دورية أكاديمية
أعرض في EDS

Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor.

التفاصيل البيبلوغرافية
العنوان: Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor.
المؤلفون: Moein A; Faculty of Pharmaceutical Sciences, University of British Columbia, Office 5505, Pharmaceutical Sciences Building, Vancouver, BC, Canada.; Genentech, Inc., South San Francisco, CA, USA., Jin JY; Genentech, Inc., South San Francisco, CA, USA., Wright MR; Genentech, Inc., South San Francisco, CA, USA., Alicke B; Genentech, Inc., South San Francisco, CA, USA., Wong H; Faculty of Pharmaceutical Sciences, University of British Columbia, Office 5505, Pharmaceutical Sciences Building, Vancouver, BC, Canada. harvey.wong@ubc.ca.
المصدر: Drugs in R&D [Drugs R D] 2024 Jun; Vol. 24 (2), pp. 155-167. Date of Electronic Publication: 2024 May 03.
نوع المنشور: Clinical Trial, Phase I; Journal Article; Multicenter Study
اللغة: English
بيانات الدورية: Publisher: Adis, Springer International Country of Publication: New Zealand NLM ID: 100883647 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-6901 (Electronic) Linking ISSN: 11745886 NLM ISO Abbreviation: Drugs R D Subsets: MEDLINE
أسماء مطبوعة: Publication: Auckland : Adis, Springer International
Original Publication: Auckland ; Philadelphia : Adis International, c1999-
مواضيع طبية MeSH: Carcinoma, Renal Cell*/drug therapy , Kidney Neoplasms*/drug therapy , MTOR Inhibitors*/therapeutic use , MTOR Inhibitors*/pharmacology , MTOR Inhibitors*/pharmacokinetics , Phosphoinositide-3 Kinase Inhibitors*/pharmacokinetics , Phosphoinositide-3 Kinase Inhibitors*/pharmacology , Phosphoinositide-3 Kinase Inhibitors*/therapeutic use, Animals ; Female ; Humans ; Mice ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Neoplasms/drug therapy ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Retrospective Studies ; Xenograft Model Antitumor Assays
مستخلص: Background and Objectives: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models.
Methods: Integrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response.
Results: Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients.
Conclusions: These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development.
Trial Registry: ClinicalTrials.gov NCT00854152 and NCT00854126.
(© 2024. The Author(s).)
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سلسلة جزيئية: ClinicalTrials.gov NCT00854152; NCT00854126
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (MTOR Inhibitors)
EC 2.7.1.1 (MTOR protein, human)
0 (Phosphoinositide-3 Kinase Inhibitors)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
تواريخ الأحداث: Date Created: 20240503 Date Completed: 20240809 Latest Revision: 20240814
رمز التحديث: 20240814
مُعرف محوري في PubMed: PMC11315854
DOI: 10.1007/s40268-024-00459-5
PMID: 38700808
قاعدة البيانات: MEDLINE
الوصف
تدمد:1179-6901
DOI:10.1007/s40268-024-00459-5