35 results on '"Chinn, Leslie"'
Search Results
2. Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial
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Metz, Martin, Sussman, Gordon, Gagnon, Rémi, Staubach, Petra, Tanus, Tonny, Yang, William H., Lim, Jeremy J., Clarke, Holly J., Galanter, Joshua, Chinn, Leslie W., Chu, Tom, Teterina, Anastasia, Burgess, Tracy, Haddon, D. James, Lu, Timothy T., and Maurer, Marcus
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- 2021
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3. Effects of Quinidine or Rifampin Co‐administration on the Single‐Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants.
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Rask‐Madsen, Christian, Katragadda, Suresh, Li, Mengyao, Ucpinar, Sibel, Chinn, Leslie, Arora, Puneet, and Smith, Patrick
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RIFAMPIN ,QUINIDINE ,BRUTON tyrosine kinase ,PHARMACOKINETICS - Abstract
This open‐label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug‐drug interaction between rilzabrutinib and quinidine (an inhibitor of P‐glycoprotein [P‐gp] and CYP2D6) or rifampin (an inducer of CYP3A and P‐gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash‐out period, after co‐administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0‐∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P‐gp. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Simulation‐based evaluation of personalized dosing approaches for anti‐FGFR/KLB bispecific antibody fazpilodemab.
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Yoshida, Kenta, Poon, Victor, Dash, Ajit, Kunder, Rebecca, Chinn, Leslie, and Kågedal, Matts
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NON-alcoholic fatty liver disease ,BISPECIFIC antibodies ,MARKOV processes ,DYNAMIC simulation ,DRUG development ,CLINICAL trials - Abstract
Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure‐response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure‐response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure‐response analysis, as well as longitudinal adverse event (AE) analysis using discrete‐time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure‐response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE‐based personalized dosing is the most effective approach for optimizing the benefit–risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms
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Micheli, Janine E, Chinn, Leslie W, Shugarts, Sarah B, Patel, Ashish, Martin, Jeffrey N, Bangsberg, David R, and Kroetz, Deanna L
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Patient Safety ,Sexually Transmitted Infections ,Infectious Diseases ,Clinical Research ,Genetics ,ATP Binding Cassette Transporter ,Subfamily B ,ATP Binding Cassette Transporter ,Subfamily B ,Member 1 ,Adult ,Black or African American ,Aged ,Anti-HIV Agents ,Aryl Hydrocarbon Hydroxylases ,Cytochrome P-450 CYP2B6 ,Female ,Genetic Variation ,Genotype ,HIV Infections ,Humans ,Male ,Middle Aged ,Nevirapine ,Pharmacogenetics ,Polymorphism ,Genetic ,White People ,CYP2B6 ,human immunodeficiency virus ,nevirapine ,pharmacogenetics ,pharmacokinetics ,Pharmacology & Pharmacy ,Pharmacology and pharmaceutical sciences - Abstract
ObjectiveNevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability.MethodsTwo doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6 h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics.ResultsA significant r(GC) for nevirapine AUC(0-6 h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6 h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19).ConclusionThis study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.
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- 2013
6. Steady State Bioequivalence of Generic and Innovator Formulations of Stavudine, Lamivudine, and Nevirapine in HIV-Infected Ugandan Adults
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Byakika-Tusiime, Jayne, Chinn, Leslie W, Oyugi, Jessica H, Obua, Celestino, Bangsberg, David R, and Kroetz, Deanna L
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Medical Microbiology ,Biomedical and Clinical Sciences ,HIV/AIDS ,Clinical Research ,Infection ,Adult ,Anti-HIV Agents ,Cross-Over Studies ,Drugs ,Generic ,Drugs ,Investigational ,Female ,HIV Infections ,HIV-1 ,Humans ,Lamivudine ,Male ,Middle Aged ,Nevirapine ,Patient Compliance ,Stavudine ,Therapeutic Equivalency ,Uganda ,General Science & Technology - Abstract
BackgroundGeneric antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune) or the corresponding brand formulations (Epivir, Zerit, and Viramune).Methodology/principal findingsAn open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC(0-12h) and C(max). Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8-1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C(max), 1.3 (0.99-1.71) and AUC(0-12h), 1.1 (0.87-1.38); lamivudine C(max), 0.8 (0.63-0.98) and AUC(0-12h), 0.8 (0.65-0.99); and nevirapine C(max), 1.1 (0.95-1.23) and AUC(0-12h), 1.1 (0.95-1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.Conclusions/significant findingsThese findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical.
