Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development
© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology..
The BCR-ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model-based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration-time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed-effects modeling. Ponatinib pharmacokinetics were described by a 2-compartment model with first-order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19-85 years), race, body weight (40.7-152.0 kg), total bilirubin (0.1-3.16 mg/dL), alanine aminotransferase (6-188 U/L), albumin (23.0-52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady-state average concentrations that are in the pharmacological range for BCR-ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Journal of clinical pharmacology - 62(2022), 4 vom: 26. Apr., Seite 555-567 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hanley, Michael J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.04.2022 Date Revised 31.07.2022 published: Print-Electronic ClinicalTrials.gov: NCT01667133, NCT00660920, NCT01650805 Citation Status MEDLINE |
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| doi: |
10.1002/jcph.1990 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM332391205 |
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| 100 | 1 | |a Hanley, Michael J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development |
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| 500 | |a ClinicalTrials.gov: NCT01667133, NCT00660920, NCT01650805 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology. | ||
| 520 | |a The BCR-ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model-based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration-time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed-effects modeling. Ponatinib pharmacokinetics were described by a 2-compartment model with first-order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19-85 years), race, body weight (40.7-152.0 kg), total bilirubin (0.1-3.16 mg/dL), alanine aminotransferase (6-188 U/L), albumin (23.0-52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady-state average concentrations that are in the pharmacological range for BCR-ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a BCR-ABL | |
| 650 | 4 | |a Philadelphia chromosome | |
| 650 | 4 | |a acute lymphoblastic leukemia | |
| 650 | 4 | |a chronic myeloid leukemia | |
| 650 | 4 | |a pediatric | |
| 650 | 4 | |a pharmacokinetics | |
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| 650 | 7 | |a Pyridazines |2 NLM | |
| 650 | 7 | |a ponatinib |2 NLM | |
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| 650 | 7 | |a Fusion Proteins, bcr-abl |2 NLM | |
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| 700 | 1 | |a Diderichsen, Paul M |e verfasserin |4 aut | |
| 700 | 1 | |a Narasimhan, Narayana |e verfasserin |4 aut | |
| 700 | 1 | |a Srivastava, Shouryadeep |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Neeraj |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatakrishnan, Karthik |e verfasserin |4 aut | |
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