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Clinical Pharmacology in Drug Development

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https://read.qxmd.com/read/30900816/pharmacokinetic-profile-of-a-generic-formulation-of-sofosbuvir-and-its-metabolite-gs-331007-in-healthy-chinese-subjects
#1
Zhenwei Shen, Xiaoxue Zhu, Hong Zhang, Hong Chen, Junqi Niu, Guiling Chen, Xiaojiao Li, Yanhua Ding
Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method...
March 22, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30897305/pharmacokinetic-properties-of-ibuprofen-ibu-from-the-fixed-dose-combination-ibu-caffeine-400-100-mg-fdc-in-comparison-with-400-mg-ibu-as-acid-or-lysinate-under-fasted-and-fed-conditions-data-from-2-single-center-single-dose-randomized-crossover-studies-in-healthy
#2
Thomas Weiser, Cornelia Schepers, Tobias Mück, Robert Lange
Rapid onset of analgesic action is linked with rapid absorption of analgesics (high maximum concentration [Cmax ] and short time to maximum concentration [tmax ]). After overnight fasting, ibuprofen lysinate reaches higher peak plasma levels (Cmax ) earlier than ibuprofen acid (tmax ) with comparable exposure (area under the plasma concentration-time curve [AUC]); however, subjects usually take ibuprofen with or within a short time of a meal. Therefore, pharmacokinetic (PK) studies under fed conditions may better characterize properties under real-life conditions...
March 21, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30861340/drug-drug-interactions-of-tacrolimus-or-cyclosporine-with-glecaprevir-and-pibrentasvir-in-healthy-subjects
#3
Matthew P Kosloski, Weihan Zhao, Hong Li, David Pugatch, Armen Asatryan, Jens Kort, Federico J Mensa, Wei Liu
A fixed-dose combination of glecaprevir and pibrentasvir is approved for treatment of chronic infection with hepatitis C virus (HCV) genotypes 1-6. Three phase 1 open-label studies were conducted in healthy volunteers to evaluate the potential for clinically relevant drug-drug interactions of the glecaprevir 300-mg and pibrentasvir 120-mg combination with the immunosuppressants tacrolimus (1 mg) or cyclosporine (100 and 400 mg). Glecaprevir and pibrentasvir exposure was unaffected by tacrolimus, whereas the tacrolimus area under the curve (AUC) value was 45% higher with glecaprevir and pibrentasvir...
March 12, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30861337/a-randomized-double-blind-placebo-controlled-first-time-in-human-study-to-assess-the-safety-tolerability-and-pharmacokinetics-of-single-and-multiple-ascending-doses-of-gsk3389404-in-healthy-subjects
#4
Kelong Han, Jennifer Cremer, Robert Elston, Stuart Oliver, Sharon Baptiste-Brown, Shuguang Chen, David Gardiner, Matt Davies, Joanne Saunders, Robert Hamatake, Jan Losos, Martin Leivers, Steve Hood, Frans van der Berg, Melanie Paff, James M Ritter, Dickens Theodore
GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo...
March 12, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30840357/pharmacokinetics-of-tacrolimus-coadministered-with-letermovir-in-allogeneic-hematopoietic-stem-cell-transplantation-patients
#5
LETTER
Yong-Mei Guo, Maiko Abumiya, Takaya Yamashita, Kumi Ubukawa, Naoto Takahashi
No abstract text is available yet for this article.
March 6, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30811880/a-phase-1-study-to-evaluate-the-pharmacokinetics-and-safety-of-cabotegravir-in-patients-with-hepatic-impairment-and-healthy-matched-controls
#6
Jafar Sadik B Shaik, Susan L Ford, Yu Lou, Zhiping Zhang, Kalpana K Bakshi, Allan R Tenorio, Christine Trezza, William R Spreen, Parul Patel
Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection. Liver disease is a major cause of morbidity and mortality in HIV-infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30-mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations...
