Response-Based Dosing for Ponatinib : Model-Based Analyses of the Dose-Ranging OPTIC Study
© 2023 Takeda Pharmaceutical. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
ABL1IS (≥ molecular response with 2-log reduction (MR2)). The exposure-molecular response relationship was described using a four-state, discrete-time Markov model. Time-to-event models were used to characterize the relationship between exposure and arterial occlusive events (AOEs), grade ≥ 3 neutropenia, and thrombocytopenia. Increasing systemic exposures were associated with increasing probability of transitioning from no response to ≥ MR1, and from MR1 to ≥ MR1, with odds ratios of 1.63 (95% confidence interval (CI), 1.06-2.73) and 2.05 (95% CI, 1.53-2.89) for a 15-mg dose increase, respectively. Ponatinib exposure was a significant predictor of AOEs (hazard ratio (HR) 2.05, 95% CI, 1.43-2.93, for a 15-mg dose increase). In the exposure-safety models for neutropenia and thrombocytopenia, exposure was a significant predictor of grade ≥ 3 thrombocytopenia (HR 1.31, 95% CI, 1.05-1.64, for a 15-mg dose increase). Model-based simulations predicted a clinically meaningful higher rate of ≥ MR2 response at 12 months for the 45-mg starting dose (40.4%) vs. 30-mg (34%) and 15-mg (25.2%). The exposure-response analyses supported a ponatinib starting dose of 45 mg with reduction to 15 mg at response for patients with CP-CML.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:114 |
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| Enthalten in: |
Clinical pharmacology and therapeutics - 114(2023), 2 vom: 01. Aug., Seite 413-422 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hanley, Michael J [VerfasserIn] |
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| Links: |
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| Themen: |
4340891KFS |
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| Anmerkungen: |
Date Completed 24.07.2023 Date Revised 25.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cpt.2956 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357218248 |
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| 245 | 1 | 0 | |a Response-Based Dosing for Ponatinib |b Model-Based Analyses of the Dose-Ranging OPTIC Study |
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| 520 | |a Optimizing Ponatinib Treatment in CP-CML (OPTIC) was a randomized, phase II dose-optimization trial of ponatinib in chronic phase-chronic myeloid leukemia (CP-CML) resistant to ≥ 2 tyrosine kinase inhibitors or with T315I mutation. Patients were randomized to starting doses of 45-, 30-, or 15-mg ponatinib once daily. Patients receiving 45- or 30-mg reduced to 15-mg upon achievement of ≤ 1% BCR::ABL1IS (≥ molecular response with 2-log reduction (MR2)). The exposure-molecular response relationship was described using a four-state, discrete-time Markov model. Time-to-event models were used to characterize the relationship between exposure and arterial occlusive events (AOEs), grade ≥ 3 neutropenia, and thrombocytopenia. Increasing systemic exposures were associated with increasing probability of transitioning from no response to ≥ MR1, and from MR1 to ≥ MR1, with odds ratios of 1.63 (95% confidence interval (CI), 1.06-2.73) and 2.05 (95% CI, 1.53-2.89) for a 15-mg dose increase, respectively. Ponatinib exposure was a significant predictor of AOEs (hazard ratio (HR) 2.05, 95% CI, 1.43-2.93, for a 15-mg dose increase). In the exposure-safety models for neutropenia and thrombocytopenia, exposure was a significant predictor of grade ≥ 3 thrombocytopenia (HR 1.31, 95% CI, 1.05-1.64, for a 15-mg dose increase). Model-based simulations predicted a clinically meaningful higher rate of ≥ MR2 response at 12 months for the 45-mg starting dose (40.4%) vs. 30-mg (34%) and 15-mg (25.2%). The exposure-response analyses supported a ponatinib starting dose of 45 mg with reduction to 15 mg at response for patients with CP-CML | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a ponatinib |2 NLM | |
| 650 | 7 | |a 4340891KFS |2 NLM | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 700 | 1 | |a Diderichsen, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Rich, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Largajolli, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Schindler, Emilie |e verfasserin |4 aut | |
| 700 | 1 | |a Vorog, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatakrishnan, Karthik |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Neeraj |e verfasserin |4 aut | |
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