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Pharmacokinetics pharmacodynamics

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https://www.readbyqxmd.com/read/28817561/comparing-efficacies-of-moxifloxacin-levofloxacin-and-gatifloxacin-in-tuberculosis-granulomas-using-a-multi-scale-systems-pharmacology-approach
#1
Elsje Pienaar, Jansy Sarathy, Brendan Prideaux, Jillian Dietzold, Véronique Dartois, Denise E Kirschner, Jennifer J Linderman
Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim...
August 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28817342/hypoglycemia-risk-related-to-double-dose-is-markedly-reduced-with-basal-insulin-peglispro-versus-insulin-glargine-in-patients-with-type-2-diabetes-mellitus-in-a-randomized-trial-imagine-8
#2
Cynthia Harris, Thomas Forst, Tim Heise, Leona Plum-Mörschel, Elaine Watkins, Qianyi Zhang, Ludi Fan, Parag Garhyan, Niels Porksen
BACKGROUND: Basal insulin peglispro (BIL) has a peripheral-to-hepatic distribution of action that resembles endogenous insulin and a prolonged duration of action with a flat pharmacokinetic/pharmacodynamic profile at steady state, characteristics that tend to reduce hypoglycemia risk compared to insulin glargine (GL). The primary objective was to demonstrate that clinically significant hypoglycemia (blood glucose ≤54 mg/dL [3.0 mmol/L] or symptoms of severe hypoglycemia) occurred less frequently within 84 h after a double dose (DD) of BIL than a DD of GL...
August 2017: Diabetes Technology & Therapeutics
https://www.readbyqxmd.com/read/28817223/single-dose-euglycemic-clamp-studies-demonstrating-pharmacokinetic-and-pharmacodynamic-similarity-between-mk-1293-insulin-glargine-and-originator-insulin-glargine-lantus-in-type-1-diabetes-and-healthy-subjects
#3
Michael Crutchlow, John S Palcza, Kate M Mostoller, Chantal D Mahon, April M Barbour, Michael C Marcos, Yang Xu, Elaine Watkins, Linda Morrow, Marcus Hompesch
AIMS: MK-1293 is an insulin glargine that has an identical amino acid sequence to that of Lantus, the originator insulin glargine. Two euglycemic clamp studies, one in subjects with Type 1 diabetes (T1D) and one in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293 and Lantus commercially procured in both the European Union (EU-Lantus) and United States (US-Lantus). MATERIALS AND METHODS: Both studies were single-dose, randomized, double-blind, single-center, crossover studies with ≥7 days between dosing periods...
August 17, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28817201/exposure-response-modeling-and-power-analysis-of-components-of-acr-response-criteria-in-rheumatoid-arthritis-part-2-continuous-model
#4
Liang Li, Yi Zhang, Lian Ma, Ping Ji, Sarah Yim, Badrul A Chowdhury, Suresh Doddapaneni, Jiang Liu, Yaning Wang, Chandrahas Sahajwalla
Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure-response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender-joint count (TJC), swollen-joint count (SJC), C-reactive protein, patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, and patient's assessment of physical function for 5 biologics approved for use in rheumatoid arthritis...
September 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28817199/exposure-response-modeling-and-power-analysis-of-components-of-acr-response-criteria-in-rheumatoid-arthritis-part-1-binary-model
#5
Liang Li, Yi Zhang, Lian Ma, Ping Ji, Sarah Yim, Badrul Chowdhury, Suresh Doddapaneni, Jiang Liu, Yaning Wang, Chandrahas Sahajwalla
American College of Rheumatology (ACR) response criteria is used to assess improvement in tender and swollen joint counts and in 3 of the 5 core measures (acute-phase reactant, physician global assessment, patient global assessment, pain, and physical function). From the clinical trial data on 5 approved biological products for the treatment of rheumatoid arthritis, population pharmacokinetic/pharmacodynamic models were developed to quantitatively describe the relationship between exposure and response rates of 3 individual components of ACR response criteria...
September 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28816757/therapeutic-drug-monitoring-during-induction-of-anti-tumor-necrosis-factor-therapy-in-inflammatory-bowel-disease-defining-a-therapeutic-drug-window
#6
Konstantinos Papamichael, Niels Vande Casteele, Marc Ferrante, Ann Gils, Adam S Cheifetz
Anti-tumor necrosis factor (TNF) therapy has revolutionized the treatment of inflammatory bowel disease (IBD). However, up to 30% of patients with IBD show no clinical benefit and are defined as having a primary nonresponse. Primary nonresponse to a biologic can be attributed to either pharmacokinetic or pharmacodynamic issues, such as those involved in secondary loss of response. Pharmacokinetic issues are linked to undetectable or subtherapeutic drug concentrations because of either an accelerated non-immune-mediated clearance or immunogenicity and the development of antidrug antibodies, whereas pharmacodynamic issues are likely related to "non-TNF driven" disease...
