Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study
Cancer Chemotherapy and Pharmacology, ISSN: 1432-0843, Vol: 93, Issue: 5, Page: 471-479
2024
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Most Recent News
Findings from Agios Pharmaceuticals Inc. Update Knowledge of Cholangiocarcinoma (Pharmacokinetics/pharmacodynamics of Ivosidenib In Advanced idh1 -mutant Cholangiocarcinoma: Findings From the Phase Iii Claridhy Study)
2024 FEB 29 (NewsRx) -- By a News Reporter-Staff News Editor at Clinical Oncology Daily -- Investigators discuss new findings in Oncology - Cholangiocarcinoma. According
Article Description
Purpose: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population. Methods: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 − 2, pre-dose and 2 h post-dose on D15 of C1 − 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously. Results: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [T] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease). Conclusion: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma. Clinical trial registration: NCT02989857 Registered February 20, 2017.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85183168375&origin=inward; http://dx.doi.org/10.1007/s00280-023-04633-5; http://www.ncbi.nlm.nih.gov/pubmed/38278871; https://clinicaltrials.gov/ct2/show/NCT02989857; https://link.springer.com/10.1007/s00280-023-04633-5; https://dx.doi.org/10.1007/s00280-023-04633-5; https://link.springer.com/article/10.1007/s00280-023-04633-5
Springer Science and Business Media LLC
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