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https://www.readbyqxmd.com/read/27836941/target-site-investigation-for-the-plasma-prolactin-response-mechanism-based-pharmacokinetic-pharmacodynamic-analysis-of-risperidone-and-paliperidone-in-the-rat
#1
Shinji Shimizu, Sandra M den Hoedt, Victor Mangas Sanjuan, Sinziana Cristea, Jana K Geuer, Dirk-Jan van den Berg, Robin Hartman, Francisco Bellanti, Elizabeth C M de Lange
In order to understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semi-physiologically-based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). A microdialysis study in rats was performed to obtain detailed plasma, brain extracellular fluid (brainECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-gp functioning on brain distribution, experiments were performed in absence or presence of the P-glycoprotein (P-gp) inhibitor tariquidar (TQD)...
November 11, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27832147/model-linking-plasma-and-intracellular-tenofovir-emtricitabine-with-deoxynucleoside-triphosphates
#2
Xinhui Chen, Sharon M Seifert, Jose R Castillo-Mancilla, Lane R Bushman, Jia-Hua Zheng, Jennifer J Kiser, Samantha MaWhinney, Peter L Anderson
The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy...
2016: PloS One
https://www.readbyqxmd.com/read/27779354/pharmacokinetics-and-analgesic-effectiveness-of-intravenous-parecoxib-for-tonsillectomy-%C3%A2-adenoidectomy
#3
Lena Tan, Elsa Taylor, Jacqueline A Hannam, Lesley Salkeld, Sam Salman, Brian J Anderson
BACKGROUND: Few pharmacokinetic (PK) and pharmacodynamic (PD) data exist for COX-2 selective inhibitors in children. We wished to characterize the PKPD of parecoxib and its active metabolite, valdecoxib, in this population. METHODS: Children (n = 59) were randomized to parecoxib 0.25 mg·kg(-1) , 1 mg·kg(-1) , and 2 mg·kg(-1) during tonsillectomy ± adenoidectomy. Samples (4-6 per child) were obtained from indwelling cannula over 6 h. A second group of inpatient children (n = 15) given 1 mg·kg(-1) contributed PK data from 6 to 24 h...
December 2016: Paediatric Anaesthesia
https://www.readbyqxmd.com/read/27763679/theory-based-pkpd-of-s-and-r-warfarin-and-effects-on-inr-influence-of-body-size-composition-and-genotype-in-cardiac-surgery-patients
#4
Ling Xue, Nick Holford, Xiao-Liang Ding, Zhen-Ya Shen, Chen-Rong Huang, Hua Zhang, Jing-Jing Zhang, Zhe-Ning Guo, Cheng Xie, Ling Zhou, Zhi-Yao Chen, Lin-Sheng Liu, Li-Yan Miao
AIMS: The aims of this study are to apply a theory based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population pharmacokinetic parameter with data method was used to describe the international normalized ratio (INR) time course...
October 20, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27713822/population-pharmacokinetic-and-pharmacodynamic-analyses-of-safinamide-in-subjects-with-parkinson-s-disease
#5
Luca Loprete, Chiara Leuratti, Carlo Cattaneo, Mita M Thapar, Colm Farrell, Marco Sardina
Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time)...
October 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/27713650/glibenclamide-population-pharmacokinetic-pharmacodynamic-modeling-in-south-african-type-2-diabetic-subjects
#6
Virendra Rambiritch, Poobalan Naidoo, Goonaseelan Pillai
AIM: To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients. PATIENTS AND METHODS: A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis...
2016: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/27693714/the-implications-of-model-informed-drug-discovery-and-development-for-tuberculosis
#7
Morris Muliaditan, Geraint R Davies, Ulrika S H Simonsson, Stephen H Gillespie, Oscar Della Pasqua
Despite promising advances in the field and highly effective first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokinetic-pharmacodynamic (PK/PD) relations. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development...
September 28, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27671925/how-to-optimise-drug-study-design-pharmacokinetics-and-pharmacodynamics-studies-introduced-to-paediatricians
#8
Eric Vermeulen, John N van den Anker, Oscar Della Pasqua, Kalle Hoppu, Johanna H van der Lee
OBJECTIVES: In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. METHODS: Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies...
September 27, 2016: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/27638857/combining-nonclinical-experiments-with-translational-pkpd-modeling-to-differentiate-erlotinib-and-gefitinib
#9
Miro J Eigenmann, Nicolas Frances, Gerhard Hoffmann, Thierry Lavé, Antje-Christine Walz
We quantitatively compare the efficacy of two approved EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, based on in vivo and in vitro data and show how a modeling approach can be used to scale from animal to humans. Gefitinib shows a higher tumor uptake in cancer patients, and we explored the potential impact on pharmacologic and antitumor activity in in vitro and in xenograft mice. Tumor growth inhibition was monitored, and the pharmacokinetics (PK) in plasma and tumor, as well as temporal changes of phospho-Erk (pErk) signals were examined in patient-derived tumor xenograft mice...
December 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27617278/summary-data-of-potency-and-parameter-information-from-semi-mechanistic-pkpd-modeling-of-prolactin-release-following-administration-of-the-dopamine-d2-receptor-antagonists-risperidone-paliperidone-and-remoxipride-in-rats
#10
Amit Taneja, An Vermeulen, Dymphy R H Huntjens, Meindert Danhof, Elizabeth C M De Lange, Johannes H Proost
We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, "A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats" (Taneja et al., 2016) [1]. All information is tabulated. Summary level data on the in vitro potencies and the physicochemical properties is presented in Table 1...