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- 2008
7. Correction to: Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis
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Chan, Phyllis, Yu, Jiajie, Chinn, Leslie, Prohn, Marita, Huisman, Jan, Matzuka, Brett, Hanley, William, Tuckwell, Katie, and Quartino, Angelica
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- 2020
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8. Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis
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Chan, Phyllis, Yu, Jiajie, Chinn, Leslie, Prohn, Marita, Huisman, Jan, Matzuka, Brett, Hanley, William, Tuckwell, Katie, and Quartino, Angelica
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- 2020
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9. Genome-Wide Association Study Implicates PARD3B-Based AIDS Restriction
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Troyer, Jennifer L., Nelson, George W., Lautenberger, James A., Chinn, Leslie, McIntosh, Carl, Johnson, Randall C., Sezgin, Efe, Kessing, Bailey, Malasky, Michael, Hendrickson, Sher L., Li, Guan, Pontius, Joan, Tang, Minzhong, An, Ping, Winkler, Cheryl A., Limou, Sophie, Le Clerc, Sigrid, Delaneau, Olivier, Zagury, Jean-François, Schuitemaker, Hanneke, van Manen, Daniëlle, Bream, Jay H., Gomperts, Edward D., Buchbinder, Susan, Goedert, James J., Kirk, Gregory D., and O'Brien, Stephen J.
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- 2011
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10. Genetic Associations of Variants in Genes Encoding HIV-Dependency Factors Required for HIV-1 Infection
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Chinn, Leslie W., Tang, Minzhong, Kessing, Bailey D., Lautenberger, James A., Troyer, Jennifer L., Malasky, Michael J., McIntosh, Carl, Kirk, Gregory D., Wolinsky, Steven M., Buchbinder, Susan P., Gomperts, Edward D., Goedert, James J., and O'Brien, Stephen J.
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- 2010
11. An Overview of Transporter Information in Package Inserts of Recently Approved New Molecular Entities
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Agarwal, Sheetal, Chinn, Leslie, and Zhang, Lei
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- 2013
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12. Response to “Predictable difficulty or difficulty to predict”
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Kelly, Libusha, Fukushima, Hisayo, Karchin, Rachel, Gow, Jason M., Chinn, Leslie W., Pieper, Ursula, Segal, Mark R., Kroetz, Deanna L., and Sali, Andrej
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- 2011
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13. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib (GDC‐0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double‐Blind, Placebo‐Controlled Trial.
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Isenberg, David, Furie, Richard, Jones, Nicholas S., Guibord, Pascal, Galanter, Joshua, Lee, Chin, McGregor, Anna, Toth, Balazs, Rae, Julie, Hwang, Olivia, Desai, Rupal, Lokku, Armend, Ramamoorthi, Nandhini, Hackney, Jason A., Miranda, Pedro, de Souza, Viviane A., Jaller‐Raad, Juan J., Maura Fernandes, Anna, Garcia Salinas, Rodrigo, and Chinn, Leslie W.
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DRUG efficacy ,RESEARCH ,BIOMARKERS ,CONFIDENCE intervals ,MEDICAL cooperation ,PROTEIN-tyrosine kinase inhibitors ,RANDOMIZED controlled trials ,DESCRIPTIVE statistics ,BLIND experiment ,SYSTEMIC lupus erythematosus ,DATA analysis software ,PATIENT safety ,PHARMACODYNAMICS - Abstract
Objective: Fenebrutinib (GDC‐0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo‐controlled study. Methods: Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI‐4) response at week 48. Results: Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI‐4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group–based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK‐dependent plasmablast RNA signature, anti–double‐stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. Conclusion: While fenebrutinib had an acceptable safety profile, the primary end point, SRI‐4 response, was not met despite evidence of strong pathway inhibition. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein
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Chinn, Leslie W., Gow, Jason M., Tse, Man Ming, Becker, Stephen L., and Kroetz, Deanna L.
