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Clinical Pharmacology in Drug Development

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https://www.readbyqxmd.com/read/28074640/evaluation-of-pharmacokinetic-interactions-between-lesinurad-a-new-selective-urate-reabsorption-inhibitor-and-commonly-used-drugs-for-gout-treatment
#1
Zancong Shen, Kathy Tieu, David Wilson, Gail Bucci, Michael Gillen, Caroline Lee, Bradley Kerr
Lesinurad is a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors (XOIs). Open-label pharmacokinetic studies were performed in volunteers or subjects with hyperuricemia (serum uric acid ≥ 8 mg/dL) to investigate interactions of lesinurad (with and without concurrent XOIs) with colchicine and 2 nonsteroidal anti-inflammatory drugs: naproxen and indomethacin. Colchicine studies included consecutive 7-day treatment periods of (1) allopurinol 300 mg, allopurinol 300 mg plus lesinurad 400 or 600 mg, and continued lesinurad 400 or 600 mg; or (2) febuxostat 40 or 80 mg, febuxostat 40 or 80 mg plus lesinurad 400 mg, and continued febuxostat 40 or 80 mg plus lesinurad 600 mg...
January 11, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28067999/evaluation-of-pharmacokinetic-interactions-between-lesinurad-a-new-selective-urate-reabsorption-inhibitor-and-cyp-enzyme-substrates-sildenafil-amlodipine-tolbutamide-and-repaglinide
#2
Michael Gillen, Chun Yang, David Wilson, Shakti Valdez, Caroline Lee, Bradley Kerr, Zancong Shen
Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction)...
January 9, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28052588/absolute-bioavailability-and-pharmacokinetic-comparability-of-sirukumab-following-subcutaneous-administration-by-a-prefilled-syringe-or-an-autoinjector
#3
Y Zhuang, D E de Vries, S J Marciniak, H Liu, H Zhou, H M Davis, F Leon, D Raible, Z Xu
This phase 1, randomized, open-label study assessed the absolute bioavailability and pharmacokinetic comparability of sirukumab, a human anti-interleukin-6 monoclonal antibody, following subcutaneous (SC) administration via Prefilled Syringe-UltraSafe Passive® Delivery System (PFS-U) or Prefilled Syringe-SmartJect® Autoinjector (PFS-AI; Janssen Research & Development, LLC, Spring House, Pennsylvania). A total of 144 healthy male subjects were randomized to 5 single-dose treatment groups: sirukumab 50 mg and 100 mg (each by PFS-U and PFS-AI) and sirukumab 100 mg intravenous (IV) infusion...
January 3, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28032482/population-pharmacokinetics-of-edoxaban-in-japanese-atrial-fibrillation-patients-with-severe-renal-impairment
#4
Takako Shimizu, Masaya Tachibana, Tetsuya Kimura, Tomohiko Kumakura, Kazutaka Yoshihara
This is a population pharmacokinetic (PopPK) analysis to predict PK of edoxaban, a direct-acting oral anticoagulant, in nonvalvular atrial fibrillation (NVAF) patients with severe renal impairment (SRI; creatinine clearance [CLcr ] <30 mL/min). Data from a phase 3 study recently conducted in Japanese NVAF patients (n = 90), including patients with SRI, were used to update the ENGAGE PopPK model that had been developed based on pooled data from the phase 3 ENGAGE AF-TIMI 48 study and 13 phase 1 PK studies, which included few patients with SRI...
December 29, 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28032481/safety-tolerability-and-antihypertensive-effect-of-ser100-an-opiate-receptor-like-1-orl-1-partial-agonist-in-patients-with-isolated-systolic-hypertension
#5
Ilkka Kantola, Mika Scheinin, Trygve Gulbrandsen, Nils Meland, Knut T Smerud
The purpose of the present trial was to evaluate safety, tolerability, and effect on systolic blood pressure (SBP) of SER100 in a small group of patients with isolated systolic hypertension (ISH) in treatment with at least 1 antihypertensive drug. Eligible patients were randomized to either SER100 (10 mg) or placebo in a crossover design, and 2 doses were given subcutaneously (SC), 8 hours apart, on 2 consecutive days. On all treatment days patients were monitored with an ambulatory blood pressure measurement device for 12 daytime hours...
