Interdisciplinary model-informed drug development for extending duration of elagolix treatment in patients with uterine fibroids
© 2022 AbbVie Inc and Analysis Group, Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
AIM: Elagolix, a gonadotropin-releasing hormone receptor antagonist, was recently approved for heavy menstrual bleeding associated with uterine fibroids (UF, Oriahnn) at a dose of 300 mg twice daily (BID) in combination with add-back therapy (oestradiol 1 mg/norethindrone acetate 0.5 mg [E2/NETA] once daily) for 24 months use. The limited duration of treatment is related to elagolix dose- and duration-dependent decrease in oestrogen that is mechanistically linked to changes in bone mineral density (BMD). The work herein supported the extended treatment duration of 24 months.
METHODS: An integrated exposure-response and epidemiological modelling framework of elagolix effects on femoral neck BMD (FN-BMD), informed by real-world data and phase 3 clinical trials data, was developed to predict the time course and magnitude of changes in BMD and its relation to risk of bone fracture in women with UF.
RESULTS: Model results indicated that women treated with elagolix 300 mg BID + E2/NETA in the long term (ie, >24 months) may experience less than 1% loss in FN-BMD per year, relative to placebo. The exposure-response model simulations and clinical risk factors were used to estimate 10-year risk of fractures using the clinically validated Fracture Risk Assessment Tool (FRAX). The impact of elagolix 300 mg BID + E2/NETA treatment on the 10-year risk of hip or major osteoporotic fractures estimated from the FRAX model was minimal compared to that of placebo.
CONCLUSION: The elagolix integrated exposure-BMD analysis and translation to fracture risk provided an interdisciplinary model-informed drug development framework for clinical benefit-risk evaluation and enabled approval of longer treatment duration to benefit the patient.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:88 |
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| Enthalten in: |
British journal of clinical pharmacology - 88(2022), 12 vom: 29. Dez., Seite 5257-5268 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Beck, Denise [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.11.2022 Date Revised 31.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15440 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM34217407X |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 AbbVie Inc and Analysis Group, Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a AIM: Elagolix, a gonadotropin-releasing hormone receptor antagonist, was recently approved for heavy menstrual bleeding associated with uterine fibroids (UF, Oriahnn) at a dose of 300 mg twice daily (BID) in combination with add-back therapy (oestradiol 1 mg/norethindrone acetate 0.5 mg [E2/NETA] once daily) for 24 months use. The limited duration of treatment is related to elagolix dose- and duration-dependent decrease in oestrogen that is mechanistically linked to changes in bone mineral density (BMD). The work herein supported the extended treatment duration of 24 months | ||
| 520 | |a METHODS: An integrated exposure-response and epidemiological modelling framework of elagolix effects on femoral neck BMD (FN-BMD), informed by real-world data and phase 3 clinical trials data, was developed to predict the time course and magnitude of changes in BMD and its relation to risk of bone fracture in women with UF | ||
| 520 | |a RESULTS: Model results indicated that women treated with elagolix 300 mg BID + E2/NETA in the long term (ie, >24 months) may experience less than 1% loss in FN-BMD per year, relative to placebo. The exposure-response model simulations and clinical risk factors were used to estimate 10-year risk of fractures using the clinically validated Fracture Risk Assessment Tool (FRAX). The impact of elagolix 300 mg BID + E2/NETA treatment on the 10-year risk of hip or major osteoporotic fractures estimated from the FRAX model was minimal compared to that of placebo | ||
| 520 | |a CONCLUSION: The elagolix integrated exposure-BMD analysis and translation to fracture risk provided an interdisciplinary model-informed drug development framework for clinical benefit-risk evaluation and enabled approval of longer treatment duration to benefit the patient | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Chiuve, Stephanie E |e verfasserin |4 aut | |
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| 700 | 1 | |a Shebley, Mohamad |e verfasserin |4 aut | |
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