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- 2007
15. A nonpeptide provides insight into mechanisms that regulate Drosophila melanogaster heart contractions
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Mispelon, Melissa, Thakur, Kiran, Chinn, Leslie, Owen, Ryan, and Nichols, Ruthann
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- 2003
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16. 371 - Itolizumab, a Novel Targeted Anti-CD6 Therapy, Induces Cleavage of Cell Surface CD6 and Rapid Onset of Efficacy in Subjects with Newly Diagnosed Acute Graft-Versus-Host Disease
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Ng, Cherie Tracy, Chinn, Leslie, Acevedo, Lisette M, Chu, Dalena, Fung, Maple, Rothman, Joel, Connelly, Stephen, Thomas, Dolca, Cutler, Corey, and Koreth, John
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- 2022
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17. 372 - Updated Interim Results from the Equate Study: Preliminary Safety and Efficacy of Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Newly Diagnosed Acute Graft-Versus-Host Disease
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Koreth, John, Waller, Edmund K., Nakamura, Ryotaro, Loren, Alison W., Chinn, Leslie, Ng, Cherie Tracy, Acevedo, Lisette M, Chu, Dalena, Fung, Maple, Rothman, Joel, Connelly, Stephen, Thomas, Dolca, and Cutler, Corey
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- 2022
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18. Understanding the Effect of Hydroxypropyl‐β‐Cyclodextrin on Fenebrutinib Absorption in an Itraconazole–Fenebrutinib Drug–Drug Interaction Study.
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Durk, Matthew R., Jones, Nicholas S., Liu, Jia, Nagapudi, Karthik, Mao, Chen, Plise, Emile G., Wong, Susan, Chen, Jacob Z., Chen, Yuan, Chinn, Leslie W., and Chiang, Po‐Chang
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ABSORPTION ,BINDING constant ,PROTEIN-tyrosine kinases ,CYCLODEXTRINS ,INCLUSION compounds ,SKIN permeability - Abstract
Cyclodextrins are widely used pharmaceutical excipients, particularly for insoluble compounds dosed orally, such as the oral solution of itraconazole, which is frequently used in clinical drug–drug interaction studies to inhibit cytochrome P450 3A. Since cyclodextrins act by forming inclusion complexes with their coformulated drug, they could have an unintended consequence of affecting absorption if they form a strong complex with the potential victim drug in an itraconazole drug–drug interaction study. This observation was made in a drug–drug interaction study with the Bruton's tyrosine kinase (BTK) inhibitor fenebrutinib and itraconazole, in which, relative to the control group, the expected increase in fenebrutinib maximum plasma concentration (Cmax) was not observed in the itraconazole group, and a delay in time to reach maximum plasma concentration (Tmax) was observed in the itraconazole group. The in vitro binding constant between fenebrutinib and hydroxypropyl‐β‐cyclodextrin was determined to be 2 × 105 M−1, and the apparent permeability of fenebrutinib across a Madin‐Darby canine kidney cell monolayer decreased in a cyclodextrin concentration‐dependent manner. This observation was confirmed in vivo, in a pentagastrin‐pretreated dog model, in which fenebrutinib was administered with or without cyclodextrin; a reduction in Cmax, a prolonged Tmax, and increased fenebrutinib recovery in feces replicated the previous observation in healthy volunteers and supported the hypothesis that complexation with cyclodextrin decreased rate and extent of fenebrutinib absorption. Physiologically‐based pharmacokinetic modeling was used to translate the in vitro effect of cyclodextrin on fenebrutinib apparent permeability to the in vivo effect on absorption, which was then confirmed using the in vivo dog pharmacokinetic data. [ABSTRACT FROM AUTHOR]
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- 2020
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19. Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial.
