep 22.

Department of Medical Genetics, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, Vancouver, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, Canada; Pharmaceutical Outcomes Program, British Columbia Children's Hospital, Vancouver, Canada. Electronic address:

Background: The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia.

Methods: We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants.

Results: We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04-0.34, P = 2.94 × 10) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P = 8.66 ×10; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P = 0.0437).

Conclusions: GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction.
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http://dx.doi.org/10.1016/j.biopha.2021.112195DOI Listing
November 2021

A Comparative Analysis of Drug Therapy, Disease Phenotype, and Health Care Outcomes for Men and Women with Inflammatory Bowel Disease.

Dig Dis Sci 2021 Jul 27. Epub 2021 Jul 27.

Division of Clinical Pharmacology, Department of Medicine, Western University, 339 Windermere Road A10-221a, London, ON, N6A 5A5, Canada.

Background: Sex and gender refer to biological and social differences between men and women. While well-evaluated in other disciplines, their roles in inflammatory bowel disease (IBD) are not well-defined. This study aimed to characterize differences in healthcare outcomes in men and women with IBD.

Methods: A retrospective single-centre cohort study was conducted to evaluate differences between men and women receiving care for Crohn's disease (CD) and ulcerative colitis (UC) at the Western University Personalized Medicine Clinic from March 2012 to September 2019. The primary endpoint was the proportion of IBD drugs used for all drug classes. Additional outcomes in healthcare utilization and disease phenotype were assessed. Student's t test and Fisher's exact test were used to assess differences RESULTS: A total of 1015 participants were included (CD = 656; UC = 359). In UC and CD, 47.9% and 59.0% were women, respectively. Overall, women were more likely prescribed budesonide than men (23.6% vs. 13.4%; p < 0.0001), while more men were exposed to prednisone for IBD management (73.5% vs. 67.4%; p = 0.04). Immunomodulator use was higher in men with CD versus women (86.6% vs. 78.3%; p = 0.008) and of those exposed, women more commonly experienced ADRs (29.5% vs. 21.2%; p = 0.01). Though no sex-related difference was identified, age was a predictor of biologic exposure in women with CD and men with UC, with those > 55 being less likely to receive biologics.

Conclusions: These findings highlight differences in disease course and treatment approaches between men and women with IBD and support the consideration of sex and gender when researching disease outcomes.
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http://dx.doi.org/10.1007/s10620-021-07177-xDOI Listing
July 2021

Pharmacogenomic-based personalized medicine: Multistakeholder perspectives on implementational drivers and barriers in the Canadian healthcare system.

Clin Transl Sci 2021 11 16;14(6):2231-2241. Epub 2021 Jul 16.

Ivey Business School, University of Western Ontario, London, Ontario, Canada.

Pharmacogenomics (PGx)-based personalized medicine (PM) is increasingly utilized to guide treatment decisions for many drug-disease combinations. Notably, London Health Sciences Centre (LHSC) has pioneered a PGx program that has become a staple for London-based specialists. Although implementational studies have been conducted in other jurisdictions, the Canadian healthcare system is understudied. Herein, the multistakeholder perspectives on implementational drivers and barriers are elucidated. Using a mixed-method qualitative model, key stakeholders, and patients from LHSC's PGx-based PM clinic were interviewed and surveyed, respectively. Interview transcripts were thematically analyzed in a stepwise process of customer profiling, value mapping, and business model canvasing. Value for LHSC located specialist users of PGx was driven by the quick turnaround time, independence of the PGx clinic, and the quality of information. Engagement of external specialists was only limited by access and awareness, whereas other healthcare nonusers were limited by education and applicability. The major determinant of successful adoption at novel sites were institutional champions. Patients valued and approved of the service, expressed a general willingness to pay, but often traveled far to receive genotyping. This paper discusses the critical pillars of education, awareness, advocacy, and efficiency required to address implementation barriers to healthcare service innovation in Canada. Further adoption of PGx practices into Canadian hospitals is an important factor for advancing system-level changes in care delivery, patient experiences, and outcomes. The findings in this paper can help inform efforts to advance clinical PGx practices, but also the potential adoption and implementation of other innovative healthcare service solutions.
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http://dx.doi.org/10.1111/cts.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604218PMC
November 2021

Letter: genetic variation in the HLA-DQA1*05 allele predicts tumour necrosis factor-α antagonist immunogenicity - does location matter?

