Abstract |
Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.
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Authors | Hisham Abdallah, Joy C Hsu, Peng Lu, Scott Fettner, Xiaoping Zhang, Wendy Douglass, Min Bao, Lucy Rowell, Gerd R Burmester, Alan Kivitz |
Journal | Journal of clinical pharmacology
(J Clin Pharmacol)
Vol. 57
Issue 4
Pg. 459-468
(04 2017)
ISSN: 1552-4604 [Electronic] England |
PMID | 27599663
(Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | © 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology. |
Chemical References |
- Antibodies, Monoclonal, Humanized
- Antirheumatic Agents
- tocilizumab
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Topics |
- Administration, Intravenous
- Adult
- Aged
- Antibodies, Monoclonal, Humanized
(administration & dosage, blood, pharmacokinetics)
- Antirheumatic Agents
(administration & dosage, blood, pharmacokinetics)
- Arthritis, Rheumatoid
(blood, drug therapy)
- Double-Blind Method
- Female
- Humans
- Injections, Subcutaneous
- Male
- Middle Aged
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