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Open Access Publications from the University of California

Scholarly Works (9 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2021)

Real world data (RWD), data from various sources other than clinical trials, is increasingly being integrated into the research setting. In particular, electronic health records (EHRs), which serve as a clinical record to document a patient’s medical history as well as support administrative functions, have been an invaluable resource rich with patient data. Here we present three projects spanning four chapters where EHRs, in combination with clinical trials and pharmacokinetic and pharmacodynamic (PKPD) modelling, were used to extend and complement studies and findings in the laboratory focusing on transporter-mediated drug interactions. Transporter-mediated drug interactions have the potential to influence both drug efficacy as well as toxicity. During the clinical development of the Janus Kinase 2 (JAK2) inhibitor fedratinib, several patients developed symptoms similar to Wernicke’s encephalopathy, a life-threating disease caused by Vitamin B1 (thiamine) deficiency; subsequent in vitro studies showed that fedratinib is a potent inhibitor of ThTR-2. Motivated by this drug-nutrient interaction (DNI) observed in the fedratinib trial, we investigated if commonly used prescription drugs can inhibit ThTR-2. Using a multifaceted approach, we started with an in vitro high-throughput screen which was further complemented by quantitative structure activity relationship (QSAR) modelling and real world data. Our comprehensive analysis suggested that several marketed drugs inhibit ThTR-2 and may contribute to thiamine deficiency, especially in at-risk populations. In order to further explore the impact of these potential inhibitors in humans, we designed and conducted a clinical study in healthy volunteers. Interestingly, we observed that thiamine concentrations were higher when co-administered with trimethoprim, one of the potent, clinically relevant inhibitors identified in our screen. The maximum concentration achieved (Cmax) and area under the curve from 0 to 24 hours (AUC0-24) were 2.7- and 4.6-fold higher in the combination arm, respectively. We hypothesized that trimethoprim may inhibit OCT1, a hepatic uptake transporter, in addition to ThTR-2, which was supported using EHR data by comparing laboratory values of endogenous OCT1 biomarkers in patients prescribed trimethoprim versus patients not prescribed trimethoprim. Next, we shifted our focus to pharmacogenomics, that is, genetic factors that affect drug response. Response to allopurinol, the first line treatment for gout, is highly variable; the reduced function variant BCRP p.Q141K has been associated with poor response to allopurinol. Thus, we aimed to characterize the relationship between BCRP p.Q141K, allopurinol/oxypurinol, and serum uric acid (SUA) levels by performing a clinical trial, building a PKPD model, and mining EHRs. Our clinical study found that p.Q141K associated with longer half-life of oxypurinol and our PKPD model found that gender affected oxypurinol volume of distribution while BCRP genotype and kidney function were significant covariates for baseline SUA levels. Additionally, using RWD, we found that drugs that were clinical inhibitors of BCRP associated with increased SUA levels, suggesting the potential of these drugs to cause hyperuricemia. Finally, given the ongoing COVID19 pandemic, we conducted extensive in vitro experiments aimed at predicting the potential for 25 small molecule drugs in clinical trials for COVID19 to cause transporter-mediated drug-drug interactions (DDIs). We found that 21 of the drugs were predicted to cause a clinically relevant DDI, and we were able to provide preliminary validation of these in vitro findings using EHR data, including a database representing nearly 120,000 COVID19 patients.

Collectively, my dissertation research demonstrates how the integration of benchwork, clinical trials, and real world data provides us a new approach to translational research, bridging findings from the laboratory to patients.

    Cover page: Integration of benchwork, clinical trials, and real world data to investigate drug interactions
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2020)

    Background

    Transporter-mediated drug-nutrient interactions have the potential to cause serious adverse events. However, unlike drug-drug interactions, these drug-nutrient interactions receive little attention during drug development. The clinical importance of drug-nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2; SLC19A3).

    Objective

    In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency.

    Methods

    For this exploration, we took a multifaceted approach, starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors.

    Results

    Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 μM. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 μM to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR-2, particularly in vulnerable populations (e.g., individuals with alcoholism).

