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Clinical Pharmacology in Drug Development

Masayuki Hashiguchi, Junya Maruyama, Mikiko Shimizu, Daichi Takahashi, Tsuyoshi Shiga
To investigate whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) use is associated with an increased risk of diabetes mellitus and hyperglycemia, we performed a nested case-control study using a postmarketing surveillance database in Japan. The database cohort included 26,849 cases of statin use and 5308 cases of other lipid-lowering drug use in patients with hyperlipidemia. Participants received at least 1 type of statin, had a clear medication history of statin use, and had no complications of diabetes mellitus...
February 20, 2018: Clinical Pharmacology in Drug Development
Xia Chen, Ji Jiang, Pei Hu, Stefan Zajic, Wen Liu, Jacqueline McCrea, Fang Liu, Rose Witter, Eric Mangin, S Aubrey Stoch
Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this phase 1 open-label study, 12 healthy Chinese postmenopausal women received single-dose ODN 50 mg on day 1 and multiple-dose ODN 50 mg once weekly on days 15, 22, 29, and 36 under fasted conditions. Pharmacokinetic (PK) parameters were evaluated on days 1 and 36. Multiple-dose area under the concentration-time profile (AUC0-168h) and maximum plasma concentration (Cmax) were compared with historical data from 9 non-Chinese postmenopausal women who also received ODN 50 mg once weekly for 4 weeks...
February 14, 2018: Clinical Pharmacology in Drug Development
Sabina Paglialunga, Bruce H Morimoto, Amparo de la Peña, Caroline Fortier
Continuous glucose monitoring (CGM) systems allow patients with diabetes mellitus to closely track glucose concentrations over several days, identify trends in glucose levels, and avoid glucose excursions. This technology has not only advanced diabetes mellitus management but has increased patient safety through greater glycemic awareness. Due to these attributes, CGM is now being applied in therapeutic research as a pharmacodynamic tool to support early clinical drug development programs. However, to date only a handful of studies have utilized CGM in type 2 diabetes mellitus (T2DM) drug development...
February 14, 2018: Clinical Pharmacology in Drug Development
William McKeand, Susan Baird-Bellaire, James Ermer, Alain Patat
Bazedoxifene, a selective estrogen receptor modulator with proestrogenic effects on bone and lipid metabolism and antiestrogenic effects on the breast and endometrium, is a treatment option for osteoporosis in postmenopausal women. It is extensively metabolized by the liver; therefore, a decrease in liver function was expected to decrease bazedoxifene clearance. This single-dose, open-label, inpatient/outpatient, nonrandomized study assessed the pharmacokinetics of bazedoxifene 20 mg in 18 postmenopausal women with hepatic impairment and 18 matched healthy postmenopausal women...
February 14, 2018: Clinical Pharmacology in Drug Development
Ryan Dammerman, Sonnie Kim, Mathews Adera, Alex Schwarz
A subcutaneous risperidone implant (RI) formulation was developed to improve medication adherence in schizophrenia. Two phase 1 studies were conducted to evaluate the pharmacokinetics of RI in adult patients with schizophrenia. In study 1, all subjects were stable on 4 mg oral risperidone; subsequently, the first subject received 375 mg RI for 1 month, and the remaining subjects received 375 mg RI for 3 months. In study 2, all subjects were stable on oral risperidone 4 mg, 6 mg, or 8 mg and subsequently received RI 480 mg, 720 mg, or 960 mg, respectively, for 6 months...
February 8, 2018: Clinical Pharmacology in Drug Development
Scott Rasmussen, Kathleen Halabuk Horkan, Mitchell Kotler
Smoking continues to be a major preventable cause of early mortality worldwide, and nicotine replacement therapy has been demonstrated to increase rates of abstinence among smokers attempting to quit. Nicotine transdermal systems (also known as nicotine patches) attach to the skin via an adhesive layer composed of a mixture of different-molecular-weight polyisobutylenes (PIBs) in a specific ratio. This randomized, single-dose, 2-treatment, crossover pharmacokinetic (PK) trial assessed the bioequivalence of nicotine patches including a replacement PIB adhesive (test) compared with the PIB adhesive historically used on marketed patches (reference)...
