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CPT: Pharmacometrics & Systems Pharmacology

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https://www.readbyqxmd.com/read/28548387/a-quantitative-systems-physiology-model-of-renal-function-and-blood-pressure-regulation-model-description
#1
K M Hallow, Y Gebremichael
Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses...
May 26, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28544534/time-to-event-analysis-of-polatuzumab-vedotin-induced-peripheral-neuropathy-to-assist-in-the-comparison-of-clinical-dosing-regimens
#2
D Lu, W R Gillespie, S Girish, P Agarwal, C Li, J Hirata, Y-W Chu, M Kagedal, L Leon, V Maiya, J Y Jin
Polatuzumab vedotin, an antibody-drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55-72% in patients with indolent non-Hodgkin lymphoma in a phase II study, when dosed 1.8-2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time-to-event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration...
May 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28504472/thoughtflow-standards-and-tools-for-provenance-capture-and-workflow-definition-to-support-model-informed-drug-discovery-and-development
#3
J J Wilkins, Pls Chan, J Chard, G Smith, M K Smith, M Beer, A Dunn, C Flandorfer, C Franklin, R Gomeni, L Harnisch, R Kaye, S Moodie, M L Sardu, E Wang, E Watson, K Wolstencroft, Sya Cheung
Pharmacometric analyses are complex and multifactorial. It is essential to check, track, and document the vast amounts of data and metadata that are generated during these analyses (and the relationships between them) in order to comply with regulations, support quality control, auditing, and reporting. It is, however, challenging, tedious, error-prone, and time-consuming, and diverts pharmacometricians from the more useful business of doing science. Automating this process would save time, reduce transcriptional errors, support the retention and transfer of knowledge, encourage good practice, and help ensure that pharmacometric analyses appropriately impact decisions...
May 15, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28418603/towards-quantitative-systems-pharmacology-models-of-chemotherapy-induced-neutropenia
#4
REVIEW
M Craig
Neutropenia is a serious toxic complication of chemotherapeutic treatment. For years, mathematical models have been developed to better predict hematological outcomes during chemotherapy in both the traditional pharmaceutical sciences and mathematical biology disciplines. An increasing number of quantitative systems pharmacology (QSP) models that combine systems approaches, physiology, and pharmacokinetics/pharmacodynamics have been successfully developed. Here, I detail the shift towards QSP efforts, emphasizing the importance of incorporating systems-level physiological considerations in pharmacometrics...
April 18, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28417561/population-pharmacokinetics-of-morphine-in-patients-with-nonalcoholic-steatohepatitis-nash-and-healthy-adults
#5
V Pierre, C K Johnston, B C Ferslew, Klr Brouwer, D Gonzalez
Altered expression and function of transporters in nonalcoholic steatohepatitis (NASH) patients may affect the pharmacokinetics (PK), efficacy, and safety of substrate drugs. A population pharmacokinetic (PopPK) analysis was performed to assess differences in morphine and morphine-3-glucuronide (M3G) disposition in NASH and healthy subjects. A total of 315 serum and 42 urine samples from 21 subjects (14 healthy; 7 NASH) were analyzed using NONMEM. Morphine and M3G PK were described by three- and one-compartment models, respectively...
April 18, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28398693/development-and-qualification-of-physiologically-based-pharmacokinetic-models-for-drugs-with-atypical-distribution-behavior-a-desipramine-case-study
#6
T S Samant, V Lukacova, S Schmidt
Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also accounts for the extended time to reach maximum concentration after oral dosing due to enterocyte trapping...
April 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28379643/integrating-in-vitro-modeling-and-in-vivo-approaches-to-investigate-warfarin-bioequivalence
#7
Xinyuan Zhang, Hong Wen, Jianghong Fan, Bradley Vince, Tonglei Li, Wei Gao, Minori Kinjo, Jill Brown, Wanjie Sun, Wenlei Jiang, Robert Lionberger
We demonstrate the use of modeling and simulation to investigate bioequivalence concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH have significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors, or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size and density, or dissolution rate in pH 4...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28379635/pharmacometric-modeling-of-liver-metastases-diameter-volume-and-density-and-their-relation-to-clinical-outcome-in-imatinib-treated-gist-patients
#8
Emilie Schindler, Sreenath M Krishnan, Ron H J Mathijssen, Alessandro Ruggiero, Gaia Schiavon, Lena E Friberg
Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting non-uniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastro-intestinal patients, the time-courses of liver metastases' maximum trans-axial diameters, software-calculated actual volumes (Vactual ) and calculated ellipsoidal volumes were characterized by logistic growth models, where imatinib induced a linear dose-dependent size reduction...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378945/translational-pharmacometric-evaluation-of-typical-antibiotic-broad-spectrum-combination-therapies-against-staphylococcus-aureus-exploiting-in-vitro-information
#9
Sebastian G Wicha, Wilhelm Huisinga, Charlotte Kloft
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid or vancomycin combined with meropenem against Staphylococcus aureus as the most frequent causative pathogen of severe infections. A semi-mechanistic PK-PD model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of linezolid, vancomycin and meropenem alone and in dual combinations...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378926/translational-modeling-of-drug-induced-myelosuppression-and-effect-of-pre-treatment-myelosuppression-for-azd5153-a-selective-brd4-inhibitor
#10
Teresa A Collins, Maureen Hattersley, James W T Yates, Edwin Clark, Madhu Mondal, Jerome T Mettetal
In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both QD and BID dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28378918/a-pharmacometric-framework-for-axitinib-exposure-efficacy-and-safety-in-metastatic-renal-cell-carcinoma-patients
#11
Emilie Schindler, Michael A Amantea, Mats O Karlsson, Lena E Friberg
The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, 2, 3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP) and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker time-courses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, 2 and 3 production, and VEGF degradation...