December 29, 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28099796/a-fixed-dose-combination-of-bisoprolol-and-amlodipine-for-hypertension-a-potential-benefit-to-selected-patients
#6
EDITORIAL
Brian J Cohen
No abstract text is available yet for this article.
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27653022/management-of-hypertension-with-a-fixed-dose-single-pill-combination-of-bisoprolol-and-amlodipine
#7
REVIEW
Ulrike Gottwald-Hostalek, Ningling Sun, Christian Barho, Steven Hildemann
Hypertension is currently one of the greatest global health care challenges. Although many effective drugs are available, combinations of 2 or more medications are often required to meet clinical targets. Combination therapy has several advantages over monotherapy: lower doses of each drug can be used to achieve therapeutic goals; lower doses may lead to fewer adverse events, facilitating patient adherence; and using multiple drugs with different modes of action may be more effective in treating multifactorial diseases, including hypertension...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27364900/single-and-multiple-dose-pharmacokinetics-of-immediate-release-extended-release-ibuprofen-tablets
#8
Thomas Legg, Edward Paluch, Shyamalie Jayawardena
A single-dose, randomized, open-label, crossover study (study 1; n = 35) and a multiple-dose, randomized, open-label, crossover study (study 2; n = 28) compared the pharmacokinetics of a new immediate-release/extended-release (IR/ER) bilayer tablet formulation of ibuprofen 600 mg every 12 hours with standard ibuprofen 200 mg IR every 4 hours. In both studies, the 2 formulations were bioequivalent to each other for the area under the plasma concentration-versus-time curve from time 0 to the last measurable concentration (AUCL), to infinity (AUC∞ ), and to 12 hours (AUC0-12 ) and maximum concentration (Cmax )...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27297519/pharmacokinetics-of-lidocaine-and-its-metabolites-following-vaginal-administration-of-lidocaine-gel-to-healthy-female-subjects
#9
Bridget Martell, Harvey Kushner, Elaine Richardson, Amy Mize, Philip Mayer
Lidocaine vaginal bioadhesive gel is being developed as a local anesthetic for use in minimally invasive outpatient gynecological procedures and was investigated in single-dose and multiple-dose studies in healthy young adult women. Lidocaine doses of 2.5%, 5%, and 10% (w/w) were administered, and parent drug and metabolites monoethylglycinexylidide and glycinexylidide were measured in plasma. Lidocaine was absorbed through vaginal tissue and into the systemic circulation in a dose-proportional manner, and there was little systemic accumulation...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27278712/pharmacokinetic-and-pharmacodynamic-evaluation-of-the-drug-drug-interaction-between-isavuconazole-and-warfarin-in-healthy-subjects
#10
Amit Desai, Takao Yamazaki, Albert J Dietz, Donna Kowalski, Christopher Lademacher, Helene Pearlman, Shahzad Akhtar, Robert Townsend
This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration-time curves from time 0 to infinity of S- and R-warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S- and R-warfarin by 12% and 7%, respectively, relative to warfarin alone...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27273461/pharmacokinetic-evaluation-of-cyp3a4-mediated-drug-drug-interactions-of-isavuconazole-with-rifampin-ketoconazole-midazolam-and-ethinyl-estradiol-norethindrone-in-healthy-adults
#11
Robert Townsend, Albert Dietz, Christine Hale, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Kenneth Lasseter, Helene Pearlman, Diane Rammelsberg, Anne Schmitt-Hoffmann, Takao Yamazaki, Amit Desai
This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27273343/pharmacokinetic-assessment-of-drug-drug-interactions-of-isavuconazole-with-the-immunosuppressants-cyclosporine-mycophenolic-acid-prednisolone-sirolimus-and-tacrolimus-in-healthy-adults
#12
Andreas H Groll, Amit Desai, David Han, Corrie Howieson, Kota Kato, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, William Lewis, Helene Pearlman, Debra Mandarino, Takao Yamazaki, Robert Townsend
This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter)...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27273248/pharmacokinetic-interaction-between-isavuconazole-and-a-fixed-dose-combination-of-lopinavir-400-mg-ritonavir-100-mg-in-healthy-subjects
#13