February 2, 2018: Clinical Pharmacology in Drug Development
Robert Bissonnette, Lakshmi S Vasist, Jonathan N Bullman, Therese Collingwood, Geng Chen, Tomoko Maeda-Chubachi
Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts...
February 1, 2018: Clinical Pharmacology in Drug Development
William McKeand, Susan Baird-Bellaire, James Ermer, Alain Patat
The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45-65 years) received either a single oral dose of ibuprofen (600-mg tablet), bazedoxifene (20-mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance...
February 1, 2018: Clinical Pharmacology in Drug Development
Joanne Sloan-Lancaster, Eyas Raddad, Mark A Deeg, Michelle Eli, Amy Flynt, James Tumlin
Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF-α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo...
January 31, 2018: Clinical Pharmacology in Drug Development
Takuma Yonemura, Nozomi Okada, Koichi Sagane, Kazuhiro Okamiya, Hideki Ozaki, Toshiaki Iida, Hiroyuki Yamada, Hiroki Yagura
Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) is specified in its package insert to be taken with food to obtain sufficient exposure of EVG. It has been reported that a nutritional protein-rich drink shows comparable pharmacokinetics (PK) of EVG to those with a standard breakfast. In this study, the PK profiles of EVG and COBI were evaluated by administration of a single dose of EVG/COBI/FTC/TAF, after ingestion of either a nutritional protein-rich drink, milk, or apple juice...
January 24, 2018: Clinical Pharmacology in Drug Development
Vaishali Sahasrabudhe, Didier Saur, Kyle Matschke, Steven G Terra, Anne Hickman, Isabelle Huyghe, Haihong Shi, David L Cutler
Ertugliflozin, a selective sodium-glucose cotransporter-2 inhibitor, is being developed for the treatment of type 2 diabetes mellitus. This randomized, 6-sequence, 3-period crossover study assessed the effect of ertugliflozin (100 mg; supratherapeutic dose) vs placebo and moxifloxacin (400 mg; positive control) on the QT interval corrected for heart rate (QTc) in 42 male or female healthy subjects. Triplicate electrocardiograms were performed predose and serially over 48 hours postdose in each treatment period...
January 18, 2018: Clinical Pharmacology in Drug Development
Eng-Huat Tan, Wan-Teck Lim, Myung-Ju Ahn, Quan-Sing Ng, Jin Seok Ahn, Daniel Shao-Weng Tan, Jong-Mu Sun, May Han, Francis C Payumo, Krista McKee, Wei Yin, Marc Credi, Shefali Agarwal, Jaroslaw Jac, Keunchil Park
Hepatocyte growth factor (HGF)/c-Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV-299; SCH 900105), a humanized IgG1 κ HGF inhibitory monoclonal antibody, prevents HGF/c-Met pathway ligand-mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non-small cell lung cancer (NSCLC)...
January 18, 2018: Clinical Pharmacology in Drug Development
Fraser Lewis, Mark P Connolly, Aomesh Bhatt
The pharmacokinetics of a novel locally applied ibuprofen topical patch was evaluated. Healthy subjects (n = 28) were administered a 200-mg ibuprofen patch every 24 hours for 5 days, and steady-state pharmacokinetics was determined. The amount of ibuprofen remaining in the patch following each patch removal was also assessed. The maximum steady-state drug concentration and area under the concentration curve from time 0 on day 5 (t = 0) to the 24-hours sample on day 6 were 514 ng/mL (95% CI 439 to 603 ng/mL) and 9...
