FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3182904245> ?p ?o ?g. }

• W3182904245 abstract "Introduction: Paxalisib is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. Paxalisib is taken daily on a continuous basis in 28-day cycles. A phase I study (NCT01547S46) in recurrent high-grade gliomas identified an MTD of 45mg daily and is complete. This phase II study (NCT03522298) in patients with newly diagnosed GBM and an unmethylated MGMT promotor identified an MTD of 60mg daily and is now fully recruited and in follow-up. The phase I study showed paxalisib was rapidly absorbed (Tmax approx 2 hours) and displayed an approximately linear and dose proportional increase in Cmax and AUC0-24, with a half-life of approximately 18.7 hours, which is supportive of once-daily dosing. This study explores pharmacokinetics in a slightly different patient population, at an increased dose, and explores the effect of food. Methods: For all patients, on Day 1 of Cycle 1, plasma samples were collected at least 15 minutes prior to the visit dose, and then at 30 minutes, 1, 2, 3, 4, 6, 8, 24 hours post dose. In the escalation portion of the study (Stage 1), patients fasted for 10 hours pre-dose on PK days. In the expansion portion of this study (Stage 2), subjects were randomized to be fasted for 10 hours pre-dose or consume a high-fat, high-calorie meal approximately 30 minutes prior to dosing, on PK days. All samples were analyzed by a central laboratory using a validated LC/MS-MS method. Analysis was non-compartmental. Results: A total of 30 patients were dosed and PK analysis performed, 24 at the 60 mg dose (14 fasted/10 fed) and 6 at the 75mg dose (all fasted). Paxalisib was rapidly and steadily absorbed at the 60 mg and 75 mg dose levels in the fasted state, with median Tmax values of 3.50 (2-8) and 2.50 (2-4) hours post-dose respectively. The geometric mean (range) of t1/2 values for the 60 mg fasted , 60 mg fed , and 75 mg fasted dose levels were 21.3 hours (6.0-54.6), 19.6 hours (7.7-30.0), and 29.2 hours (15.0-88.2), respectively. Mean systemic exposure to paxalisib at fasted state based on AUC0-∞ increased in a manner that was slightly less than dose proportional between 60 mg and 75 mg dose levels. This is probably indicative of a saturation effect at the 75 mg dose. Systemic exposure to paxalisib increased for the 60 mg fed status compared to 60 mg fasted status. Geometric mean ratios for Cmax, AUClast, and AUC0-∞ were 1.40, 1.38, and 1.12, respectively. Conclusion: The pharmacokinetics of paxalisib in newly-diagnosed patients are similar to those in recurrent patients, and remain compatible with daily oral dosing. There is evidence that PK parameters begin to show saturation at doses higher than 60 mg, likely representing the limit of solubility of the molecule. Paxalisib demonstrates a mild food effect, which is unlikely to necessitate fasted administration in clinical practice. These data inform further ongoing studies with paxalisib and have just commenced recruitment into the pivotal GBM AGILE study (NCT03970447).Citation Format: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, Denise Damek, James S. Garner, Jeremy A. Simpson, Alan Olivero, Timothy Cloughesy. Pharmacokinetics of paxalisib in phase 2 clinical study in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB125." @default.
• W3182904245 created "2021-07-19" @default.
• W3182904245 creator A5006374240 @default.
• W3182904245 creator A5013663538 @default.
• W3182904245 creator A5021656597 @default.
• W3182904245 creator A5029581528 @default.
• W3182904245 creator A5055183757 @default.
• W3182904245 creator A5056817906 @default.
• W3182904245 creator A5062059537 @default.
• W3182904245 creator A5063511816 @default.
• W3182904245 creator A5071814678 @default.
• W3182904245 date "2021-07-01" @default.
• W3182904245 modified "2023-10-16" @default.
• W3182904245 title "Abstract LB125: Pharmacokinetics of paxalisib in phase 2 clinical study in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status" @default.
• W3182904245 doi "https://doi.org/10.1158/1538-7445.am2021-lb125" @default.
• W3182904245 hasPublicationYear "2021" @default.
• W3182904245 type Work @default.
• W3182904245 sameAs 3182904245 @default.
• W3182904245 citedByCount "0" @default.
• W3182904245 crossrefType "proceedings-article" @default.
• W3182904245 hasAuthorship W3182904245A5006374240 @default.
• W3182904245 hasAuthorship W3182904245A5013663538 @default.
• W3182904245 hasAuthorship W3182904245A5021656597 @default.
• W3182904245 hasAuthorship W3182904245A5029581528 @default.
• W3182904245 hasAuthorship W3182904245A5055183757 @default.
• W3182904245 hasAuthorship W3182904245A5056817906 @default.
• W3182904245 hasAuthorship W3182904245A5062059537 @default.
• W3182904245 hasAuthorship W3182904245A5063511816 @default.
• W3182904245 hasAuthorship W3182904245A5071814678 @default.
• W3182904245 hasConcept C112705442 @default.
• W3182904245 hasConcept C126322002 @default.
• W3182904245 hasConcept C22979827 @default.
• W3182904245 hasConcept C2776694085 @default.
• W3182904245 hasConcept C2777288759 @default.
• W3182904245 hasConcept C2777389519 @default.
• W3182904245 hasConcept C2908647359 @default.
• W3182904245 hasConcept C31760486 @default.
• W3182904245 hasConcept C71924100 @default.
• W3182904245 hasConcept C90924648 @default.
• W3182904245 hasConcept C98274493 @default.
• W3182904245 hasConcept C99454951 @default.
• W3182904245 hasConceptScore W3182904245C112705442 @default.
• W3182904245 hasConceptScore W3182904245C126322002 @default.
• W3182904245 hasConceptScore W3182904245C22979827 @default.
• W3182904245 hasConceptScore W3182904245C2776694085 @default.
• W3182904245 hasConceptScore W3182904245C2777288759 @default.
• W3182904245 hasConceptScore W3182904245C2777389519 @default.
• W3182904245 hasConceptScore W3182904245C2908647359 @default.
• W3182904245 hasConceptScore W3182904245C31760486 @default.
• W3182904245 hasConceptScore W3182904245C71924100 @default.
• W3182904245 hasConceptScore W3182904245C90924648 @default.
• W3182904245 hasConceptScore W3182904245C98274493 @default.
• W3182904245 hasConceptScore W3182904245C99454951 @default.
• W3182904245 hasLocation W31829042451 @default.
• W3182904245 hasOpenAccess W3182904245 @default.
• W3182904245 hasPrimaryLocation W31829042451 @default.
• W3182904245 hasRelatedWork W2002127959 @default.
• W3182904245 hasRelatedWork W2004706469 @default.
• W3182904245 hasRelatedWork W2080969318 @default.
• W3182904245 hasRelatedWork W2379280247 @default.
• W3182904245 hasRelatedWork W2604417740 @default.
• W3182904245 hasRelatedWork W2604484584 @default.
• W3182904245 hasRelatedWork W2899072855 @default.
• W3182904245 hasRelatedWork W2942467058 @default.
• W3182904245 hasRelatedWork W2972898444 @default.
• W3182904245 hasRelatedWork W3151787567 @default.
• W3182904245 isParatext "false" @default.
• W3182904245 isRetracted "false" @default.
• W3182904245 magId "3182904245" @default.
• W3182904245 workType "article" @default.