Bin Fan, Ghassan K Abou-Alfa, Andrew X Zhu, Shuchi S Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, Hua Yang
{"title":"伊沃西地尼治疗晚期IDH1突变胆管癌的药代动力学/药效学：ClarIDHy III期研究结果。","authors":"Bin Fan, Ghassan K Abou-Alfa, Andrew X Zhu, Shuchi S Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, Hua Yang","doi":"10.1007/s00280-023-04633-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sub>max</sub>] 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).</p><p><strong>Conclusion: </strong>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.</p><p><strong>Clinical trial registration: </strong>NCT02989857 Registered February 20, 2017.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043204/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.\",\"authors\":\"Bin Fan, Ghassan K Abou-Alfa, Andrew X Zhu, Shuchi S Pandya, Hongxia Jia, Feng Yin, Camelia Gliser, Zhaowei Hua, Mohammad Hossain, Hua Yang\",\"doi\":\"10.1007/s00280-023-04633-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sub>max</sub>] 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. 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Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.
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 [Tmax] 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.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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