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María J Garrido, Pedro Berraondo, Iñaki F Trocóniz
No abstract text is available yet for this article.
December 20, 2016: CPT: Pharmacometrics & Systems Pharmacology
Julia F Slejko, Richard J Willke, Jakob Ribbing, Peter Milligan
BACKGROUND: A model-based meta-analysis (MBMA) is a type of meta-regression that uses nonlinear mixed-effects models estimated on trial-level data to relate patient and trial characteristics, dosing, biomarkers, and outcomes of treatment. OBJECTIVES: To use a pharmacometric MBMA within a pharmacoeconomic model of chronic obstructive pulmonary disease (COPD). METHODS: A Markov microsimulation model was developed to estimate monthly changes in the key disease severity metrics of COPD (forced expiratory volume in 1 second [FEV1] and exacerbations) to compare a hypothetical drug that increases FEV1 to usual care...
December 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Thi-Huyen-Tram Nguyen, Mohamad-Samer Mouksassi, Nick Holford, Nidal Al-Huniti, Immanuel Freedman, Andrew C Hooker, Jyothy John, Mats O Karlsson, Diane R Mould, Juan José Pérez Ruixo, Elodie L Plan, Rada Savic, Johan G C van Hasselt, Benjamin Weber, Chenguang Zhou, Emmanuelle Comets, France Mentré
This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEM), from the ISoP Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons and recalls the definition of metrics used. This article is protected by copyright...
November 24, 2016: CPT: Pharmacometrics & Systems Pharmacology
Nopphon Siranart, Eleanor A Blakely, Alden Cheng, Naval Handa, Rainer K Sachs
Complex mixed radiation fields exist in interplanetary space, and little is known about their late effects on space travelers. In silico synergy analysis default predictions are useful when planning relevant mixed-ion-beam experiments and interpreting their results. These predictions are based on individual dose-effect relationships (IDER) for each component of the mixed-ion beam, assuming no synergy or antagonism. For example, a default hypothesis of simple effect additivity has often been used throughout the study of biology...
December 2016: Radiation Research
Hien Tinh Tran, Nicholas J White, Thuy-Nhien Thanh Nguyen, Hoa Thi Nhu, Thuan Duc Phung, Joel Tarning, François Nosten, Baldur Magnusson, Jay Prakash Jain, Kamal Hamed
The minimum inhibitory concentration (MIC) of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure cure of malaria the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate polymerase chain reaction quantitation of low-density malaria parasitemia enables prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects, and now allows identification of the in-vivo MIC...
November 21, 2016: Antimicrobial Agents and Chemotherapy
S B Duffull
The framework for systems pharmacology style models does not naturally sit with the usual scientific dogma of parsimony and falsifiability based on deductive reasoning. This does not invalidate the importance or need for overarching models based on pharmacology to describe and understand complicated biological systems. However, it does require some consideration on how systems pharmacology fits into the overall scientific approach.
December 2016: CPT: Pharmacometrics & Systems Pharmacology
Fahima Nekka, Chantal Csajka, Mélanie Wilbaux, Sachin Sanduja, Jun Li, Marc Pfister
The healthcare system is experiencing a paradigm shift in delivering its services, evolving from a reactive 'one size-fits-all' structure to a patient-centric model focusing on individualized medicine. This change is driven by scientific progress, including quantitative evaluation and optimization of treatment strategies through pharmacometric approaches, harnessing the power of the digital revolution. Areas covered: This review describes four main steps to apply pharmacometrics-based decision support tools, consisting of validated scientific components, available technical options, consideration of regulatory aspects, and achievement of efficient commercialization...
January 2017: Expert Review of Clinical Pharmacology
Jason D Robarge, Ingrid F Metzger, Jessica Lu, Nancy Thong, Todd C Skaar, Zeruesenay Desta, Robert R Bies
Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6 While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported...
January 2017: Antimicrobial Agents and Chemotherapy
V R Knight-Schrijver, V Chelliah, L Cucurull-Sanchez, N Le Novère
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response...