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Cohen, Stanley, Tuckwell, Katie, Katsumoto, Tamiko R., Zhao, Rui, Galanter, Joshua, Lee, Chin, Rae, Julie, Toth, Balazs, Ramamoorthi, Nandhini, Hackney, Jason A., Berman, Alberto, Damjanov, Nemanja, Fedkov, Dmytro, Jeka, Slawomir, Chinn, Leslie W., Townsend, Michael J., Morimoto, Alyssa M., Genovese, Mark C., Porto, Alejandro, and Granel, Amelia
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ANTI-inflammatory agents ,AUTOANTIBODIES ,B cells ,BIOMARKERS ,COMPARATIVE studies ,CYTOKINES ,LONGITUDINAL method ,METHOTREXATE ,PLACEBOS ,RHEUMATOID arthritis ,STATISTICAL sampling ,PROTEIN-tyrosine kinase inhibitors ,RANDOMIZED controlled trials ,TREATMENT effectiveness ,BLIND experiment ,ADALIMUMAB ,PHARMACODYNAMICS ,EVALUATION - Abstract
Objective: To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods: Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results: In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion: Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA. [ABSTRACT FROM AUTHOR]
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- 2020
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20. Physiologically‐Based Pharmacokinetic Model‐Informed Drug Development for Fenebrutinib: Understanding Complex Drug‐Drug Interactions.
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Chen, Yuan, Ma, Fang, Jones, Nicholas S., Yoshida, Kenta, Chiang, Po‐Chang, Durk, Matthew R., Wright, Matthew R., Jin, Jin Yan, and Chinn, Leslie W.
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PHARMACOKINETICS ,DRUG development ,SENSITIVITY analysis ,PHARMACEUTICAL powders - Abstract
Fenebrutinib is a CYP3A substrate and time‐dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically‐based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug‐drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic‐absorption model accounting for the effects of excipient complexation with fenebrutinib was used to rationalize the unexpected observation of itraconazole‐fenebrutinib DDI (maximum plasma concentration (Cmax) decreased, and area under the curve (AUC) increased). The totality of the evidence from sensitivity analysis and clinical and nonclinical data suggested that fenebrutinib is likely a sensitive CYP3A substrate. This advanced PBPK application allowed the use of model‐informed approach to facilitate the development of concomitant medication recommendations for fenebrutinib without requiring additional clinical DDI studies. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI.
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Jones, Nicholas S., Yoshida, Kenta, Salphati, Laurent, Kenny, Jane R., Durk, Matthew R., and Chinn, Leslie W.
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BIOMARKERS ,MIDAZOLAM ,BIOAVAILABILITY ,CLINICAL pharmacology ,CURVES - Abstract
Mechanistic understanding of complex clinical drug–drug interactions (DDIs) with potential involvement of multiple elimination pathways has been challenging, especially given the general lack of specific probe substrates for transporters. Here, we conducted a clinical DDI study to evaluate the interaction potential of fenebrutinib using midazolam (MDZ; CYP3A), simvastatin (CYP3A and OATP1B), and rosuvastatin (BCRP and OATP1B) as probe substrates. Fenebrutinib (200 mg) increased the area under the curve (AUC) of these probe substrates twofold to threefold. To evaluate the mechanism of the observed DDIs, we measured the concentration of coproporphyrin I (CP‐I) and coproporphyrin III (CP‐III), endogenous biomarkers of OATP1B. There was no change in CP‐I or CP‐III levels with fenebrutinib, suggesting that the observed DDIs were caused by inhibition of CYP3A and BCRP rather than OATP1B, likely due to increased bioavailability. This is the first published account using an endogenous transporter biomarker to understand the mechanism of complex DDIs involving multiple elimination pathways. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC‐0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor.
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Herman, Ann E., Chinn, Leslie W., Kotwal, Shweta G., Murray, Elaine R., Zhao, Rui, Florero, Marilyn, Lin, Alyse, Moein, Anita, Wang, Rena, Bremer, Meire, Kokubu, Serika, Serone, Adrian P., Morimoto, Alyssa M., Winter, Helen R., Katsumoto, Tamiko R., Hanze, Eva L., and Viberg, Anders
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PHARMACOKINETICS ,PHARMACODYNAMICS ,VOLUNTEERS ,PROTEIN-tyrosine kinase inhibitors ,RHEUMATOID arthritis ,AUTOIMMUNE diseases ,PATIENTS - Abstract
GDC‐0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double‐blind, randomized, and placebo‐controlled phase I healthy volunteer studies, GDC‐0853 was well tolerated, with no dose‐limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14‐day multiple ascending dose (MAD) study). Plasma concentrations peaked 1–3 hours after oral administration and declined thereafter, with a steady‐state half‐life ranging from 4.2–9.9 hours. Independent assays demonstrated dose‐dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once‐daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC‐0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. [ABSTRACT FROM AUTHOR]
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- 2018
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23. CRT-115 Demographics Of Study Participants In Clinical Trials For Cardiovascular Drugs Approved By FDA From 2010 To 2011
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Eshera, Noha, Marsh, Amber, Chinn, Leslie, Zhang, Lei, and Fadiran, Emmanuel O.