Aliment Pharmacol Ther 2021 05;53(9):1055-1056

Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada.

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http://dx.doi.org/10.1111/apt.16338DOI Listing
May 2021

Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study.

Clin Transl Gastroenterol 2021 04 5;12(4):e00332. Epub 2021 Apr 5.

Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada.

Introduction: Azathioprine-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of azathioprine-exposed patients with inflammatory bowel disease (IBD). The haplotype HLADQA1-HLADRB1*07:01A>C is strongly associated with azathioprine-induced pancreatitis in IBD. We aimed to evaluate whether pretreatment HLADQA1-HLADRB1*07:01A>C screening will reduce the risk of azathioprine-induced pancreatitis.

Methods: Participants with IBD were screened for HLADQA1-HLADRB1*07:01A>C, and participants with a variant genotype were excluded from azathioprine treatment. Wild-type participants were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared with unscreened historical controls.

Results: HLADQA1-HLADRB1*07:01A>C screening resulted in an 11-fold reduction in the incidence of azathioprine-induced pancreatitis (n = 1/328 or 0.30% vs n = 13/373 or 3.4%). In propensity score-matched cohorts (age and sex), HLA DQA1-HLADRB1*07:01A>C screening was significantly associated with a reduction in the incidence of AZA-induced pancreatitis independent of weight, glucocorticoid exposure, and smoking status (adjusted odds ratio = 0.075, 95% confidence interval = 0.01-0.58, P = 0.01). Up to 45% (n = 271/599) of participants were excluded from azathioprine therapy based on the haplotype in the HLADQA1-HLADRB1*07:01A>C-screened cohort.

Discussion: HLADQA1-HLADRB1*07:01A>C screening reduced the risk of azathioprine-induced pancreatitis; however, using this strategy to guide the use of azathioprine therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with azathioprine. In regions where there is access to other IBD therapies, and given the short-term and long-term toxicities associated with azathioprine, HLADQA1-HLADRB1*07:01A>C-screening may be a clinically relevant strategy for enhancing the safe use of azathioprine in IBD. In addition, cost-effectiveness analyses are needed to further solidify the utility of HLADQA1-HLADRB1*07:01A>C screening in IBD populations.
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http://dx.doi.org/10.14309/ctg.0000000000000332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345912PMC
April 2021

Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment.

Ann Intern Med 2021 03;174(3):432

University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.7326/L20-1456DOI Listing
March 2021

Near Miss or Standard of Care? Screening for Cancer Patients Receiving Fluorouracil.

Curr Oncol 2020 12 18;28(1):94-97. Epub 2020 Dec 18.

London Health Sciences Centre and Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada.

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the gene, and variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of screening on patient outcomes.
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http://dx.doi.org/10.3390/curroncol28010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816174PMC
December 2020

Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events.

Clin Transl Sci 2021 07 23;14(4):1338-1348. Epub 2021 Feb 23.

Department of Physiology and Pharmacology, University of Western Ontario, London, Canada.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.
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http://dx.doi.org/10.1111/cts.12981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301551PMC
July 2021

High infliximab trough concentrations are associated with sustained histologic remission in inflammatory bowel disease: a prospective cohort study.

BMC Gastroenterol 2021 Feb 18;21(1):77. Epub 2021 Feb 18.

Divisions of Clinical Pharmacology, Department of Medicine, Western University, 339 A Wilson 339 Windermere Road A10-221a, London, ON, N6A 5A5, Canada.

Background: The threshold concentration of infliximab during maintenance therapy has not been well-defined in relation to histologic remission. The aim of the study is to dentify the maintenance-phase infliximab concentration associated with histologic remission in inflammatory bowel disease patients (IBD).

Methods: A prospective cohort study was carried out in 104 IBD patients seen at a tertiary care centre in London, Canada. Infliximab trough concentrations were collected during the maintenance phase of treatment and compared between participants with and without evidence of histologic remission. Participants were additionally evaluated for sustained histologic remission, and relapse to active disease.

Results: Participants in histologic remission attained higher mean concentrations of infliximab during the maintenance phase (10.34 ± 0.69 μg/ml) compared to those with persistent disease activity (6.23 ± 0.67 μg/ml, p-value < 0.0001). Additionally, during the maintenance phase, sustained histologic remission was also associated with a higher mean concentration of infliximab (10.81 ± 5.46 μg/ml) compared to those who relapsed to active disease (5.68 ± 3.70, p < 0.001). Overall, participants with a mean infliximab trough concentration greater than 8ug/ml were more likely to have histologic remission (area under the receiver operating characteristic curve, AUROC = 0.72, 95%CI = 0.65-0.84, p < 0.0001) and sustained histologic remission (AUC = 0.77, 95%CI = 0.63-0.91, p = 0.002).

