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Population pharmacokinetics

Matthew Cardinal, Constantino Kantaridis, Tong Zhu, Pengling Sun, Debra D Pittman, John E Murphy, Steven Arkin
BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of tissue factor-activated coagulation factor VII (TF-FVIIa) complex and activated factor X (FXa). PF-06741086 is a monoclonal antibody that targets TFPI to increase clotting activity. OBJECTIVES: This study was a randomized, double-blind, sponsor-open, placebo-controlled, single intravenous (IV) or subcutaneous (SC) dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06741086...
June 16, 2018: Journal of Thrombosis and Haemostasis: JTH
Kristin Cecilie Carlsson Petri, Steen Hvass Ingwersen, Anne Flint, Jeppe Zacho, Rune Viig Overgaard
INTRODUCTION: Semaglutide, a new treatment option approved for the treatment of patients with type 2 diabetes mellitus, is a glucagon-like peptide-1 receptor agonist to be injected subcutaneously once weekly. This analysis used a population pharmacokinetic model of semaglutide to identify clinically relevant covariates for exposure. METHODS: A total of 1612 patients with up to seven pharmacokinetic observations each were included in the analysis. All subjects had type 2 diabetes mellitus and were enrolled in one of five trials in the phase III development program for subcutaneous semaglutide once weekly (the SUSTAIN program)...
June 15, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Jill M Butterfield-Cowper, Thomas P Lodise, Manjunath P Pai
OBJECTIVES: To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed dose in morbidly-obese and non-obese subjects METHODS: We performed a nonparametric population pharmacokinetic analysis of daptomycin concentration-time data from a prior obese and non-obese kidney function matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (Cmax ), minimum concentrations (Cmin ), and area under the curve (AUC) with the standard daptomycin 6-mg/kg/day dose or a 500-mg daily fixed dose in obese and non-obese subjects...
June 15, 2018: Pharmacotherapy
Anna Vildhede, Emi Kimoto, A David Rodrigues, Manthena V S Varma
Organic anion transporter (OAT) 2 and OAT7 were recently shown to be involved in the hepatic uptake of drugs; however, there is limited understanding of the population variability in the expression of these transporters in liver. There is also a need to derive relative expression-based scaling factors (REFs) that can be used to bridge in vitro functional data to the in vivo drug disposition. To this end, we quantified OAT2 and OAT7 surrogate peptide abundance in a large number of human liver tissue samples (n=52), as well as several single-donor cryopreserved human hepatocyte lots (n=30) by a novel, validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method...
June 15, 2018: Molecular Pharmaceutics
Maiko Nomoto, Jim Ferry, Ziad Hussein
Avatrombopag, a c-Mpl agonist, has been developed to provide an alternative therapy to standard platelet transfusion care for the treatment of thrombocytopenia. The main objectives of this article were to describe the pharmacokinetics (PK) of avatrombopag, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma avatrombopag concentrations and platelet count, and to identify potential intrinsic and extrinsic factors affecting PK or PK/PD in patients with chronic liver disease (CLD)...
June 15, 2018: Journal of Clinical Pharmacology
Hongjun Zhao, Pengfei Ge, Xuhong Chang, Xiaolan Ren, Lijuan Chen, Jinxia Gao, Jianming Hu, Xinghui Li
OBJECTIVE: To estimate the metabolic parameters in different tissues and organs, build the physiologically based pharmacokinetic( PBPK) model of rat and occupational population, and predict the toxic dynamic characteristics exposure to nickel. METHODS: The partition coefficients in different tissues and organs were estimated using vector datas of nickel by the optimization and statistics files of acslx software. The PBTK model of occupational population exposure to nickel was built according to the metabolic parameters by acslx software...
September 2017: Wei Sheng Yan Jiu, Journal of Hygiene Research
Sulav Duwal, Laura Dickinson, Saye Khoo, Max von Kleist
To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections needs to decrease to approximately 500,000 by 2020. One of the 'five pillars' to achieve this goal is pre-exposure prophylaxis (PrEP). Truvada (emtricitabine-tenofovir) is currently the only medication approved for PrEP. Despite its advantages, Truvada is costly and requires individuals to adhere to the once-daily regimen. To improve PrEP, many next-generation regimen, including long-acting formulations, are currently investigated...
