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Clinical Pharmacology in Drug Development

Rajesh Patel, Jonathan L Palmer, Shashidhar Joshi, Alejandro Di Ció Gimena, Florencia Esquivel
Two bioavailability/bioequivalence studies were carried out to evaluate the pharmacokinetics of candesartan cilexetil 16mg tablet formulations. A pilot study was used to optimise the formulation and manufacturing process prior to conducting the definitive study. The pilot study was a single dose, randomised two period crossover and the definitive study was a single dose randomised three period, 6 sequence cross over study in healthy adults. In the pilot study the test formulation was 24% and 18% greater for Cmax and AUC compared to the innovator product...
October 18, 2016: Clinical Pharmacology in Drug Development
Michael Burdick, Richard Mamelok, Michele Hurliman, Mariève Dupuis, Yuli Xie, Julie Grenier, Curtis Sheldon, Michael Gartner, Peter Noymer
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity with no sedative or anxiolytic properties. Twelve (12) healthy male subjects were enrolled in a study to receive either one of two treatments over two periods in an open-label, randomized, two-way crossover design: (A) 120 mg of ketorolac tromethamine administered as a continuous subcutaneous (SC) infusion over a 24-hour period; or (B) an identical total daily dose administered as 4 intramuscular (IM) bolus injections of 30 mg each given every 6 hours (current labeled treatment regimen)...
October 14, 2016: Clinical Pharmacology in Drug Development
Seol Ju Moon, Sun-Young Kim, Cheol-Hee Lim, Hwan Bong Jang, Min-Gul Kim, Ji-Young Jeon
We investigated botanical drug-pharmaceutical drug interactions between DW1029 (a botanical extract of Morus alba linne root bark and Puerariae radix) and metformin, losartan, and linagliptin in the steady state. Three studies were conducted as a randomized, open-label, two-period, two-treatment, multiple-dose, two-way crossover designs. Eligible subjects received metformin (500 mg twice daily), losartan (50 mg once daily), or linagliptin (5 mg once daily) with DW1029M (300 mg × 2T twice daily) every 12 h on days 1 through 6 and a single dose in the morning of day 7...
October 14, 2016: Clinical Pharmacology in Drug Development
Thomas Schluep, Jason Lickliter, James Hamilton, David L Lewis, Ching-Lung Lai, Johnson Yn Lau, Stephen A Locarnini, Robert G Gish, Bruce D Given
ARC-520 Injection, an RNA interference drug for the treatment of hepatitis B that targets cccDNA-derived viral mRNA transcripts with high specificity, effectively reduces the production of viral proteins and HBV DNA. In this phase I, randomized, double-blind, placebo-controlled study, 54 healthy volunteers (half male, half female) received a single, intravenous dose of 0.01-4.0 mg/kg ARC-520 Injection (N = 36) or placebo (N = 18). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (cytokines and complement)...
October 14, 2016: Clinical Pharmacology in Drug Development
Susanne Johansson, Maria Leonsson-Zachrisson, Mikael Knutsson, Andrew G Spencer, Eric D Labonté, Desiree Deshpande, Jill Kohler, Kenji Kozuka, Dominique Charmot, David P Rosenbaum
Tenapanor (RDX5791, AZD1722), a first-in-class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether co-administration of tenapanor with phosphate binders (sevelamer or calcium-based binders) impacts on the pharmacodynamic effects of tenapanor...
September 22, 2016: Clinical Pharmacology in Drug Development
Ulrike Gottwald-Hostalek, Ningling Sun, Christian Barho, Steven Hildemann
Hypertension is currently one of the greatest global healthcare 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...
September 22, 2016: Clinical Pharmacology in Drug Development
Kazuo Umemura, Yasuhiko Ikeda, Nobuko Matsushima, Kazunao Kondo
We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single-administration study, 23 subjects also received prasugrel 20 mg or 30 mg; and in the multiple-administration study, 20 subjects received a loading dose of prasugrel 20 mg or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 mg/day or 7.5 mg/day, respectively, on days 2-5. In both studies, the plasma concentration of the active metabolite of prasugrel, R-138727, reached a maximum at 0...
