کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5855809 | 1562122 | 2016 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
An FDA oncology analysis of immune activating products and first-in-human dose selection
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کلمات کلیدی
DLTinvestigational new drug applicationRecommended phase 2 dosecytokine release assayOBDNOAELMABELHHDADCCRHDMTDNHPIRRmAbCRAEMACRSMonoclonal antibody - آنتی بادی مونوکلونالantibody-dependent cellular cytotoxicity - آنتی بادی-وابسته به سمیت سلولی سلولیEuropean Medicines agency - آژانس دارویی اروپاReceptor occupancy - اشباع گیرندهind - اندرfirst-in-human - اول در انسانMaximum tolerated dose - حداکثر دوز قابل تحملdose limiting toxicity - دوز محدودیت سمیتCytokine Release Syndrome - سندرم آزاد سازی سیتوکینFIH - شاملICH - منnon-human primate - نخستیسانان غیرانسانیPAD - پد
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Regulatory Toxicology and Pharmacology - Volume 81, November 2016, Pages 448-456
Journal: Regulatory Toxicology and Pharmacology - Volume 81, November 2016, Pages 448-456
نویسندگان
Haleh Saber, Ramadevi Gudi, Michael Manning, Emily Wearne, John K. Leighton,