February 27, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30809978/a-phase-i-study-to-evaluate-the-pharmacokinetics-and-safety-of-cabotegravir-in-adults-with-severe-renal-impairment-and-healthy-matched-control-participants
#7
Ridhi Parasrampuria, Susan L Ford, Yu Lou, Caifeng Fu, Kalpana K Bakshi, Allan R Tenorio, Christine Trezza, William R Spreen, Parul Patel
This study investigates the impact of severe renal impairment on the pharmacokinetics of cabotegravir, an investigational HIV-1 integrase inhibitor. This was a phase I, open-label, parallel-group, multicenter study conducted in 8 participants with severe renal impairment (creatinine clearance <30 mL/min; no renal replacement therapy) and 8 healthy participants (creatinine clearance >90 mL/min; 2 women/group; 6 men/group) matched for sex, age (±10 years), and body mass index (±25%). Participants received a single 30-mg oral cabotegravir tablet to determine total and unbound plasma cabotegravir concentrations...
February 27, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30809967/study-on-drug-drug-interactions-between-chiglitazar-a-novel-ppar-pan-agonist-and-metformin-hydrochloride-in-healthy-subjects
#8
Ling Yi, Hua Zhang, Jin-Wen Zhang, Xiao-Ming You, Zhi-Qiang Ning, Jia Yu, Li-Fang Qian, Li-Yan Miao
Chiglitazar (CHI) is a potent and selective peroxisome proliferator-activated receptor potentially for the treatment of patients with type 2 diabetes mellitus (T2DM). An open-label, randomized, 3-period crossover and self-controlled study was conducted to investigate drug-drug interaction potential between CHI and metformin hydrochloride (MET). Eligible subjects received a single oral dose of CHI (48 mg), MET (1000 mg), or a combination in each period, followed by serial blood sampling collected for up to 48 hours postdose, and safety was assessed throughout the trial...
February 27, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30791225/a-phase-1-open-label-pharmacokinetic-trial-to-investigate-possible-drug-drug-interactions-between-clobazam-stiripentol-or-valproate-and-cannabidiol-in-healthy-subjects
#9
Gilmour Morrison, Julie Crockett, Graham Blakey, Kenneth Sommerville
GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug...
February 21, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30786162/a-phase-3-randomized-placebo-controlled-evaluation-of-the-safety-of-intravenous-meloxicam-following-major-surgery
#10
Sergio D Bergese, Timothy I Melson, Keith A Candiotti, Sabry S Ayad, Randall J Mack, Stewart W McCallum, Wei Du, Alexis Gomez, Jorge E Marcet
An intravenous (IV) formulation of meloxicam is being studied for moderate to severe pain management. This phase 3, randomized, multicenter, double-blind, placebo-controlled trial evaluated the safety of once-daily meloxicam IV 30 mg in subjects following major elective surgery. Eligible subjects were randomized (3:1) to receive meloxicam IV 30 mg or placebo administered once daily. Safety was evaluated via adverse events, clinical laboratory tests, vital signs, wound healing, and opioid consumption. The incidence of adverse events was similar between meloxicam IV- and placebo-treated subjects (63...
February 20, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30779479/pharmacokinetics-food-effect-ketoconazole-interaction-and-safety-of-jtk-853-a-novel-nonnucleoside-hcv-polymerase-inhibitor-after-ascending-single-and-multiple-doses-in-healthy-subjects
#11
Sekihiro Tamaki, Tsutomu Shibata, Thomas Hunt, Barbara Gerhardt, Hiroyuki Yamada, Sudhakar M Pai
Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUCinf increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUCinf (approximately 1...
February 19, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30768860/the-relative-bioavailability-and-effects-of-food-and-acid-reducing-agents-on-filgotinib-tablets-in-healthy-subjects
#12
Kacey Anderson, Hao Zheng, Mona Kotecha, Jennifer Cuvin, Bob Scott, Shringi Sharma, Ann Ran-Ran Qin, Florence Namour, Yan Xin
Filgotinib is a potent, selective Janus kinase-1 inhibitor being developed to treat chronic inflammatory diseases. This phase 1 study in healthy subjects evaluated the relative bioavailability of filgotinib maleate tablets versus the reference tablet (filgotinib hydrochloride) and effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of filgotinib and its major metabolite. Noncompartmental pharmacokinetic parameters of filgotinib and its major metabolite were compared between the 2 tablets at 100- and 200-mg doses and with or without food or ARAs...
