Intravenous tocilizumab for the treatment of giant cell arteritis : a phase Ib dose-ranging pharmacokinetic bridging study
© 2022. The Author(s)..
BACKGROUND: Subcutaneous tocilizumab (TCZ SC) is approved globally for giant cell arteritis (GCA). This phase Ib study investigated the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of intravenous (IV) TCZ 6 and 7 mg/kg in patients with GCA. This study explored an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA).
METHODS: Patients with GCA who had received ≥ 5 doses of TCZ IV 8 mg/kg Q4W and achieved remission were enrolled. Patients received 5 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, 5 doses of 6 mg/kg Q4W in period 2. Pharmacokinetic endpoints were maximum concentration (Cmax), minimum concentration (Ctrough), area under the curve over a dosing interval (AUCτ), and mean concentration (Cmean) of TCZ after the last dose of each period. Other endpoints included pharmacodynamic markers, safety, and exploratory efficacy.
RESULTS: In 24 patients, the median (range) age was 65.5 (57-90) years, and 62.5% were female. TCZ exposures (Cmax and AUCτ) were 11.2% and 20.0% lower at the 6- than 7-mg/kg dose. The mean interleukin 6 (IL-6) serum concentrations were elevated at baseline and remained elevated, with slightly higher concentrations in period 1 than in period 2. The mean serum soluble IL-6 receptor concentrations were elevated at baseline and comparable between the 2 doses at steady state. C-reactive protein levels and most erythrocyte sedimentation rates were within normal ranges throughout the study. Overall, 22 patients (91.7%) had ≥ 1 adverse event, and 4 (16.7%) had a serious adverse event. No patients experienced a GCA flare, and all remained in remission throughout the study.
CONCLUSIONS: Both doses of TCZ IV Q4W were generally well tolerated in patients with GCA. The Cmax and Cmean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those in patients with RA treated with 8 mg/kg IV Q4W, and Ctrough was within the range observed in patients with GCA treated with SC dosing every week or every 2 weeks.
TRIAL REGISTRATION: ClinicalTrials.gov , NCT03923738.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Arthritis research & therapy - 24(2022), 1 vom: 04. Juni, Seite 133 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schmitt, Christophe [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.06.2022 Date Revised 16.07.2022 published: Electronic ClinicalTrials.gov: NCT03923738 Citation Status MEDLINE |
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| doi: |
10.1186/s13075-022-02815-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM341811890 |
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| 245 | 1 | 0 | |a Intravenous tocilizumab for the treatment of giant cell arteritis |b a phase Ib dose-ranging pharmacokinetic bridging study |
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| 500 | |a Date Completed 08.06.2022 | ||
| 500 | |a Date Revised 16.07.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03923738 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a BACKGROUND: Subcutaneous tocilizumab (TCZ SC) is approved globally for giant cell arteritis (GCA). This phase Ib study investigated the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of intravenous (IV) TCZ 6 and 7 mg/kg in patients with GCA. This study explored an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA) | ||
| 520 | |a METHODS: Patients with GCA who had received ≥ 5 doses of TCZ IV 8 mg/kg Q4W and achieved remission were enrolled. Patients received 5 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, 5 doses of 6 mg/kg Q4W in period 2. Pharmacokinetic endpoints were maximum concentration (Cmax), minimum concentration (Ctrough), area under the curve over a dosing interval (AUCτ), and mean concentration (Cmean) of TCZ after the last dose of each period. Other endpoints included pharmacodynamic markers, safety, and exploratory efficacy | ||
| 520 | |a RESULTS: In 24 patients, the median (range) age was 65.5 (57-90) years, and 62.5% were female. TCZ exposures (Cmax and AUCτ) were 11.2% and 20.0% lower at the 6- than 7-mg/kg dose. The mean interleukin 6 (IL-6) serum concentrations were elevated at baseline and remained elevated, with slightly higher concentrations in period 1 than in period 2. The mean serum soluble IL-6 receptor concentrations were elevated at baseline and comparable between the 2 doses at steady state. C-reactive protein levels and most erythrocyte sedimentation rates were within normal ranges throughout the study. Overall, 22 patients (91.7%) had ≥ 1 adverse event, and 4 (16.7%) had a serious adverse event. No patients experienced a GCA flare, and all remained in remission throughout the study | ||
| 520 | |a CONCLUSIONS: Both doses of TCZ IV Q4W were generally well tolerated in patients with GCA. The Cmax and Cmean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those in patients with RA treated with 8 mg/kg IV Q4W, and Ctrough was within the range observed in patients with GCA treated with SC dosing every week or every 2 weeks | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrials.gov , NCT03923738 | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Giant cell arteritis | |
| 650 | 4 | |a Intravenous | |
| 650 | 4 | |a Pharmacodynamics | |
| 650 | 4 | |a Pharmacokinetics | |
| 650 | 4 | |a Safety | |
| 650 | 4 | |a Tocilizumab | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 650 | 7 | |a tocilizumab |2 NLM | |
| 650 | 7 | |a I031V2H011 |2 NLM | |
| 700 | 1 | |a Brockwell, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Giraudon, Mylène |e verfasserin |4 aut | |
| 700 | 1 | |a Zucchetto, Mauro |e verfasserin |4 aut | |
| 700 | 1 | |a Christ, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Bannert, Bettina |e verfasserin |4 aut | |
| 700 | 1 | |a Daikeler, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Villiger, Peter M |e verfasserin |4 aut | |
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