Conclusion: Maintenance-phase infliximab trough concentrations greater than 8 μg/ml, which is higher than the currently recommended target concentration, are highly associated with histologic remission and sustained histologic remission.
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http://dx.doi.org/10.1186/s12876-021-01650-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890824PMC
February 2021

Association of Baclofen With Falls and Fractures in Patients With CKD.

Am J Kidney Dis 2021 09 10;78(3):470-473. Epub 2021 Feb 10.

ICES Western, London ON, Canada; Department of Epidemiology & Biostatistics, London ON, Canada; Division of Nephrology, Department of Medicine, London ON, Canada.

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http://dx.doi.org/10.1053/j.ajkd.2020.12.017DOI Listing
September 2021

Mouse NTCP-Mediated Rosuvastatin Uptake In Vitro and in Slc10a1-Deficient Mice.

AAPS J 2021 01 6;23(1):17. Epub 2021 Jan 6.

Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

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http://dx.doi.org/10.1208/s12248-020-00540-2DOI Listing
January 2021

Higher-Dose Sitagliptin and the Risk of Congestive Heart Failure in Older Adults with CKD.

Clin J Am Soc Nephrol 2020 12 25;15(12):1728-1739. Epub 2020 Nov 25.

ICES, Kidney, Dialysis and Transplantation Research Program, Ontario, Canada.

Background And Objectives: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d.

Design, Setting, Participants, & Measurements: This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95% confidence intervals were obtained using bootstrap variance estimators.

Results: Of 9215 patients, 6518 started sitagliptin at >50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at >50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, -0.12%; 95% confidence interval, -0.19 to -0.06) and a lower risk of all-cause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98).

Conclusions: The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at >50 versus ≤50 mg/d.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_25_CJN08310520_final.mp3.
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http://dx.doi.org/10.2215/CJN.08310520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769019PMC
December 2020

Rosuvastatin Myotoxicity After Starting Canagliflozin Treatment: A Case Report.

Ann Intern Med 2020 10 4;173(7):585-587. Epub 2020 Aug 4.

University of Toronto, Toronto, Ontario, Canada (E.B., D.J.).

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http://dx.doi.org/10.7326/L20-0549DOI Listing
October 2020

Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients.

Sci Rep 2020 07 16;10(1):11725. Epub 2020 Jul 16.

Clinical Pharmacology, Department of Medicine, Western University, 339 Windermere Rd, London, ON, N6A 5A5, Canada.

The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G > T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G > T, MDR1 3435C > T and PXR -25385C > T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR = 3.34, 95% CI = 1.58-7.05, p = 0.002) and earlier progression to surgery (hazard ratio, HR = 3.00, 95% CI = 1.86-4.83, p < 0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22-52.38, p < 0.0001) and early progression to surgery (HR = 6.28, 95% CI = 3.62-10.90, p < 0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p < 0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.
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http://dx.doi.org/10.1038/s41598-020-68686-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366697PMC
July 2020

Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients.

Breast Cancer Res Treat 2020 Sep 6;183(2):365-372. Epub 2020 Jul 6.

Department of Medicine, Division of Clinical Pharmacology, Western University, London, ON, Canada.

Purpose: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer.

Methods: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia.

Results: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia.

Conclusions: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.
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http://dx.doi.org/10.1007/s10549-020-05777-1DOI Listing
September 2020

Baclofen has a risk of encephalopathy in older adults receiving dialysis.

Kidney Int 2020 10 22;98(4):979-988. Epub 2020 May 22.