Takao Yamazaki, Amit Desai, David Han, Kota Kato, Donna Kowalski, Shahzad Akhtar, Christopher Lademacher, Laura Kovanda, Robert Townsend
This phase 1, open-label study evaluated the pharmacokinetic effects of coadministration of the antifungal agent, isavuconazole (administered as its water-soluble prodrug isavuconazonium sulfate), with the antiretroviral agent lopinavir/ritonavir in healthy adults. In part 1, 13 subjects were randomized to 2 arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In part 2, a different group of 55 subjects were randomized to 3 arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27273149/pharmacokinetic-effects-of-isavuconazole-coadministration-with-the-cytochrome-p450-enzyme-substrates-bupropion-repaglinide-caffeine-dextromethorphan-and-methadone-in-healthy-subjects
#14
Takao Yamazaki, Amit Desai, Ronald Goldwater, David Han, Corrie Howieson, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Helene Pearlman, Diane Rammelsberg, Robert Townsend
This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23)...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27273004/pharmacokinetic-interactions-between-isavuconazole-and-the-drug-transporter-substrates-atorvastatin-digoxin-metformin-and-methotrexate-in-healthy-subjects
#15
Takao Yamazaki, Amit Desai, Ronald Goldwater, David Han, Kenneth C Lasseter, Corrie Howieson, Shahzad Akhtar, Donna Kowalski, Christopher Lademacher, Diane Rammelsberg, Robert Townsend
This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein-1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P-glycoprotein (P-gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P-gp substrate), digoxin (0...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27138546/an-exposure-response-modeling-approach-to-examine-the-relationship-between-potency-of-cyp3a-inducer-and-plasma-4%C3%AE-hydroxycholesterol-in-healthy-subjects
#16
Xuemin Jiang, Catherine Dutreix, Venkateswar Jarugula, Sam Rebello, Christina S Won, Haiying Sun
The objectives of this analysis were to establish the exposure-response relationship between plasma rifampicin and 4β-hydroxycholesterol (4βHC) concentration and to estimate the effect of weak, moderate, and potent CYP3A induction. Plasma rifampicin and 4βHC concentration-time data from a drug-drug interaction study with rifampicin 600 mg were used for model development. An indirect response model with an effect compartment described the relationship between rifampicin and 4βHC concentrations. The model predicted that the equilibration t1/2 and 4βHC t1/2 were 72...
January 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27870481/glycemic-effect-and-safety-of-a-systemic-partial-glucokinase-activator-pf-04937319-in-patients-with-type-2-diabetes-mellitus-inadequately-controlled-on-metformin-a-randomized-crossover-active-controlled-study
#17
William S Denney, Douglas S Denham, Michael R Riggs, Neeta B Amin
Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic β cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily)...
November 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27870480/pharmacokinetics-and-safety-of-defibrotide-in-healthy-japanese-subjects
#18
Kazuo Umemura, Takayuki Iwaki, Toshimi Kimura, Chitose Ogawa, Takahiro Fukuda, Shuichi Taniguchi, Keizo Horibe, Hiroaki Goto, Kenichi Yoshimura, Yasutaka Watanabe, Chika Nitani, Atsushi Kikuta
No abstract text is available yet for this article.
November 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27870479/impact-of-renal-impairment-on-the-pharmacokinetics-of-apremilast-and-metabolite-m12
#19
Yong Liu, Simon Zhou, Mahmoud Assaf, Jim Nissel, Maria Palmisano
The pharmacokinetics of apremilast and its major metabolite M12 were evaluated in subjects with varying degrees of renal impairment. Men and women with renal impairment (estimated glomerular filtration rate, 60-89 mL/min [mild, n = 8], 30-59 mL/min [moderate, n = 8], or <30 mL/min [severe, n = 8]) or demographically healthy matched (control) subjects (n = 24) received a single oral dose of apremilast 30 mg. Plasma apremilast and metabolite M12 concentrations were determined, and pharmacokinetic parameters were calculated from samples obtained predose and up to 72 hours postdose...
November 2016: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/27870478/clinical-pharmacology-in-drug-development-five-years-in-the-books
#20
EDITORIAL
David J Greenblatt
No abstract text is available yet for this article.
November 2016: Clinical Pharmacology in Drug Development
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