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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
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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...
September 15, 2016: AAPS Journal
Anne Smits, Aida Kulo, John van den Anker, Karel Allegaert
INTRODUCTION: 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...
September 21, 2016: 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; 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
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
Mahesh N Samtani, Partha Nandy, Paulien Ravenstijn, Bart Remmerie, An Vermeulen, Alberto Russu, Peter D'hoore, Ellen Z Baum, Adam Savitz, Srihari Gopal, David Hough
AIM: To prospectively select the dose of the paliperidone palmitate 3-month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1-month (PP1M) formulation previously approved for schizophrenia treatment. METHODS: Pharmacokinetic (PK) data from a 6-month interim analysis of a single dose PP3M phase-I clinical trial was integrated with a previously developed PP1M population-PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the phase-III study: the PP1M-to-PP3M dose multiplier for patients switching formulations...
June 22, 2016: British Journal of Clinical Pharmacology
G Smania, P Baiardi, A Ceci, P Magni, M Cella
Alternative designs can increase the feasibility of pediatric trials when compared to classical parallel designs (PaD). In this work we present a model-based approach based on clinical trial simulations for the comparison of PaD with the alternative sequential, crossover, and randomized withdrawal (RWD) designs. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), treatment exposures, and parameter estimate precision (EP). The crossover requires the lowest SS and TD, although it implies higher placebo and no treatment exposures...
June 2016: CPT: Pharmacometrics & Systems Pharmacology
R J Svensson, Ush Simonsson
This is the first clinical implementation of the Multistate Tuberculosis Pharmacometric (MTP) model describing fast-, slow-, and nonmultiplying bacterial states of Mycobacterium tuberculosis. Colony forming unit data from 19 patients treated with rifampicin were analyzed. A previously developed rifampicin population pharmacokinetic (PK) model was linked to the MTP model previously developed using in vitro data. Drug effect was implemented as exposure-response relationships tested at several effect sites, both alone and in combination...
May 2016: CPT: Pharmacometrics & Systems Pharmacology
E Schindler, M A Amantea, M O Karlsson, L E Friberg
Pharmacometric models were developed to characterize the relationships between lesion-level tumor metabolic activity, as assessed by the maximum standardized uptake value (SUVmax) obtained on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), tumor size, and overall survival (OS) in 66 patients with gastrointestinal stromal tumor (GIST) treated with intermittent sunitinib. An indirect response model in which sunitinib stimulates tumor loss best described the typically rapid decrease in SUVmax during on-treatment periods and the recovery during off-treatment periods...
April 2016: CPT: Pharmacometrics & Systems Pharmacology
S Mehrotra, J Gobburu
Pharmacometricians require three skills to be influential: technical, business (e.g., drug development), and soft skills (e.g., communication). Effective communication is required to translate technical and often complicated quantitative findings to interdisciplinary team members in order to influence drug development or regulatory decisions. In this tutorial, we highlight important aspects related to communicating pharmacometric analysis to influence decisions.
April 2016: CPT: Pharmacometrics & Systems Pharmacology
Roseane Costa Diniz, Andrea Martins Melo Fontenele, Luiza Helena Araújo do Carmo, Aurea Celeste da Costa Ribeiro, Fábio Henrique Silva Sales, Sally Cristina Moutinho Monteiro, Ana Karoline Ferreira de Castro Sousa
Pharmacometrics or Quantitative Pharmacology aims to quantitatively analyze the interaction between drugs and patients whose tripod: pharmacokinetics, pharmacodynamics and disease monitoring to identify variability in drug response. Being the subject of central interest in the training of pharmacists, this work was out with a view to promoting this idea on methods to access the therapeutic response of drugs with central action. This paper discusses quantitative methods (Fast Fourier Transform, Magnitude Square Coherence, Conditional Entropy, Generalised Linear semi-canonical Correlation Analysis, Statistical Parametric Network and Mutual Information Function) used to evaluate the EEG signals obtained after administration regimen of drugs, the main findings and their clinical relevance, pointing it as a contribution to construction of different pharmaceutical practice...
July 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Roberto Andrea Abbiati, Davide Manca
Background Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies. Method This article summarizes the features we recently introduced in PBPK modeling within a three-year research project funded by Italian Research Ministry...
May 24, 2016: Current Drug Delivery
Xiaoxi Liu, Yuhuan Wang
For the purpose of population pharmacometric modeling, a variety of mathematic algorithms are implemented in major modeling software packages to facilitate the maximum likelihood modeling, such as FO, FOCE, Laplace, ITS and EM. These methods are all designed to estimate the set of parameters that maximize the joint likelihood of observations in a given problem. While FOCE is still currently the most widely used method in population modeling, EM methods are getting more popular as the current-generation methods of choice because of their robustness with more complex models and sparse data structures...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
Chenhui Deng, Elodie L Plan, Mats O Karlsson
Parameter variation in pharmacometric analysis studies can be characterized as within subject parameter variability (WSV) in pharmacometric models. WSV has previously been successfully modeled using inter-occasion variability (IOV), but also stochastic differential equations (SDEs). In this study, two approaches, dynamic inter-occasion variability (dIOV) and adapted stochastic differential equations, were proposed to investigate WSV in pharmacometric count data analysis. These approaches were applied to published count models for seizure counts and Likert pain scores...
June 2016: Journal of Pharmacokinetics and Pharmacodynamics
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