June 2018: PLoS Computational Biology
Bella Ungar, Yoav Glidai, Miri Yavzori, Orit Picard, Ella Fudim, Avishay Lahad, Yael Haberman, Dror S Shouval, Ilana Weintraub, Rami Eliakim, Shomron Ben-Horin, Batia Weiss
OBJECTIVES: While infliximab pharmacokinetics are associated with therapy outcome in adult IBD population, limited data is available in pediatric patients. We aimed to define the relationship between Infliximab trough and antibodies' levels (IFX-TL, ATI) and clinical, biomarker remission. METHODS: IFX-TL and ATI were routinely obtained between 2011-2017. Associations with clinical and inflammatory (C-reactive protein, CRP) end-points were studied throughout the first year of infliximab therapy...
June 12, 2018: Journal of Pediatric Gastroenterology and Nutrition
Andrea L Goodnight, Sherry Cox
  Meloxicam, a COX-2 selective nonsteroidal anti-inflammatory medication, has been used in many exotic animals at doses extrapolated from domestic animal pharmacokinetic and pharmacodynamic studies. Increasing evidence suggests that significant species differences exist in meloxicam metabolism. Because of this, dose extrapolation from domestic animals may not be appropriate for exotic species. The objective of this study was to investigate the pharmacokinetics of meloxicam in a population of male Malayan flying foxes, Pteropus vampyrus, following a single oral dose of 0...
June 2018: Journal of Zoo and Wildlife Medicine: Official Publication of the American Association of Zoo Veterinarians
Eugenia Bruzzese, Marcella Pesce, Giovanni Sarnelli, Alfredo Guarino
INTRODUCTION: Rifaximin is a poorly absorbable antibiotic with a broad-spectrum activity against both Gram-negative and -positive bacteria. It is active in the small intestine due to its high bile solubility, whereas in the aqueous environment of the colon, it shows limited efficacy against highly susceptible bacteria. These unique pharmacokinetic properties limit its systemic effects and can correct gut microflora imbalances. Thus, rifaximin has become a major therapeutic agent in several gastrointestinal diseases in which an imbalance in gut microflora may play a role, including diarrhea predominant irritable bowel syndrome (IBS-D)...
June 13, 2018: Expert Opinion on Drug Metabolism & Toxicology
Brady S Moffett, Mindl M Weingarten, Marianne Galati, Jennifer L Placencia, Emily A Rodman, James J Riviello, Simon Y Kayyal
OBJECTIVE: Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. METHODS: A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19 years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient...
June 13, 2018: Epilepsia
Frank Kloprogge, Lesley Workman, Steffen Borrmann, Mamadou Tékété, Gilbert Lefèvre, Kamal Hamed, Patrice Piola, Johan Ursing, Poul Erik Kofoed, Andreas Mårtensson, Billy Ngasala, Anders Björkman, Michael Ashton, Sofia Friberg Hietala, Francesca Aweeka, Sunil Parikh, Leah Mwai, Timothy M E Davis, Harin Karunajeewa, Sam Salman, Francesco Checchi, Carole Fogg, Paul N Newton, Mayfong Mayxay, Philippe Deloron, Jean François Faucher, François Nosten, Elizabeth A Ashley, Rose McGready, Michele van Vugt, Stephane Proux, Ric N Price, Juntra Karbwang, Farkad Ezzet, Rajesh Bakshi, Kasia Stepniewska, Nicholas J White, Philippe J Guerin, Karen I Barnes, Joel Tarning
BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations...
June 2018: PLoS Medicine
José C Nicolau, Luciano M Baracioli, Robert P Giugliano
Cardiovascular disease (CVD) is the main cause of death in the world. Coronary artery disease (CAD) is the most common form of CVD presentation, but the prevalence of peripheral artery disease (PAD) is increasing. Patients with polyvascular disease comprise a very high-risk population that has been infrequently studied. Areas covered: The authors review the current evidence of the efficacy and safety of ticagrelor in the setting of acute coronary syndrome and stable patients post-MI with and without PAD and summarize its pharmacokinetics, pharmacodynamics, and regulatory issues...
