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1.
Blood ; 137(13): 1792-1803, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33024987

RESUMEN

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.


Asunto(s)
Aminopiridinas/uso terapéutico , Antineoplásicos/uso terapéutico , Glicina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Piridinas/uso terapéutico , Triazinas/uso terapéutico , Adulto , Anciano , Aminopiridinas/efectos adversos , Antineoplásicos/efectos adversos , Femenino , Glicina/efectos adversos , Glicina/uso terapéutico , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación/efectos de los fármacos , Piridinas/efectos adversos , Resultado del Tratamiento , Triazinas/efectos adversos , Adulto Joven
2.
Eur J Clin Pharmacol ; 75(8): 1099-1108, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31011758

RESUMEN

PURPOSE: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. METHODS: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972). RESULTS: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib Cmax. CONCLUSIONS: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.


Asunto(s)
Antineoplásicos/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Glicina/análogos & derivados , Itraconazol/farmacología , Síndrome de QT Prolongado/epidemiología , Piridinas/farmacocinética , Administración Oral , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Área Bajo la Curva , Pueblo Asiatico , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/etnología , Femenino , Interacciones Alimento-Droga/etnología , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/farmacocinética , Voluntarios Sanos , Humanos , Itraconazol/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/etiología , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Piridinas/efectos adversos
3.
Clin Pharmacol Drug Dev ; 11(4): 429-441, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35166065

RESUMEN

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib and enasidenib are oral inhibitors of mIDH1 and mIDH2, respectively. An open-label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed mIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib. Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2-HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration-time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2-HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2-HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2-HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML.


Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Adulto , Aminopiridinas , Quimioterapia de Consolidación , Glicina/análogos & derivados , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Piridinas , Triazinas
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