September 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28816748/therapeutic-drug-monitoring-during-induction-of-anti-tumor-necrosis-factor-therapy-in-inflammatory-bowel-disease-defining-a-therapeutic-drug-window
#7
Konstantinos Papamichael, Niels Vande Casteele, Marc Ferrante, Ann Gils, Adam S Cheifetz
Anti-tumor necrosis factor (TNF) therapy has revolutionized the treatment of inflammatory bowel disease (IBD). However, up to 30% of patients with IBD show no clinical benefit and are defined as having a primary nonresponse. Primary nonresponse to a biologic can be attributed to either pharmacokinetic or pharmacodynamic issues, such as those involved in secondary loss of response. Pharmacokinetic issues are linked to undetectable or subtherapeutic drug concentrations because of either an accelerated non-immune-mediated clearance or immunogenicity and the development of antidrug antibodies, whereas pharmacodynamic issues are likely related to "non-TNF driven" disease...
August 14, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28816644/cyp2b6-haplotype-predicts-efavirenz-plasma-concentration-in-black-south-african-hiv-1-infected-children-a-longitudinal-pediatric-pharmacogenomic-study
#8
Riaan Reay, Collet Dandara, Michelle Viljoen, Malie Rheeders
South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa...
August 2017: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/28816632/the-liver-circadian-clock-modulates-biochemical-and-physiological-responses-to-metformin
#9
Emma Henriksson, Anne-Laure Huber, Erin K Soto, Anna Kriebs, Megan E Vaughan, Drew Duglan, Alanna B Chan, Stephanie J Papp, Madelena Nguyen, Megan E Afetian, Katja A Lamia
Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice...
August 2017: Journal of Biological Rhythms
https://www.readbyqxmd.com/read/28815798/infant-spinal-anesthesia-do-girls-need-a-larger-dose-of-local-anesthetic
#10
Geoff Frawley, Md Hamidul Huque
BACKGROUND: Gender differences in absorption, distribution, and metabolism of a number of anesthetic agents have been identified in adults. Clinically, adult studies suggest women demonstrate slower onset of opioid analgesic effects, lower spinal and epidural dose requirements, and greater sensitivity to neuromuscular blocking agents. Sex-related differences in the pharmacokinetics and pharmacodynamics of local anesthetics in neonates and infants, however, have not been well documented...
August 17, 2017: Paediatric Anaesthesia
https://www.readbyqxmd.com/read/28814243/a-pharmacokinetic-pharmacodynamic-model-of-tamoxifen-and-endoxifen-to-predict-their-distribution-and-effects-on-inhibition-of-tumor-growth
#11
Shengyue Yuan, Qingrong Sun, Yao Chen, Jun Liao
BACKGROUND: Tamoxifen is widely used in the therapy for breast cancer and has three major metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen. Endoxifen has played a major role in the inhibition of tumor growth of breast cancer and the tumor growth is related to endoxifen concentration. OBJECTIVES: The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to predict the distribution of tamoxifen and endoxifen quantitatively, and to discover the anti-tumor effect patterns of tamoxifen and endoxifen...
August 15, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28814143/ly3045697-results-from-two-randomized-clinical-trials-of-a-novel-inhibitor-of-aldosterone-synthase
#12
Joanne Sloan-Lancaster, Eyas Raddad, Amy Flynt, Yan Jin, James Voelker, Jeffrey W Miller
INTRODUCTION: LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects. MATERIALS AND METHODS: Two incomplete, placebo-controlled crossover-design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects...
July 2017: Journal of the Renin-angiotensin-aldosterone System: JRAAS
https://www.readbyqxmd.com/read/28812389/evolocumab-for-the-treatment-of-hypercholesterolemia
#13
Brian Tomlinson, Miao Hu, Yuzhen Zhang, Paul Chan, Zhong-Min Liu
Evolocumab is a fully human monoclonal immunoglobulin G2 directed against human proprotein convertase subtilisin/kexin type 9 (PCSK9). It is administered by subcutaneous injection every 2 weeks or once monthly. Area covered: Herein, the authors discuss the rationale for inhibiting PCSK9 and describe the pharmacodynamics, pharmacokinetics and clinical trials with evolocumab. Evolocumab reduces low density lipoprotein cholesterol (LDL-C) levels by 50 to 60% in most patients with and without background treatment with statins or other lipid lowering agents...