September 22, 2016: Clinical Pharmacology in Drug Development
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
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
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
David J Greenblatt
No abstract text is available yet for this article.
November 2016: Clinical Pharmacology in Drug Development
Paul Glue, Gavin Cape, Donna Tunnicliff, Michelle Lockhart, Fred Lam, Noelyn Hung, C Tak Hung, Sarah Harland, Jane Devane, R S Crockett, John Howes, Borje Darpo, Meijian Zhou, Holger Weis, Lawrence Friedhoff
Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level)...
November 2016: Clinical Pharmacology in Drug Development
Kazuo Umemura, Takayuki Iwaki
The dosing regimen of prasugrel adjusted for Japanese patients was compared with that of clopidogrel by analyzing the pharmacokinetics and pharmacodynamics in 40 healthy Japanese subjects in a randomized, single-blind crossover study. In period 1, the subjects received either 300 mg clopidogrel or 20 mg prasugrel; after a >2-week interval (period 2), the drug was switched. Blood samples of 36 of the 40 subjects were collected for analysis of pharmacokinetics, pharmacodynamics, and CYP2C19 genotypes. The plasma concentration of the active metabolite of prasugrel increased rapidly and reached its peak 30 minutes postadministration, whereas that of the active metabolite of clopidogrel reached its peak 1 hour postadministration...
November 2016: Clinical Pharmacology in Drug Development
Roland Heinig, Nina Kimmeskamp-Kirschbaum, Atef Halabi, Silvia Lentini
Finerenone (BAY 94-8862) is a nonsteroidal mineralocorticoid receptor antagonist in development for the treatment of diabetic kidney disease. This observational trial compared the pharmacokinetics of a single oral dose of finerenone 10 mg (immediate-release tablet) in adults with mild (creatinine clearance [CLCR ] 50-80 mL/min; n = 8), moderate (CLCR 30 to < 50 mL/min; n = 8), or severe (CLCR < 30 mL/min; n  =  9) renal impairment with those in adults with normal renal function (CLCR > 80 mL/min; n  = 8) over 96 hours postdose...
November 2016: Clinical Pharmacology in Drug Development
Bart Remmerie, Marc De Meulder, Sveta Weiner, Adam Savitz
Risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole are antipsychotic drugs approved for treating various psychiatric disorders, including schizophrenia. The objective of this randomized, parallel-group, open-label study was to compare finger-stick-based capillary with corresponding venous whole-blood and plasma concentrations for these drugs after administration of a single dose to healthy volunteers. All whole-blood and plasma drug concentrations were measured with validated liquid chromatography-tandem mass spectrometry methods...
November 2016: Clinical Pharmacology in Drug Development
Bart Remmerie, Marc De Meulder, Jay Ariyawansa, Adam Savitz
Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open-label, parallel-group study was performed to compare finger-stick-based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger-stick-based capillary and venous blood samples were collected at various times within a dosing interval...
November 2016: Clinical Pharmacology in Drug Development
Charles D Meyers, Adele Noe, Atish Salunke, Aishwarya Movva, Kenneth Kulmatycki, Srikanth Neelakantham, Anne Crissey, Tapan Majumdar, Jin Chen
Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure...
November 2016: Clinical Pharmacology in Drug Development
S Zhai, A Georgy, Z Liang, J Zhi
A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments...
November 2016: Clinical Pharmacology in Drug Development
Ying Jun Cao, Taiji Sawamoto, Udaya Valluri, Kathy Cho, Michaelene Lewand, Suzanne Swan, Kenneth Lasseter, Mark Matson, John Holman, James Keirns, Tong Zhu
Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days...
November 2016: Clinical Pharmacology in Drug Development
Yu Lou, Ann M Buchanan, Shuguang Chen, Susan L Ford, Elizabeth Gould, David Margolis, William R Spreen, Parul Patel
A randomized, partial-blind, repeat-dose, 3-period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open-label 400-mg dose of the positive control moxifloxacin, with a 21-day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2...
November 2016: Clinical Pharmacology in Drug Development
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