    Conclusions

    Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations.
      Cover page: Drug–nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3)
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2018)
      Preterm birth (PTB) is the leading cause of newborn deaths around the world. Spontaneous preterm birth (sPTB) accounts for two-thirds of all PTBs; however, there remains an unmet need of detecting and preventing sPTB. Although the dysregulation of the immune system has been implicated in various studies, small sizes and irreproducibility of results have limited identification of its role. Here, we present a cross-study meta-analysis to evaluate genome-wide differential gene expression signals in sPTB. A comprehensive search of the NIH genomic database for studies related to sPTB with maternal whole blood samples resulted in data from three separate studies consisting of 339 samples. After aggregating and normalizing these transcriptomic datasets and performing a meta-analysis, we identified 210 genes that were differentially expressed in sPTB relative to term birth. These genes were enriched in immune-related pathways, showing upregulation of innate immunity and downregulation of adaptive immunity in women who delivered preterm. An additional analysis found several of these differentially expressed at mid-gestation, suggesting their potential to be clinically relevant biomarkers. Furthermore, a complementary analysis identified 473 genes differentially expressed in preterm cord blood samples. However, these genes demonstrated downregulation of the innate immune system, a stark contrast to findings using maternal blood samples. These immune-related findings were further confirmed by cell deconvolution as well as upstream transcription and cytokine regulation analyses. Overall, this study identified a strong immune signature related to sPTB as well as several potential biomarkers that could be translated to clinical use.
        Cover page: Meta-Analysis of Maternal and Fetal Transcriptomic Data Elucidates the Role of Adaptive and Innate Immunity in Preterm Birth
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2021)
        The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.
          Cover page: Oxypurinol pharmacokinetics and pharmacodynamics in healthy volunteers: Influence of BCRP Q141K polymorphism and patient characteristics
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2021)
          A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.
            Cover page: The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2021)
            Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID-19); however, well-established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID-19 to cause clinically relevant drug-drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real-world data from electronic health records, including a database representing nearly 120,000 patients with COVID-19, were consistent with several of the drugs causing transporter-mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID-19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.
              Cover page: Drugs in COVID‐19 Clinical Trials: Predicting Transporter‐Mediated Drug‐Drug Interactions Using In Vitro Assays and Real‐World Data
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2023)
              Trimethoprim is predicted to inhibit several thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR-2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real-world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co-administration (P value = 0.031). Similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real-world data further supported this finding, showing an association between trimethoprim use and higher levels of triglycerides, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition (P values: 2.2 × 10-16 , 5.75 × 10-7 , and 5.82 × 10-7 , respectively). These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, consistent with inhibition of renal organic cation transporters. This inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug-nutrient interactions involving transporters, in addition to transporters' established role in drug-drug interactions.
                Cover page: The Effect of Trimethoprim on Thiamine Absorption: A Transporter‐Mediated Drug‐Nutrient InteractionCreative Commons 'BY-NC-ND' version 4.0 license
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2020)
                Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R-N=N-R') dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.
                  Cover page: Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2022)
                  Artificial Intelligence (AI) has the power to improve our lives through a wide variety of applications, many of which fall into the healthcare space; however, a lack of diversity is contributing to limitations in how broadly AI can help people. The UCSF AI4ALL program was established in 2019 to address this issue by targeting high school students from underrepresented backgrounds in AI, giving them a chance to learn about AI with a focus on biomedicine, and promoting diversity and inclusion. In 2020, the UCSF AI4ALL three-week program was held entirely online due to the COVID-19 pandemic. Thus, students participated virtually to gain experience with AI, interact with diverse role models in AI, and learn about advancing health through AI. Specifically, they attended lectures in coding and AI, received an in-depth research experience through hands-on projects exploring COVID-19, and engaged in mentoring and personal development sessions with faculty, researchers, industry professionals, and undergraduate and graduate students, many of whom were women and from underrepresented racial and ethnic backgrounds. At the conclusion of the program, the students presented the results of their research projects at the final symposium. Comparison of pre- and post-program survey responses from students demonstrated that after the program, significantly more students were familiar with how to work with data and to evaluate and apply machine learning algorithms. There were also nominally significant increases in the students' knowing people in AI from historically underrepresented groups, feeling confident in discussing AI, and being aware of careers in AI. We found that we were able to engage young students in AI via our online training program and nurture greater diversity in AI. This work can guide AI training programs aspiring to engage and educate students entirely online, and motivate people in AI to strive towards increasing diversity and inclusion in this field.
                    Cover page: Nurturing diversity and inclusion in AI in Biomedicine through a virtual summer program for high school students
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