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- 2013
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24. Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
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Kelly, Libusha, Fukushima, Hisayo, Karchin, Rachel, Gow, Jason M., Chinn, Leslie W., Pieper, Ursula, Segal, Mark R., Kroetz, Deanna L., and Sali, Andrej
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- 2010
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25. Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression.
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Hendrickson, Sher L., Lautenberger, James A., Chinn, Leslie Wei, Malasky, Michael, Sezgin, Efe, Kingsley, Lawrence A., Goedert, James J., Kirk, Gregory D., Gomperts, Edward D., Buchbinder, Susan P., Troyer, Jennifer L., and O'Brien, Stephen J.
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AIDS ,HIV infections ,GENES ,GENETICS ,MITOCHONDRIA ,MORPHOLOGY ,MITOCHONDRIAL DNA ,NUCLEOTIDES ,GENETIC polymorphisms - Abstract
Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl- CoA isomerase (PECI) on chromosome 6. Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2010
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26. Evolutionary Conservation of Vertebrate Blood-Brain Barrier Chemoprotective Mechanisms in Drosophila.
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Mayer, Fahima, Mayer, Nasima, Chinn, Leslie, Pinsonneault, Robert L., Kroetz, Deanna, and Bainton, Roland J.
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DROSOPHILA ,VASCULAR endothelium ,CEREBROSPINAL fluid ,BLOOD vessels ,PATHOLOGICAL psychology - Abstract
Pharmacologic remedy of many brain diseases is difficult because of the powerful drug exclusion properties of the blood- brain barrier (BBB). Chemical isolation of the vertebrate brain is achieved through the highly integrated, anatomically compact and functionally overlapping chemical isolation processes of the BBB. These include functions that need to be coordinated between tight diffusion junctions and unidirectionally acting xenobiotic transporters. Understanding of many of these processes has been hampered, because they are not well mimicked by ex vivo models of the BBB and have been experimentally difficult and expensive to disentangle in intact rodent models. Here we show that the Drosophila melanogaster (Dm) humoral/CNS barrier conserves the xenobiotic exclusion properties found in the vertebrate vascular endothelium. We characterize a fly ATP binding cassette (ABC) transporter, Mdr65, that functions similarly to mammalian xenobiotic BBB transporters and show that varying its levels solely in the Dm BBB changes the inherent sensitivity of the barrier to cytotoxic pharmaceuticals. Furthermore, we demonstrate orthologous function between Mdr65 and vertebrate ABC transporters by rescuing chemical protection of the Dm brain with human MDR1/Pgp. These data indicate that the ancient origins of CNS chemoprotection extend to both conserved molecular means and functionally analogous anatomic spaces that together promote CNS selective drug partition. Thus,Dmpresents an experimentally tractable system for analyzing physiological properties of the BBB in an intact organism. [ABSTRACT FROM AUTHOR]
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- 2009
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27. Very important pharmacogene summary.
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Hodges, Laura M., Markova, Svetlana M., Chinn, Leslie W., Gow, Jason M., Kroetz, Deanna L., Klein, Teri E., and Altman, Russ B.
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- 2011
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28. Absence of Pharmacokinetic Interactions between the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate.
- Author
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Jones NS, Winter H, Katsumoto TR, Florero M, Murray E, Walker H, Singh N, and Chinn LW
- Subjects
- Adult, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Antirheumatic Agents administration & dosage, Antirheumatic Agents adverse effects, Drug Interactions, Humans, Male, Methotrexate administration & dosage, Methotrexate adverse effects, Middle Aged, Piperazines administration & dosage, Piperazines adverse effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Pyridones administration & dosage, Pyridones adverse effects, Antirheumatic Agents pharmacokinetics, Methotrexate pharmacokinetics, Piperazines pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics, Pyridones pharmacokinetics
- Abstract
Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C
max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and Cmax for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX., (Copyright © 2019 The Author(s).)- Published
- 2019
- Full Text
- View/download PDF
29. In Vitro, in Silico, and in Vivo Assessments of Intestinal Precipitation and Its Impact on Bioavailability of a BCS Class 2 Basic Compound.
