Dataset Information

Exposure-Response-Based Product Profile-Driven Clinical Utility Index for Ipatasertib Dose Selection in Prostate Cancer.

ABSTRACT: The aims of this work were to characterize ipatasertib exposure-response (E-R) relationships in a phase II study and to quantitatively assess benefit-risk using a clinical utility index approach to support ipatasertib phase III dose selection in patients with metastatic castration-resistant prostate cancer. Logistic regression and Cox proportional-hazards models characterized E-R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose interruptions/reductions (modifications) were tested in the E-R models. Despite a steeper E-R relationship when accounting for dose modifications, similar dose-response projections were generated. The clinical utility index analysis assessed important attributes, weights, and clinically meaningful cutoff/tradeoff values based on predefined minimal, target, and optimistic product profiles. Ipatasertib 400 mg daily, showing the highest probability of achieving the minimal product profiles and better benefit-risk balance than other doses (200-500 mg daily), was selected for further development in metastatic castration-resistant prostate cancer.

SUBMITTER: Zhu R

PROVIDER: S-EPMC6482275 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Exposure-Response-Based Product Profile-Driven Clinical Utility Index for Ipatasertib Dose Selection in Prostate Cancer.

Zhu Rui R Poland Bill B Wada Russ R Liu Qi Q Musib Luna L Maslyar Daniel D Cho Eunpi E Yu Wei W Ma Han H Jin Jin Yan JY Budha Nageshwar N

CPT: pharmacometrics & systems pharmacology 20190306 4

The aims of this work were to characterize ipatasertib exposure-response (E-R) relationships in a phase II study and to quantitatively assess benefit-risk using a clinical utility index approach to support ipatasertib phase III dose selection in patients with metastatic castration-resistant prostate cancer. Logistic regression and Cox proportional-hazards models characterized E-R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose int ...[more]

PMID: 30762302

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Project description:Reduction of radiation dose in x-ray imaging has been recognized as a high priority in the medical community. Here the authors show that a regional adaptive exposure method can reduce dose-area product (DAP) in x-ray fluoroscopy. The authors' method is particularly geared toward providing dose savings for the pediatric population.The scanning beam digital x-ray system uses a large-area x-ray source with 8000 focal spots in combination with a small photon-counting detector. An imaging frame is obtained by acquiring and reconstructing up to 8000 detector images, each viewing only a small portion of the patient. Regional adaptive exposure was implemented by varying the exposure of the detector images depending on the local opacity of the object. A family of phantoms ranging in size from infant to obese adult was imaged in anteroposterior view with and without adaptive exposure. The DAP delivered to each phantom was measured in each case, and noise performance was compared by generating noise arrays to represent regional noise in the images. These noise arrays were generated by dividing the image into regions of about 6 mm(2), calculating the relative noise in each region, and placing the relative noise value of each region in a one-dimensional array (noise array) sorted from highest to lowest. Dose-area product savings were calculated as the difference between the ratio of DAP with adaptive exposure to DAP without adaptive exposure. The authors modified this value by a correction factor that matches the noise arrays where relative noise is the highest to report a final dose-area product savings.The average dose-area product saving across the phantom family was (42 ± 8)% with the highest dose-area product saving in the child-sized phantom (50%) and the lowest in the phantom mimicking an obese adult (23%).Phantom measurements indicate that a regional adaptive exposure method can produce large DAP savings without compromising the noise performance in the image regions with highest noise.

Project description:BACKGROUND:Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH, such as Roundup, pose a particular health risk to liver and kidneys although low environmentally relevant doses have not been examined. To address this issue, a 2-year study in rats administering 0.1 ppb Roundup (50 ng/L glyphosate equivalent) via drinking water (giving a daily intake of 4 ng/kg bw/day of glyphosate) was conducted. A marked increased incidence of anatomorphological and blood/urine biochemical changes was indicative of liver and kidney structure and functional pathology. In order to confirm these findings we have conducted a transcriptome microarray analysis of the liver and kidneys from these same animals. RESULTS:The expression of 4224 and 4447 transcript clusters (a group of probes corresponding to a known or putative gene) were found to be altered respectively in liver and kidney (p < 0.01, q < 0.08). Changes in gene expression varied from -3.5 to 3.7 fold in liver and from -4.3 to 5.3 in kidneys. Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. Pathway analysis suggests a modulation of the mTOR and phosphatidylinositol signalling pathways. Gene disturbances associated with the chronic administration of ultra-low dose Roundup reflect a liver and kidney lipotoxic condition and increased cellular growth that may be linked with regeneration in response to toxic effects causing damage to tissues. Observed alterations in gene expression were consistent with fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with and thus confirm observations of pathology made at an anatomical, histological and biochemical level. CONCLUSION:Our results suggest that chronic exposure to a GBH in an established laboratory animal toxicity model system at an ultra-low, environmental dose can result in liver and kidney damage with potential significant health implications for animal and human populations.

Dataset Information

Exposure-Response-Based Product Profile-Driven Clinical Utility Index for Ipatasertib Dose Selection in Prostate Cancer.

Publications

Exposure-Response-Based Product Profile-Driven Clinical Utility Index for Ipatasertib Dose Selection in Prostate Cancer.

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