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Model-based clinical pharmacology profiling and exposure-response relationships of the efficacy and biomarker of lebrikizumab in patients with moderate-to-severe asthma.
- Source :
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Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2017 Oct; Vol. 46, pp. 88-98. Date of Electronic Publication: 2017 Aug 24. - Publication Year :
- 2017
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Abstract
- Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV <subscript>1</subscript> ], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day <superscript>-1</superscript> for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV <subscript>1</subscript> and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV <subscript>1</subscript> and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients.<br /> (Copyright © 2017 Genentech, Inc. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Anti-Asthmatic Agents pharmacokinetics
Anti-Asthmatic Agents pharmacology
Antibodies, Monoclonal pharmacokinetics
Antibodies, Monoclonal pharmacology
Asthma physiopathology
Biological Availability
Biomarkers metabolism
Forced Expiratory Volume
Half-Life
Humans
Nitric Oxide metabolism
Randomized Controlled Trials as Topic
Severity of Illness Index
Anti-Asthmatic Agents administration & dosage
Antibodies, Monoclonal administration & dosage
Asthma drug therapy
Models, Biological
Subjects
Details
- Language :
- English
- ISSN :
- 1522-9629
- Volume :
- 46
- Database :
- MEDLINE
- Journal :
- Pulmonary pharmacology & therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 28843617
- Full Text :
- https://doi.org/10.1016/j.pupt.2017.08.010