- Author
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Kou D, Zhang C, Yiu H, Ng T, Lubach JW, Janson M, Mao C, Durk M, Chinn L, Winter H, Wigman L, and Yehl P
- Subjects
- Biological Availability, Biopharmaceutics methods, Chemistry, Pharmaceutical methods, Computer Simulation, Humans, Intestines chemistry, Solubility, Stomach physiology, Intestinal Absorption physiology, Pharmaceutical Preparations metabolism, Tablets metabolism
- Abstract
In this study, a multipronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets. The in vitro precipitate was found to be noncrystalline with higher solubility than the crystalline API, and was readily soluble when the drug concentration was lowered by dilution. A gastric transit and biphasic dissolution (GTBD) model was developed to better mimic gastric transfer and intestinal absorption. Precipitation was also observed in GTBD, but the precipitate redissolved and partitioned into the organic phase. In vivo data from the phase 1 clinical trial showed linear and dose proportional PK for the formulations with no evidence of in vivo precipitation. While the in vitro precipitation observed in the 2-stage dissolution appeared to overestimate in vivo precipitation, the GTBD model provided absorption profiles consistent with in vivo data. In silico simulation of plasma concentrations by GastroPlus using biorelevant in vitro dissolution data from the tablets and capsules and assuming negligible precipitation was in line with the observed in vivo profiles of the two formulations. The totality of data generated with Compound-A indicated that the bioavailability differences among the three formulations were better explained by the differences in gastric dissolution than intestinal precipitation. The lack of intestinal precipitation was consistent with several other BCS class 2 basic compounds in the literature for which highly supersaturated concentrations and rapid absorption were also observed.
- Published
- 2018
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30. Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.
- Author
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Kou D, Dwaraknath S, Fischer Y, Nguyen D, Kim M, Yiu H, Patel P, Ng T, Mao C, Durk M, Chinn L, Winter H, Wigman L, and Yehl P
- Subjects
- Administration, Oral, Biological Availability, Chemistry, Pharmaceutical, Drug Interactions, Humans, Hydrogen-Ion Concentration, Solubility, Tablets, Achlorhydria complications, Drug Liberation, Models, Chemical
- Abstract
In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.
- Published
- 2017
- Full Text
- View/download PDF
31. Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
- Author
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Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, and Sali A
- Subjects
- ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Adenine analogs & derivatives, Adenine chemistry, Adenine metabolism, Amino Acid Sequence, Binding Sites, Genetic Predisposition to Disease, HEK293 Cells, Humans, Models, Molecular, Molecular Sequence Annotation, Molecular Sequence Data, Multidrug Resistance-Associated Proteins chemistry, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism, Organophosphonates chemistry, Organophosphonates metabolism, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Reproducibility of Results, Sequence Alignment, Tenofovir, ATP-Binding Cassette Transporters chemistry
- Abstract
The human ATP-binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small α-helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease-associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.
- Published
- 2010
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32. The human multidrug resistance protein 4 (MRP4, ABCC4): functional analysis of a highly polymorphic gene.