February 15, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30758919/lesinurad-evaluation-of-pharmacokinetic-and-pharmacodynamic-interactions-with-warfarin-in-healthy-volunteers
#13
Zancong Shen, Caroline A Lee, Kathleen Wallach, Shakti Valdez, David M Wilson, Bradley Kerr, Michael Gillen
Lesinurad is a selective uric acid reabsorption inhibitor approved for use in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia associated with gout. In vitro, lesinurad was shown to be a weak inhibitor of cytochrome P450 (CYP)2C9 and a weak inducer of CYP3A4. Warfarin is a widely prescribed oral coumarin-based anticoagulant commonly prescribed in gout patients. In an open-label clinical study in healthy adult male subjects, the effects of multiple daily doses of 400 mg lesinurad on the pharmacokinetics and pharmacodynamics of a single dose of 25 mg warfarin (racemic mixture of R- and S- enantiomers) were evaluated...
February 13, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30748125/effects-of-food-and-antacids-on-pharmacokinetics-and-pharmacodynamics-of-lesinurad-a-selective-urate-reabsorption-inhibitor
#14
Zancong Shen, Caroline A Lee, Shakti Valdez, Xiaojuan Yang, David M Wilson, Talia Flanagan, Michael Gillen
Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad...
February 12, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30730615/a-cocktail-interaction-study-evaluating-the-drug-drug-interaction-potential-of-the-perpetrator-drug-asp8477-at-multiple-ascending-dose-levels
#15
Nicoline Treijtel, Christiane Collins, Michel van Bruijnsvoort, Rainard Fuhr, Etienne Ernault, Shanti Gangaram-Panday, Paul Passier
ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4)...
February 7, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30730611/designer-benzodiazepines-a-review-of-published-data-and-public-health-significance
#16
EDITORIAL
H Karl Greenblatt, David J Greenblatt
No abstract text is available yet for this article.
February 7, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30720931/randomized-phase-i-trial-to-evaluate-the-safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-topical-daprodustat-in-healthy-volunteers-and-in-patients-with-diabetic-foot-ulcers
#17
Eric Olson, Kelly M Mahar, Lisa Morgan, Christina Fillmore, Claire Holland, Lawrence Lavery
Daprodustat, a small-molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia-inducible factor (HIF), leading to increased transcription of HIF-responsive genes. This randomized, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14-day repeat-dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness...
February 5, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30707505/use-of-population-pharmacokinetic-analyses-among-fda-approved-biologics
#18
Ken Ogasawara, G Caleb Alexander
Biologics, especially monoclonal antibodies, are increasingly important in the pharmaceutical marketplace. Population pharmacokinetic (PK) analyses could be useful to guide the need for dose adjustments among special populations, yet it is unknown how commonly such analyses are performed during biologics development. We summarized the characteristics of population PK models of biologics and examined their role in informing the drug labels. To do so, we extracted relevant characteristics of 86 biologics approved by the U...
February 1, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30676701/influence-of-renal-function-on-evolocumab-exposure-pharmacodynamics-and-safety
#19
Edward Lee, John P Gibbs, Maurice G Emery, Geoffrey Block, Scott M Wasserman, Lisa Hamilton, Sreeneeranj Kasichayanula, Patrick Hanafin, Ransi Somaratne, Ogo Egbuna
We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of evolocumab. The effects of evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups...
January 24, 2019: Clinical Pharmacology in Drug Development
https://read.qxmd.com/read/30667592/exposure-response-analysis-for-efficacy-of-daclatasvir-asunaprevir-and-beclabuvir-combinations-in-hcv-infected-patients
#20
T Ueno, M Osawa, T Shiozaki, M Green, T Garimella
The combination regimen of daclatasvir, asunaprevir, and beclabuvir (3DAA regimen) was developed as a fixed-dose combination for the treatment of hepatitis C virus (HCV) infection in Japan. The objectives of this analysis were to characterize the relationship between drug exposure and sustained virologic response at posttreatment week 12 (SVR12) in HCV-infected subjects and to evaluate the impact of demographic covariates and clinical factors on the exposure-response (E-R) relationship. The E-R efficacy analysis was performed with data from phase 2 and phase 3 studies in HCV-infected subjects treated with the 3DAA regimen...
January 22, 2019: Clinical Pharmacology in Drug Development
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