April 5, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28326681/population-pharmacokinetics-of-selumetinib-and-its-metabolite-n-desmethyl-selumetinib-in-adult-patients-with-advanced-solid-tumors-and-children-with-low-grade-gliomas
#12
Y T Patel, V M Daryani, P Patel, D Zhou, J Fangusaro, D J Carlile, P D Martin, L Aarons, C F Stewart
Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately...
March 22, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28317328/evaluating-dosage-optimality-for-tofacitinib-an-oral-janus-kinase-inhibitor-in-plaque-psoriasis-and-the-influence-of-body-weight
#13
M M Hutmacher, K Papp, S Krishnaswami, K Ito, H Tan, R Wolk, H Valdez, C Mebus, S T Rottinghaus, P Gupta
Tofacitinib is an oral Janus kinase inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure-response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established...
March 20, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28547774/population-pharmacokinetics-pharmacodynamics-and-exploratory-exposure-response-analyses-of-apixaban-in-subjects-treated-for-venous-thromboembolism
#14
W Byon, K Sweeney, C Frost, R A Boyd
Apixaban is approved for treatment of venous thromboembolism (VTE) and prevention of recurrence. Population pharmacokinetics, pharmacokinetics-pharmacodynamics (anti-FXa activity), and exposure-response (binary bleeding and thromboembolic endpoints) of apixaban in VTE treatment subjects were characterized using data from phase I-III studies. Apixaban pharmacokinetics were adequately characterized by a two-compartment model with first-order absorption and elimination. Age, sex, and Asian race had less than 25% impact on exposure, while subjects with severe renal impairment were predicted to have 56% higher exposure than the reference subject (60-year-old non-Asian male weighing 85 kg with creatinine clearance of 100 mL/min)...
May 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28425210/corrigendum-commentary-on-pharmacometrics-for-immunotherapy
#15
M J Garrido, P Berraondo, I F Trocóniz
No abstract text is available yet for this article.
April 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28375563/afir-a-dimensionless-potency-metric-for-characterizing-the-activity-of-monoclonal-antibodies
#16
A M Stein, R Ramakrishna
For monoclonal antibody (mAb) drugs, soluble targets may accumulate several thousand fold after binding to the drug. Time course data of mAb and total target is often collected and, although free target is more closely related to clinical effect, it is difficult to measure. Therefore, mathematical models of this data are used to predict target engagement. In this article, a "potency factor" is introduced as an approximation for the model-predicted target inhibition. This potency factor is defined to be the time-Averaged Free target concentration to Initial target concentration Ratio (AFIR), and it depends on three key quantities: the average drug concentration at steady state; the binding affinity; and the degree of target accumulation...
April 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28296193/investigating-transporter-mediated-drug-drug-interactions-using-a-physiologically-based-pharmacokinetic-model-of-rosuvastatin
#17
Q Wang, M Zheng, T Leil
Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (Ki ) ∼1...
April 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28188701/response-to-quantitative-prediction-of-drug-drug-interactions-involving-inhibitory-metabolites-by-physiologically-based-pharmacokinetic-models-is-it-worth
#18
LETTER
I E Templeton, Y Chen, J Mao, J Lin, H Yu, S Peters, M Shebley, M V Varma
No abstract text is available yet for this article.
April 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28109128/population-pharmacokinetics-and-pharmacodynamics-of-benralizumab-in-healthy-volunteers-and-patients-with-asthma
#19
B Wang, L Yan, Z Yao, L K Roskos
Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α, immunoglobulin G (IgG) 1 κ monoclonal antibody. We developed a population pharmacokinetic (PK)/pharmacodynamic (PD) model for benralizumab by analyzing PK and blood eosinophil count data from two healthy volunteer studies (N = 48) and four studies in patients with asthma (N = 152). Benralizumab PK was dose-proportional and adequately described by a two-compartment model with first-order elimination from the central compartment and first-order absorption from the subcutaneous dosing site...
April 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28109060/morphine-pharmacodynamics-in-mechanically-ventilated-preterm-neonates-undergoing-endotracheal-suctioning
#20
P A Välitalo, Ehj Krekels, M van Dijk, Shp Simons, D Tibboel, Caj Knibbe
To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i...
April 2017: CPT: Pharmacometrics & Systems Pharmacology
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