- Author
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Abla N, Chinn LW, Nakamura T, Liu L, Huang CC, Johns SJ, Kawamoto M, Stryke D, Taylor TR, Ferrin TE, Giacomini KM, and Kroetz DL
- Subjects
- Adenine metabolism, Base Sequence, California, Cell Line, Ethnicity genetics, Haplotypes, Humans, Molecular Sequence Data, Sequence Alignment, Sequence Analysis, DNA, White People genetics, Adenine analogs & derivatives, Antiviral Agents metabolism, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism, Organophosphonates metabolism, Polymorphism, Single Nucleotide, Zidovudine metabolism
- Abstract
ABCC4 encodes multidrug resistance protein 4 (MRP4), a member of the ATP-binding cassette family of membrane transporters involved in the efflux of endogenous and xenobiotic molecules. The aims of this study were to identify single nucleotide polymorphisms of ABCC4 and to functionally characterize selected nonsynonymous variants. Resequencing was performed in a large ethnically diverse population. Ten nonsynonymous variants were selected for analysis of transport function based on allele frequencies and evolutionary conservation. The reference and variant MRP4 cDNAs were constructed by site-directed mutagenesis and transiently transfected into human embryonic kidney cells (HEK 293T). The function of MRP4 variants was compared by measuring the intracellular accumulation of two antiviral agents, azidothymidine (AZT) and adefovir (PMEA). A total of 98 variants were identified in the coding and flanking intronic regions of ABCC4. Of these, 43 variants are in the coding region, and 22 are nonsynonymous. In a functional screen of ten variants, there was no evidence for a complete loss of function allele. However, two variants (G187W and G487E) showed a significantly reduced function compared to reference with both substrates, as evidenced by higher intracellular accumulation of AZT and PMEA compared to the reference MRP4 (43 and 69% increase in accumulation for G187W compared with the reference MRP4, with AZT and PMEA, respectively). The G187W variant also showed decreased expression following transient transfection of HEK 293T cells. Further studies are required to assess the clinical significance of this altered function and expression and to evaluate substrate specificity of this functional change.
- Published
- 2008
- Full Text
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33. Substrate-dependent effects of human ABCB1 coding polymorphisms.
- Author
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Gow JM, Hodges LM, Chinn LW, and Kroetz DL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Cell Line, Cyclosporine pharmacology, Gene Frequency, Haplotypes, Humans, Paclitaxel metabolism, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Boron Compounds metabolism, Fluoresceins metabolism, Paclitaxel analogs & derivatives, Polymorphism, Genetic
- Abstract
One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gp-mediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency >/=2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/1236C>T/A893S/3435C>T haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrate- and inhibitor-dependent manner.
- Published
- 2008
- Full Text
- View/download PDF
34. The effects of ABCB1 3'-untranslated region variants on mRNA stability.
- Author
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Gow JM, Chinn LW, and Kroetz DL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Animals, Cell Line, DNA, Complementary genetics, Humans, Lymphocytes metabolism, 3' Untranslated Regions genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Polymorphism, Genetic, RNA Stability, RNA, Messenger genetics
- Abstract
Genetic variation in ABCB1, encoding P-glycoprotein (P-gp), is a potential cause of interindividual variation in drug response. Numerous studies have focused on the effects of coding region variants on P-gp expression and function, whereas few noncoding region variants have been investigated. The 3'-untranslated region (UTR) regulates mRNA levels or stability via RNA-protein interactions with mRNA degradation machinery. mRNA stability is a key regulatory step controlling ABCB1 mRNA expression that ultimately affects P-gp levels and function. We hypothesized that ABCB1 3'-UTR polymorphisms alter mRNA stability by disrupting RNA-protein interactions. An ethnically diverse panel of DNA samples was sequenced to identify 3'-UTR polymorphisms and determine allele frequencies. The three most common variants, along with reference ABCB1, were stably expressed in cells in order to measure mRNA half-life. The calculated half-life for ABCB1 reference in HEK293 cells was 9.4 +/- 1.3 h and was similar to that estimated for the 3'-UTR variants. Endogenous ABCB1 mRNA decay was similar in lymphoblastoid cell lines carrying 3'-UTR variant and reference alleles. Although the examined ABCB1 3'-UTR variants have no effect on ABCB1 mRNA stability, these data represent one of the first attempts to determine the influence of genetic variation in UTRs on ABCB1 mRNA levels.
- Published
- 2008
- Full Text
- View/download PDF
35. PharmGKB submission update: IV. PMT submissions of genetic variations in ATP-Binding cassette transporters to the PharmGKB network.
- Author
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Nguyen TD, Gow JM, Chinn LW, Kelly L, Jeong H, Huang CC, Stryke D, Kawamoto M, Johns SJ, Carlson E, Taylor T, Ferrin TE, Sali A, Giacomini KM, and Kroetz DL
- Subjects
- ATP-Binding Cassette Transporters metabolism, Humans, Molecular Sequence Data, Pharmacogenetics, ATP-Binding Cassette Transporters genetics, Genetic Variation
- Published
- 2006
- Full Text
- View/download PDF
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