دورية أكاديمية
أعرض في EDS

Tipifarnib physiologically-based pharmacokinetic modeling to assess drug-drug interaction, organ impairment, and biopharmaceutics in healthy subjects and cancer patients.

التفاصيل البيبلوغرافية
العنوان: Tipifarnib physiologically-based pharmacokinetic modeling to assess drug-drug interaction, organ impairment, and biopharmaceutics in healthy subjects and cancer patients.
المؤلفون: Okudaira N; Certara, UK Ltd. (Simcyp Division), Sheffield, UK., Burt H; Certara, UK Ltd. (Simcyp Division), Sheffield, UK., Mitra A; Clinical Pharmacology, Kura Oncology, Inc., Boston, Massachusetts, USA.
المصدر: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Aug; Vol. 13 (8), pp. 1366-1379. Date of Electronic Publication: 2024 May 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Wiley Country of Publication: United States NLM ID: 101580011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2163-8306 (Electronic) Linking ISSN: 21638306 NLM ISO Abbreviation: CPT Pharmacometrics Syst Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2015- : Hoboken, NJ : Wiley
Original Publication: New York, NY : Nature Pub. Group
مواضيع طبية MeSH: Drug Interactions* , Models, Biological* , Neoplasms*/drug therapy , Neoplasms*/metabolism , Quinolones*/pharmacokinetics , Quinolones*/administration & dosage, Humans ; Healthy Volunteers ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics ; Cytochrome P-450 CYP3A Inhibitors/administration & dosage ; Proton Pump Inhibitors/pharmacokinetics ; Proton Pump Inhibitors/administration & dosage ; Proton Pump Inhibitors/pharmacology ; Male ; Food-Drug Interactions ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/administration & dosage ; Cytochrome P-450 CYP3A/metabolism ; Histamine H2 Antagonists/pharmacokinetics ; Histamine H2 Antagonists/administration & dosage ; Histamine H2 Antagonists/pharmacology ; Cytochrome P-450 CYP3A Inducers/pharmacology ; Computer Simulation ; Biopharmaceutics ; Female ; Adult
مستخلص: A physiologically-based pharmacokinetic (PBPK) model for tipifarnib, which included mechanistic absorption, was built and verified by integrating in vitro data and several clinical data in healthy subjects and cancer patients. The final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations of tipifarnib in healthy subjects and cancer patients under several dosing conditions, such as co-administration with a strong CYP3A4 inhibitor and inducer, an acid-reducing agent (proton pump inhibitor and H2 receptor antagonist), and with a high-fat meal. In addition, the model was able to accurately predict the effect of mild or moderate hepatic impairment on tipifarnib exposure. The appropriately verified model was applied to prospectively simulate the liability of tipifarnib as a victim of CYP3A4 enzyme-based drug-drug interactions (DDIs) with a moderate inhibitor and inducer as well as tipifarnib as a perpetrator of DDIs with sensitive substrates of CYP3A4, CYP2B6, CYP2D6, CYP2C9, and CYP2C19 in healthy subjects and cancer patients. The effect of a high-fat meal, acid-reducing agent, and formulation change at the therapeutic dose was simulated. Finally, the model was used to predict the effect of mild, moderate, or severe hepatic, and renal impairment on tipifarnib PK. This multipronged approach of combining the available clinical data with PBPK modeling-guided dosing recommendations for tipifarnib under several conditions. This example showcases the totality of the data approach to gain a more thorough understanding of clinical pharmacology and biopharmaceutic properties of oncology drugs in development.
(© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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المشرفين على المادة: 0 (Quinolones)
0 (Cytochrome P-450 CYP3A Inhibitors)
0 (Proton Pump Inhibitors)
0 (Antineoplastic Agents)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
0 (Histamine H2 Antagonists)
0 (Cytochrome P-450 CYP3A Inducers)
تواريخ الأحداث: Date Created: 20240529 Date Completed: 20240817 Latest Revision: 20240819
رمز التحديث: 20240819
مُعرف محوري في PubMed: PMC11330181
DOI: 10.1002/psp4.13165
PMID: 38807307
قاعدة البيانات: MEDLINE
الوصف
تدمد:2163-8306
DOI:10.1002/psp4.13165