August 16, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28811125/pharmacokinetics-and-pharmacodynamics-of-thiopurines-in-an-in-vitro-model-of-human-hepatocytes-insights-from-an-innovative-mass-spectrometry-assay
#14
Marco Pelin, Elena Genova, Laura Fusco, Monzer Marisat, Ute Hofmann, Diego Favretto, Marianna Lucafò, Andrea Taddio, Stefano Martelossi, Alessandro Ventura, Gabriele Stocco, Matthias Schwab, Giuliana Decorti
AIM: To apply an innovative LC-MS/MS method to quantify thiopurine metabolites in human hepatocytes and to associate them to cytotoxicity. METHODS: Immortalized human hepatocytes (IHH cells) were treated for 48 and 96 h, with 1.4 × 10(-4) M azathioprine and 1.1 × 10(-3) M mercaptopurine, concentrations corresponding to the IC50 values calculated after 96 h exposure in previous cytotoxicity analysis. After treatments, cells were collected for LC-MS/MS analysis to quantify 11 thiopurine metabolites with different level of phosphorylation and viable cells were counted by Trypan blue exclusion assay to determine thiopurines in vitro effect on cell growth and survival...
August 12, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28811111/cell-cultures-in-drug-discovery-and-development-the-need-of-reliable-in-vitro-in-vivo-extrapolation-for-pharmacodynamics-and-pharmacokinetics-assessment
#15
REVIEW
Karol Jaroch, Alina Jaroch, Barbara Bojko
For ethical and cost-related reasons, use of animals for the assessment of mode of action, metabolism and/or toxicity of new drug candidates has been increasingly scrutinized in research and industrial applications. Implementation of the 3 "Rs"(1); rule (Reduction, Replacement, Refinement) through development of in silico or in vitro assays has become an essential element of risk assessment. Physiologically based pharmacokinetic (PBPK(2)) modeling is the most potent in silico tool used for extrapolation of pharmacokinetic parameters to animal or human models from results obtained in vitro...
July 27, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28809448/improved-pharmacokinetic-and-pharmacodynamic-attributes-of-artemether-lumefantrine-loaded-solid-smedds-for-oral-administration
#16
Sameer Bhandari, Vikram Bhandari, Jatin Sood, Sunil Jaswal, Vikas Rana, Neena Bedi, Rakesh Sehgal, Ashok K Tiwary
OBJECTIVES: To evaluate the in-vivo efficacy of solid SMEDDS containing combination of artemether and lumefantrine. METHODS: Formulation development of solid SMEDDS containing combination of artemether and lumefantrine was carried out using spray drying technique. These S-SMEDDS were evaluated for reduction in parasitemia and mortality as well as subacute toxicity in mice. Haematology, biochemical parameters and histopathology were performed for evaluating safety of formulation...
August 15, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28808915/cost-effectiveness-of-posaconazole-tablets-for-invasive-fungal-infections-prevention-in-acute-myelogenous-leukemia-or-myelodysplastic-syndrome-patients-in-spain
#17
Rafael Cámara, Irmina Gozalbo, Manuel Jurado, Jaime Sanz, Belén Aragón, Santiago Grau
INTRODUCTION: Posaconazole is superior to fluconazole (FLU) and itraconazole (ITRA) in the prevention of invasive fungal diseases (IFDs) in neutropenic patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A new tablet formulation of posaconazole with improved pharmacokinetic and pharmacodynamic properties compared to posaconazole oral solution has recently been approved. The objective of this study is to estimate the cost-effectiveness of the newly developed posaconazole tablets versus FLU oral suspension or ITRA oral solution for preventing IFDs in high-risk neutropenic patients with AML or MDS and from the perspective of the Spanish National Health System (NHS)...
August 14, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28808886/assessment-of-pharmacokinetic-interactions-between-obeticholic-acid-and-caffeine-midazolam-warfarin-dextromethorphan-omeprazole-rosuvastatin-and-digoxin-in-phase-1-studies-in-healthy-subjects
#18
Jeffrey E Edwards, Lise Eliot, Andrew Parkinson, Sharon Karan, Leigh MacConell
INTRODUCTION: Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. METHODS: Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin)...
August 14, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28808833/long-acting-ionically-paired-embonate-based-nanocrystals-of-donepezil-for-the-treatment-of-alzheimer-s-disease-a-proof-of-concept-study
#19
Naresh Mittapelly, Maharshi Thalla, Gitu Pandey, Venkatesh Teja Banala, Shweta Sharma, Abhishek Arya, Sandeep Mishra, Kalyan Mitra, Shubha Shukla, Prabhat Ranjan Mishra
PURPOSE: The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation. METHODS: D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc...
August 14, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28807911/systematic-review-and-meta-analyses-of-the-effect-of-chemotherapy-on-pulmonary-mycobacterium-abscessus-outcomes-and-disease-recurrence
#20
Jotam G Pasipanodya, Deborah Ogbonna, Beatriz E Ferro, Gesham Magombedze, Shashikant Srivastava, Devyani Deshpande, Tawanda Gumbo
Background. In pharmacokinetic/pharmacodynamics models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown.Methods We searched the literature for studies published between 1990-2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. Good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes...
August 14, 2017: Antimicrobial Agents and Chemotherapy
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