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CPT: Pharmacometrics & Systems Pharmacology

Nilay Thakkar, Jeffrey T Guptill, Kathy Aleš, David Jacobus, Laura Jacobus, Charles Peloquin, Michael Cohen-Wolkowiez, Daniel Gonzalez
Lambert-Eaton Myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine free base (3,4-DAP) is an investigational orphan drug used to treat LEM-related weakness. We performed a population PK/PD analysis using 3,4-DAP and metabolite concentrations collected from a phase 2 study in LEM patients. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1270 PK samples (49 patients) and 1091 3TUG data points (32 randomized patients) were included in the PK/PD analysis...
June 17, 2017: CPT: Pharmacometrics & Systems Pharmacology
Julia Korell, Bruce Green, Bart Remmerie, An Vermeulen
Schizophrenia is a common disease managed by a range of interventions with the primary treatment being antipsychotic medications (APS). Inadequate response, lack of adherence, and/or adverse events often prevent optimal therapeutic effects or therapeutic efficiency. Monitoring APS plasma concentrations can be used together with a full clinical evaluation to help improve patient care or offer better treatment options for the patient. To enable interpretation of individual risperidone and paliperidone plasma concentrations, we developed 'reference ranges', which consider the expected variability in plasma concentrations between subjects across the population, rather than representing a 'therapeutic range' that relates to efficacy and/or safety outcomes...
June 14, 2017: CPT: Pharmacometrics & Systems Pharmacology
Sunny Chapel, Kenneth G Kowalski
No abstract text is available yet for this article.
June 9, 2017: CPT: Pharmacometrics & Systems Pharmacology
M de Kock, J Tarning, L Workman, M M Nyunt, I Adam, K I Barnes, P Denti
Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine but decreased by 18% for pyrimethamine...
June 9, 2017: CPT: Pharmacometrics & Systems Pharmacology
B Ribba, H P Grimm, B Agoram, M R Davies, K Gadkar, S Niederer, N van Riel, J Timmis, P H van der Graaf
No abstract text is available yet for this article.
June 6, 2017: CPT: Pharmacometrics & Systems Pharmacology
Ronald G Hall, Jotam G Pasipanodya, Mark A Swancutt, Claudia Meek, Richard Leff, Tawanda Gumbo
The human species is becoming increasingly obese. Dapsone, which is extensively used across the globe for dermatological disorders, arachnid bites, and for treatment of several bacterial, fungal and parasitic diseases, could be affected by obesity. We performed a clinical experiment, using optimal design, in volunteers weighing 44-150 kilograms, to identify the effect of obesity on dapsone pharmacokinetic parameters based on maximum-likelihood solution via the expectation-maximization algorithm. Artificial intelligence-based multivariate adaptive regression splines were used for covariate selection, and identified weight and/or age as predictors of absorption, systemic clearance and volume of distribution...
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
Roberto Bizzotto, Emmanuelle Comets, Gareth Smith, Florent Yvon, Niels Rode Kristensen, Maciej Swat
No abstract text is available yet for this article.
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
Siti M Sheikh Ghadzi, Mats O Karlsson, Maria C Kjellsson
In anti-hyperglycemic drug development, drug effects are usually characterized using glucose provocations. Analyzing provocation data using pharmacometrics has been shown powerful, enabling small studies. In pre-clinical drug development, high power is attractive due to the experiment sizes, however insulin is not always available, which potentially impacts power and predictive performance. This simulation study was performed to investigate the implications of performing model-based drug characterization without insulin...
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
Bruce Green, Julia Korell, Bart Remmerie, Adam Savitz, An Vermeulen
No abstract text is available yet for this article.
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
Xinyuan Zhang, John Duan, Filippos Kesisoglou, Jasmina Novakovic, Gordon Amidon, Masoud Jamei, Viera Lukacova, Thomas Eissing, Eleftheria Tsakalozou, Liang Zhao, Robert Lionberger
No abstract text is available yet for this article.
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
Sabine Pilari, Thomas Gaub, Michael Block, Linus Görlitz
We extended a generic whole-body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems, i.e., the testes and the thyroid gland. An extensive literature search was performed, firstly, to determine the most generic organ model structures for testes and thyroid across species and, secondly, to identify the corresponding anatomical and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK-Sim® and MoBi®...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
Elke H J Krekels, Ana M Novakovic, An M Vermeulen, Lena E Friberg, Mats O Karlsson
As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data, discards information and violates the numerical nature of the scale. Here, a longitudinal analysis based on item response theory (IRT) is presented using PANSS data from Phase 3 clinical trials. Latent disease severity variables were derived from item-level data on the positive, negative and general PANSS subscales each...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
M H Diekstra, A Fritsch, F Kanefendt, J J Swen, Djar Moes, F Sörgel, M Kinzig, C Stelzer, D Schindele, T Gauler, S Hauser, D Houtsma, M Roessler, B Moritz, K Mross, L Bergmann, E Oosterwijk, L A Kiemeney, H J Guchelaar, U Jaehde
The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics. Inter-individual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic and pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662 and the soluble VEGF receptors sVEGFR-2 and sVEGFR-3 were measured in 26 mRCC patients within the EuroTARGET project and 21 metastasized colorectal cancer (mCRC) patients from the C-II-005 study...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
Tatiana Karelina, Oleg Demin, Timothy Nicholas, Yasong Lu, Sridhar Duvvuri, Hugh A Barton
A mechanistic model of amyloid beta production, degradation and distribution has been constructed for mouse, monkey and human, calibrated and externally verified across multiple data sets. Simulations of single dose avagacestat treatment demonstrate that the Aβ42 brain inhibition may exceed that in CSF. The dose which achieves 50% CSF Aβ40 inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
D Rüppel, R Dahmen, A Boss, R Jäger, M Grant, R Baughman, T Klabunde
Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to capture the full effect and higher doses were not tested...
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
M Sato, Y Ochiai, S Kijima, N Nagai, Y Ando, M Shikano, Y Nomura
In Japan in October 2016, the Pharmaceuticals and Medical Devices Agency (PMDA) began to receive electronic data in new drug applications (NDAs). These electronic data are useful to conduct regulatory assessment of sponsors' submissions and contribute to the PMDA's research. In this article, we summarize the number of submissions of quantitative modeling and simulation (M&S) documents in NDAs in Japan, and we describe our current thinking and activities about quantitative M&S in PMDA.
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
Emmanuel Chigutsa, Amanda J Long, Johan E Wallin
We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase 3 study comparing necitumumab in combination with gemcitabine and cisplatin versus gemcitabine and cisplatin alone in 1014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard...
May 31, 2017: CPT: Pharmacometrics & Systems Pharmacology
S Sanche, N Sheehan, T Mesplède, M A Wainberg, J Li, F Nekka
Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance...
May 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
K M Hallow, Y Gebremichael
Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) individuals. In this study we used a systems pharmacology model of renal function (presented in a companion article) to evaluate the ability of proposed mechanisms to produce salt-sensitivity. The model reproduced previously published data on renal functional changes in response to salt-intake, and also predicted that glomerular pressure, a variable that is not easily evaluated clinically but is a key factor in renal injury, increases with salt intake in SS hypertension...
May 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
P Gennemark, M Trägårdh, D Lindén, K Ploj, A Johansson, A Turnbull, B Carlsson, M Antonsson
In this study, we present the translational modeling used in the discovery of AZD1979, a melanin-concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body-composition models to standard linear regression...
May 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
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