Institute for Clinical Evaluative Sciences, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. Electronic address:

At least 23 case reports link the muscle relaxant baclofen to encephalopathy in patients receiving dialysis. To explore this issue, we conducted a study to quantify the risk of encephalopathy from baclofen in patients receiving dialysis. Linked healthcare databases were used to conduct a population-based cohort study of older adults receiving maintenance dialysis in Ontario, Canada (1997-2018) to compare new users of baclofen to non-users. The primary outcome was the 30-day risk of hospitalization with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, or transient cerebral ischemic attack. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. We studied 360 new baclofen users and 6109 non-users (2638 [41%] women; median age 75). The median baclofen dose was 20 mg/day. Hospitalization with encephalopathy occurred in 26 of 360 baclofen users (7.2%) and in under six of 6109 non-users (under 0.1%); weighted risk ratios, 78.3 (95% confidence interval 27.9 to 219.2); weighted risk differences, 7.1% (4.5% to 9.8%). The median time from baclofen dispensing to hospitalization with encephalopathy was three days. Among patients receiving dialysis, approximately one in 14 were hospitalized with encephalopathy shortly after starting baclofen. Thus, baclofen should be avoided in older adults receiving dialysis, and other muscle relaxants considered in its place. Hence, if baclofen must be used, a low dose should be prescribed, and older adults should be carefully monitored for signs of encephalopathy.
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http://dx.doi.org/10.1016/j.kint.2020.04.047DOI Listing
October 2020

Letter: immunogenicity of infliximab-ready for routine prediction? Authors' reply.

Aliment Pharmacol Ther 2020 04;51(8):813-814

Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada.

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http://dx.doi.org/10.1111/apt.15684DOI Listing
April 2020

In Vitro Functional Characterization and in Silico Prediction of Rare Genetic Variation in the Bile Acid and Drug Transporter, Na-Taurocholate Cotransporting Polypeptide (NTCP, ).

Mol Pharm 2020 04 10;17(4):1170-1181. Epub 2020 Mar 10.

Department of Physiology & Pharmacology, Western University, Medical Sciences Building, Rm 216, N6A 5C1 London, Ontario, Canada.

Na-taurocholate cotransporting polypeptide (NTCP, ) is a key hepatic uptake transporter for bile acids and drugs and is the main functional receptor for hepatitis B and D viruses. Next-generation sequencing has revealed that a large number of rare variants exist in the population. Little data exist regarding head-to-head comparison of in silico algorithms to predict functional effects of pharmacogenetic variants when compared to direct in vitro functional assessment. This study aimed at characterizing rare variants in vitro and to assess the performance of seven in silico algorithms to predict the observed functional impacts. Thirty-five previously uncharacterized, rare, missense variants were transiently expressed in human embryonic kidney 293 type T (HEK293T) cells. NCTP protein expression as well as uptake of substrates taurocholic acid (TCA) and rosuvastatin were assessed. Substrate-specific effects were observed for NTCP G191R, with TCA and rosuvastatin transport observed at 89 and 8% of wild-type (WT) uptake, respectively. Significantly reduced transport of TCA and rosuvastatin was observed for 19 variants ( < 0.05), with seven variants displaying decreased protein expression and marked reduction in transport of both substrates (0-13% of WT uptake, < 0.0001). Performance of in silico algorithms to predict in vitro uptake, assessed using the area under the receiver operating characteristic curves (AUC), ranged from 0.69 to 0.97 and 0.72 to 0.84 for TCA and rosuvastatin uptake, respectively. In conclusion, we identified rare variants with significantly reduced NTCP expression and function. We demonstrated that no algorithm performed robustly enough to replace functional study in vitro, particularly given the broad substrate specificity of many pharmacogenes.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01200DOI Listing
April 2020

Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn's disease.

Sci Rep 2020 02 5;10(1):1866. Epub 2020 Feb 5.

Clinical Pharmacology, Department of Medicine, Western University, 339 Windermere Rd, London, ON, N6A 5A5, Canada.

Bile acids are endogenous ligands of nuclear receptors pregnane X (PXR) and farnesoid X (FXR). PXR and FXR regulate pathways that are impaired in inflammatory bowel disease (IBD). Decreases in PXR and FXR activity are documented in IBD; however reasons for this are unknown. We aimed to assess the effect of Crohn's disease (CD) on the plasma bile acid composition in vivo and the resultant impact on PXR and FXR activation. A cross-sectional study evaluated the plasma concentrations of 12 bile acids in addition to 4β-hydroxycholesterol (4βOHC), an in vivo probe of the PXR target-gene cytochrome 3A4 (CYP3A4) and the FXR target-gene, fibroblast growth factor (FGF) 19 in individuals with (n = 74) and without (n = 71) CD. An in vitro model was used to assess the impact of CD-specific changes in the plasma bile acid composition on PXR and FXR activation. Decreases in glycochenodeoxycholic acid, taurocholic acid and lithocholic acid were seen in CD with increases in glycodeoxycholic acid and glycocholic acid relative to the total plasma bile acid profile. In vitro, increasing concentrations of bile acids applied in the same ratio as seen in the study cohorts resulted in decreased activation of both PXR and FXR in the CD model. In vivo, plasma 4βOHC (CD = 18.68 ng/ml ± 13.02 ng/ml, non-CD = 46.38 ng/ml ± 40.70 ng/ml, p ≤ 0.0001) and FGF19 (CD = 0.276 pg/L ± 0.189 pg/L, non-CD = 0.485 pg/L ± 0.42 pg/L, p = 0.0002) concentrations were lower in CD versus controls. Ultimately, CD-specific changes in the plasma bile acid composition lead to reduced activation of FXR and PXR target genes in vitro and in vivo.
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http://dx.doi.org/10.1038/s41598-020-58644-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002620PMC
February 2020

HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease.

Aliment Pharmacol Ther 2020 02 25;51(3):356-363. Epub 2019 Oct 25.

Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada.

Background: Anti-drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn's disease (CD).

Aims: To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD) METHODS: In a retrospective cohort study, infliximab-exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild-type (GG) and variant-carrying (AG or AA) individuals.

Results: Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97-17.191, P = 1.46 × 10 ) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41-3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46-3.43, P = 2.53 × 10 ) although not with infliximab-associated adverse drug events.

Conclusions: HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype-guided application of combination therapy in IBD.
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http://dx.doi.org/10.1111/apt.15563DOI Listing
February 2020

Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care.

J Thromb Thrombolysis 2020 Feb;49(2):294-303

Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada.

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average 77.2 years old, 85.5 kg, and had a serum creatinine of 103.1 µmol/L. Concomitant amiodarone, an antiarrhythmic agent and moderate CYP3A/ABCB1 inhibitor, the impaired-function variant ABCG2 c.421C > A, and sex predicted higher apixaban concentrations when controlling for age, weight and serum creatinine (multivariate regression; R = 0.34). Our findings suggest that amiodarone and ABCG2 genotype contribute to interpatient apixaban variability beyond known clinical factors.
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http://dx.doi.org/10.1007/s11239-019-01962-2DOI Listing
February 2020

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

Authors:
Richard B Kim

Clin Pharmacol Ther 2019 11 13;106(5):933-935. Epub 2019 Sep 13.

Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada.

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http://dx.doi.org/10.1002/cpt.1611DOI Listing
November 2019

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

Mol Pharm 2019 09 19;16(9):4059-4064. Epub 2019 Aug 19.

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.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00459DOI Listing
September 2019

Targeted next generation sequencing as a tool for precision medicine.

BMC Med Genomics 2019 06 3;12(1):81. Epub 2019 Jun 3.

Division of Clinical Pharmacology, Department of Medicine, Western University, London Health Sciences Centre - University Hospital, 339 Windermere Road, London, ON, N6A 5A5, Canada.

Background: 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) 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1186/s12920-019-0527-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547602PMC
June 2019

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

Drug Metab Dispos 2019 08 23;47(8):832-842. Epub 2019 May 23.

Department of Physiology and Pharmacology (S.M., M.M.J.L., M.J.K., K.L., C.Z., K.E.G., M.D.Y., U.I.S., R.B.K., R.G.T.), and Division of Clinical Pharmacology, Department of Medicine (S.E.M., C.L.S., G.K.D., U.I.S., R.B.K., R.G.T.), University of Western Ontario, London, Ontario, Canada

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. However, 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 knockout (KO) mouse model with targeted, global disruption of the gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wild-type (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration ( ) and area under the plasma concentration-time curve (AUC) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced by 80% and 88%, respectively, while the AUC values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine and AUC values 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 gene revealed that OATP2B1 is a determinant of 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 KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.
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http://dx.doi.org/10.1124/dmd.119.087619DOI Listing
August 2019

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

J Am Geriatr Soc 2019 09 21;67(9):1902-1906. Epub 2019 May 21.

School of Medicine, University of California, San Francisco, California.

Objectives: Lower 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.

Design: Convenience sample of patients receiving anticoagulation during 2017.

Setting: Academic medical center.

Participants: Stable adults older than 65 years with NVAF receiving apixaban on a chronic basis.

Measurements: Patient age, weight, creatinine, co-medications, and apixaban concentrations.

Results: A 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.

Conclusions: Apixaban 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.
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http://dx.doi.org/10.1111/jgs.15982DOI Listing
September 2019
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