June 12, 2018: Expert Opinion on Pharmacotherapy
Daniel Gonzalez, Laura P James, Amira Al-Uzri, Miroslava Bosheva, Felice C Adler-Shohet, Susan R Mendley, John S Bradley, Claudia Espinosa, Eva Tsonkova, Kathryn Moffett, Lucila Marquez, Kari A Simonsen, Stefan Stoilov, Felix Boakye-Agyeman, Theresa Jasion, Christoph P Hornik, Robert Hernandez, Daniel K Benjamin, Michael Cohen-Wolkowiez
Solithromycin is a novel fluoroketolide antibiotic, which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age 6 years [range 4 days - 17 years]) were administered intravenous (IV) or oral (capsules or suspension) solithromycin (IV 6-8 mg/kg; capsules/suspension 14-16 mg/kg on Day 1 and 7-15 mg/kg on Days 2-5). PK samples were collected after first and multi-dose administration...
June 11, 2018: Antimicrobial Agents and Chemotherapy
Candela Canton, Lucila Canton, María Paula Domínguez, Laura Moreno, Carlos Lanusse, Luis Alvarez, Laura Ceballos
The study compared the pharmacokinetic (PK) behaviour and anthelmintic efficacy against susceptible and resistant nematodes following subcutaneous (SC) and oral administration of ivermectin (IVM) to cattle. Six commercial farms were involved: Farms 1 and 2 (IVM-susceptible nematode population) and Farms 3, 4, 5 and 6 (IVM-resistant nematode population). On each farm, forty-five calves naturally infected with gastrointestinal (GI) nematodes were randomly allocated into three groups (n = 15): untreated control, IVM SC administration, and IVM oral administration (both at 0...
May 30, 2018: Veterinary Parasitology
C R Kirman, A M Belknap, A F Webster, S M Hays
Exposure to cyanide is widespread in human populations due to a variety of natural and anthropogenic sources. The potential health risks of excess cyanide exposure are dose-dependent and include effects on the thyroid, the male reproductive system, developmental effects, neuropathies and death. Many organizations have derived exposure guideline values for cyanide, which represent maximum recommended exposure levels for inhalation and oral routes of exposure. Biomonitoring Equivalents (BEs) are estimates of the average biomarker concentrations that correspond to these reference doses...
June 7, 2018: Regulatory Toxicology and Pharmacology: RTP
Suzanne L Parker, Manoj Saxena, John Gowardman, Jeffrey Lipman, John Myburgh, Jason A Roberts
PURPOSE: High-dose paracetamol (6 g/day) is a low-cost intervention that may prevent pyrexia. The purpose of this study was to describe the pharmacokinetics of high-dose intravenous paracetamol, in patients with traumatic brain injury (TBI). MATERIALS AND METHODS: A clinical pharmacokinetic study in adult patients with TBI was performed as a sub-study to a prospective, phase 2B, randomized placebo-controlled study (PARITY). Patients received 1 g of intravenous paracetamol or 0...
May 30, 2018: Journal of Critical Care
Rune Dietz, Jean-Pierre Desforges, Kim Gustavson, Frank F Rigét, Erik W Born, Robert J Letcher, Christian Sonne
Polar bears (Ursus maritimus) are among the world's highest trophic level marine predators and as such have some of the highest tissue concentrations of organohalogen contaminants (OHCs) among Arctic biota. In this paper we present the results of a three decade (1983-2013) risk assessment of OHC exposure and effects on reproduction, immunity, and cancer (genotoxicity) in polar bears from Central East Greenland. Risk of adverse effects are evaluated using a risk quotient (RQ) approach with derivation from measured OHC concentrations in polar bear tissue and critical body residues (CBR) extrapolated for polar bears using physiologically-based pharmacokinetic modelling (PBPK)...
June 5, 2018: Environment International
Marina Senek, Dag Nyholm, Elisabet I Nielsen
OBJECTIVES: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates. METHODS: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies...
June 7, 2018: European Journal of Clinical Pharmacology
Yalda Hosseinzadeh Ardakani, Hoda Lavasani, Mohammad-Reza Rouini
The stereoselective pharmacokinetic of Tramadol (T) and its main metabolites concerning the influence of CYP2D6 phenotype and gender on the phase I metabolism of this compound was studied after administration of 100 mg single oral dose of racemic T to 24 male and female subjects. The pharmacokinetic parameters were estimated from plasma concentrations of the analytes enantiomers. The metabolic ratio of T enantiomers was used for CYP2D6 phenotype determination. The plasma concentrations of both tramadol enantiomers were considerably higher in Poor metabolizers (PM) than in extensive metabolizers (EM), resulting in 43% and 37% increase in AUC values of (+)-T and (-)-T respectively...
2018: Iranian Journal of Pharmaceutical Research: IJPR
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