2016: Computational and Structural Biotechnology Journal
Luka Verrest, Thomas P C Dorlo
INTRODUCTION: Neglected tropical diseases (NTDs) affect more than one billion people, mainly living in developing countries. For most of these NTDs, treatment is suboptimal. To optimize treatment regimens, clinical pharmacokinetic studies are required where they have not been previously conducted to enable the use of pharmacometric modeling and simulation techniques in their application, which can provide substantial advantages. OBJECTIVES: Our aim was to provide a systematic overview and summary of all clinical pharmacokinetic studies in NTDs and to assess the use of pharmacometrics in these studies, as well as to identify which of the NTDs or which treatments have not been sufficiently studied...
October 15, 2016: Clinical Pharmacokinetics
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
Daniele Ouellet, Mirjam N Trame, Brian Corrigan
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
C J Musante, D R Abernethy, S R Allerheiligen, D A Lauffenburger, M G Zager
Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics. As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal.
September 2016: CPT: Pharmacometrics & Systems Pharmacology
A M Novakovic, E H J Krekels, A Munafo, S Ueckert, M O Karlsson
In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients' (unobserved) disability using a logistic model...
January 2017: AAPS Journal
Anne Smits, Aida Kulo, John van den Anker, Karel Allegaert
For safe and effective use of antibacterial agents in neonates, specific knowledge on the pharmacokinetics (PK) and its covariates is needed. This necessitates a stepwise approach, including prospective validation. Areas covered: We describe our approach throughout almost two decades to improve amikacin exposure in neonates. A dosing regimen has been developed and validated using pharmacometrics, considering current weight, postnatal age, perinatal asphyxia, and ibuprofen use. This regimen has been developed based on clinical and therapeutic drug monitoring (TDM) data collected during routine care, and subsequently underwent prospective validation...
February 2017: Expert Opinion on Drug Metabolism & Toxicology
Marc Lavielle, Benjamin Ribba
PURPOSE: For nonlinear mixed-effects pharmacometric models, diagnostic approaches often rely on individual parameters, also called empirical Bayes estimates (EBEs), estimated through maximizing conditional distributions. When individual data are sparse, the distribution of EBEs can "shrink" towards the same population value, and as a direct consequence, resulting diagnostics can be misleading. METHODS: Instead of maximizing each individual conditional distribution of individual parameters, we propose to randomly sample them in order to obtain values better spread out over the marginal distribution of individual parameters...
September 7, 2016: Pharmaceutical Research
A Chevance, A-M Jacques, M Laurentie, P Sanders, J Henri
Harmonization of the method for calculating the withdrawal period for milk dates from the 1990s. European harmonization has led to guidance with three accepted methods for determining the withdrawal period for milk that are currently applicable. These three methods can be used by marketing authorization holders, but, in some cases, their diversity can lead to very different withdrawal periods. This is particularly the case when concentrations in milk are nonmonotonic and heterogeneous, meaning that concentrations strictly increase and then strictly decrease with significant interindividual variability in the time to reach the maximal concentration...
September 7, 2016: Journal of Veterinary Pharmacology and Therapeutics
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; i.e. 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 preclinical 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
Zoe Rogers, Hiwot Hiruy, Jotam G Pasipanodya, Chris Mbowane, John Adamson, Lihle Ngotho, Farina Karim, Prakash Jeena, William Bishai, Tawanda Gumbo
N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (Vmax) and affinity (Km) in children 0-10years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS), to identify factors predicting NAT2 Vmax and Km by examining clinical, genetic, and laboratory factors in toto...
September 2016: EBioMedicine
J Henri, A-M Jacques, P Sanders, A Chevance, M Laurentie
The assessment of withdrawal periods for milk is affected by the occurrence of data below the lower analytical quantification limit (BLQ data) and the resulting uncertainty. The current regulatory approach for dealing with BLQ residues is simple and easy: BLQ data (and missing data) are arbitrarily reassigned a value of one-half the LOQ before any calculation on the data with one of the three currently applicable methods. Here, we reconsider the determination of the withdrawal period of milk with data below the limit of quantification...
July 31, 2016: Journal of Veterinary Pharmacology and Therapeutics
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