Intravenous tocilizumab for the treatment of giant cell arteritis: a phase Ib dose-ranging pharmacokinetic bridging study
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 ($ AUC_{τ} $), 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 $ AUC_{τ} $) 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 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schmitt, Christophe [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Giant cell arteritis |
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| Anmerkungen: |
© The Author(s) 2022 |
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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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SPR050758780 |
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| 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). 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 ($ AUC_{τ} $), 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 $ AUC_{τ} $) 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 | ||
| 650 | 4 | |a Giant cell arteritis |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Christ, Lisa |4 aut | |
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| 700 | 1 | |a Daikeler, Thomas |4 aut | |
| 700 | 1 | |a Villiger, Peter M. |4 aut | |
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