September 2016: Data in Brief
https://www.readbyqxmd.com/read/27614058/translating-qt-interval-prolongation-from-conscious-dogs-to-humans
#11
V F S Dubois, G Smania, H Yu, R Graf, A Chain, M Danhof, O Della Pasqua
AIM: Despite screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of pro-arrhythmic activity using a comprehensive in vitro pro-arrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. Here we evaluate the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. METHODS: Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of 9 compounds with varying QT prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymised NCEs) were analysed...
September 10, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27578330/a-whole-body-physiologically-based-pharmacokinetic-wb-pbpk-model-of-ciprofloxacin-a-step-towards-predicting-bacterial-killing-at-sites-of-infection
#12
Muhammad W Sadiq, Elisabet I Nielsen, Dalia Khachman, Jean-Marie Conil, Bernard Georges, Georges Houin, Celine M Laffont, Mats O Karlsson, Lena E Friberg
The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors...
August 30, 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27571746/pharmacokinetic-pharmacodynamic-pkpd-analysis-with-drug-discrimination
#13
S Stevens Negus, Matthew L Banks
Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location...
August 30, 2016: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/27567102/understanding-and-applying-pharmacometric-modelling-and-simulation-in-clinical-practice-and-research
#14
Joseph F Standing
Understanding the dose-concentration-effect relationship is a fundamental component of clinical pharmacology. Interpreting data arising from observations of this relationship requires the use of mathematical models; that is pharmacokinetic (PK) models to describe the relationship between dose and concentration and pharmacodynamic (PD) models describing the relationship between concentration and effect. Drug development requires several iterations of pharmacometric model-informed learning and confirming. This includes modelling to understand the dose-response in pre-clinical studies, deriving a safe dose for first-in-man, and the overall analysis of Phase I/II data to optimise the dose for safety and efficacy in Phase III pivotal trials...
August 27, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27504853/quantitative-model-for-the-blood-pressure-lowering-interaction-of-valsartan-and-amlodipine
#15
Young-A Heo, Nick Holford, Yukyung Kim, Mijeong Son, Kyungsoo Park
AIMS: The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. METHODS: PK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration...
December 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27427789/pharmacokinetic-pharmacodynamic-modelling-of-drug-induced-qtc-interval-prolongation-in-man-prediction-from-in-vitro-human-ether-%C3%A3-go-go-related-gene-binding-and-functional-inhibition-assays-and-conscious-dog-studies
#16
V F S Dubois, E Casarotto, M Danhof, O Della Pasqua
BACKGROUND AND PURPOSE: Functional measures of human ether-à-go-go-related gene (hERG; Kv 11.1) channel inhibition have been prioritized as an in vitro screening tool for candidate molecules. However, it is unclear how these results can be translated to humans. Here, we explore how data on drug binding and functional inhibition in vitro relate to QT prolongation in vivo. Using cisapride, sotalol and moxifloxacin as paradigm compounds, we assessed the relationship between drug concentrations, binding, functional measures and in vivo effects in preclinical species and humans...
October 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27330073/a-pharmacokinetic-pharmacodynamic-model-characterizing-the-emergence-of-resistant-escherichia-coli-subpopulations-during-ertapenem-exposure
#17
Wanchana Ungphakorn, Thomas Tängdén, Linus Sandegren, Elisabet I Nielsen
OBJECTIVES: Resistant subpopulations with reduced expression of outer membrane porins have been observed in ESBL-producing Escherichia coli during exposure to ertapenem. The aim of this work was to develop a pharmacokinetic-pharmacodynamic (PKPD) model to characterize the emergence of resistant E. coli during exposure to ertapenem and to predict bacterial killing following different dosing regimens of ertapenem. METHODS: Data from in vitro time-kill experiments were used to develop a mechanism-based PKPD model for three E...
September 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27269200/children-in-clinical-trials-towards-evidence-based-pediatric-pharmacotherapy-using-pharmacokinetic-pharmacodynamic-modeling
#18
Janneke M Brussee, Elisa A M Calvier, Elke H J Krekels, Pyry A J Välitalo, Dick Tibboel, Karel Allegaert, Catherijne A J Knibbe
INTRODUCTION: In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of varying ages may be anticipated, due to developmental changes occurring across pediatric life. AREAS COVERED: Beside pharmacokinetic (PK) studies, pharmacodynamic (PD) studies are urgently needed. Validated PKPD models can be used to derive optimal dosing regimens for children of different ages, which can be evaluated in a prospective study before implementation in clinical practice...
September 2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27238573/ethnic-sensitivity-assessment-of-pharmacokinetics-and-pharmacodynamics-of-omalizumab-with-dosing-table-expansion
#19
Wataru Honma, Aurélie Gautier, Ines Paule, Masayuki Yamaguchi, Philip J Lowe
A three-part license expansion for omalizumab (Xolair(®)), humanized anti-IgE antibody, was recently made in Japan for paediatric use, additional higher doses and revised dosing frequency in allergic asthma. The dosing level and frequency of omalizumab are guided by a dosing table based on the total serum IgE and bodyweight. Nonlinear mixed-effect pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation techniques described the binding between omalizumab and its target IgE. The population PKPD analysis was conducted using data from the nine studies included originally in the European application of dosing table expansion together with three Japanese clinical studies to assess the influence of the ethnicity...
June 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27186823/neutrophil-maturation-rate-determines-the-effects-of-dipeptidyl-peptidase-1-inhibition-on-neutrophil-serine-protease-activity
#20
P Gardiner, C Wikell, S Clifton, J Shearer, A Benjamin, S A Peters
BACKGROUND AND PURPOSE: Neutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model. EXPERIMENTAL APPROACH: Rats were treated with a DPP1 inhibitor twice daily for up to 14 days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response...
August 2016: British Journal of Pharmacology
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