January 11, 2018: Clinical Pharmacology in Drug Development
Naidong Ye, Scott A Monk, Pankaj Daga, David M Bender, Laura B Rosen, Jamie Mullen, Margaret C Minkwitz, Alan R Kugler
The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single-center, open-label, randomized, 3-period crossover study involved healthy male and nonfertile female subjects aged 18-55 years (NCT02039180). Subjects received a single 50-mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0-∞ (area under the plasma drug concentration-time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1...
January 10, 2018: Clinical Pharmacology in Drug Development
Shawn D Flanagan, Sonia L Minassian, Philippe Prokocimer
Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections in adults. We evaluated the pharmacokinetics of tedizolid in elderly subjects to guide dosing recommendations. In an open-label phase 1 study ( identifier NCT01496677), 14 elderly (≥65 years) and 14 younger control (18-45 years) subjects each received a single oral dose of tedizolid phosphate 200 mg. Blood samples were collected before dose and more than 72 hours after dose. The pharmacokinetic parameters of tedizolid after a single dose were similar in both age groups...
January 10, 2018: Clinical Pharmacology in Drug Development
Wei Tian, Miaowei Wu, Yongchuan Deng
Cardiovascular morbidity is closely associated with serum lipid level. We aimed to investigate the effects of different aromatase inhibitors, including letrozole, anastrozole, and exemestane, on the lipid profile of eastern Chinese breast cancer patients. We evaluated a retrospective cohort of eastern Chinese postmenopausal women with early-stage breast cancer who received aromatase inhibitors. A total of 116 postmenopausal women with early-stage breast cancer without prior cardiovascular disease were included...
December 29, 2017: Clinical Pharmacology in Drug Development
Hiroko Ino, Hiroshi Itoh, Yohei Doi, Harue Igarashi, Yotaro Numachi
No abstract text is available yet for this article.
December 28, 2017: Clinical Pharmacology in Drug Development
Olivier J David, Amy Berwick, Nicole Pezous, Michael Lang, Klaus Tiel-Wilck, Tjalf Ziemssen, Peng Li, Hisanori Hara, Robert Schmouder
The safety profile of fingolimod 0.5 mg, approved therapy for relapsing multiple sclerosis, is well established in clinical and real-world studies. As fingolimod is teratogenic in rats, it was considered important to assess the concentrations of fingolimod and its active metabolite, fingolimod-phosphate, in the semen of male patients on treatment and the risk of harming a fetus in a pregnant partner. In this multicenter open-label study, 13 male patients receiving fingolimod for at least 6 months provided 1 semen and 1 blood sample for analyte concentration measurements...
December 19, 2017: Clinical Pharmacology in Drug Development
Ulrich Gergs, Dorothea Ihlefeld, Tobias Clauss, Michael Weiss, Klaus Pönicke, Gunther O Hofmann, Joachim Neumann
Patients undergoing hip or knee replacement therapy are routinely pretreated with antibiotics before they enter the operation theater. This treatment intends to reduce the incidence of peri- or postsurgical infections. Here, we calculated the uptake kinetics of levofloxacin into bone to see whether levofloxacin could be obtained from the trabecular and cortical bone and at what time concentrations are sufficiently high to inhibit the usual hospital infections. Patients (n = 42) undergoing routine surgery were treated with 500 mg levofloxacin intravenously immediately prior to the operation...
December 18, 2017: Clinical Pharmacology in Drug Development
Alice I Nichols, Sam Liao, Richat Abbas
Desvenlafaxine exposure in Korean and US populations was compared using population pharmacokinetic (PK) analysis. Data from a single- and multiple-dose study of desvenlafaxine (50, 100, and 200 mg) in 30 healthy Korean subjects were added to a population PK model previously developed using sparse PK samples from patients with major depressive disorder, including 140 Korean patients, combined with rich PK data from healthy volunteers. The structural PK model was an open 1-compartment linear disposition model with parallel first-order and 0-order inputs...
December 11, 2017: Clinical Pharmacology in Drug Development
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