Monoclonal antibodies for severe asthma: Pharmacokinetic profiles

Abstract

Several monoclonal antibodies (mAbs) (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) are currently approved for the treatment of severe asthma. They have complex pharmacokinetic profiles. These profiles are unique in that they are dependent on their structure as well as can be markedly influenced by the biology of their target antigen, but their general behaviour can still be considered a class property, similar to their endogenous IgG counterpart. They cannot be administered by oral route, have a slow distribution into tissue, are metabolized to peptides and amino acids in several tissues but are protected from degradation by binding to protective receptors (the FcRn), which explains their long elimination half-lives. Their clearance is nonlinear because of the saturation of the target-mediated elimination. Also anti-drug antibody (ADA) response and off-target binding, as well as their glycosylation pattern, can influence the pharmacokinetics of mAbs.

The first‐in‐human study of CNTO 7160, an anti‐interleukin‐33 receptor monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis

“…In contrast, dupilumab, a humanized anti-IL-4 receptor-α monoclonal antibody, exhibited nonlinear target-mediated PK similar to CNTO 7160, with exposures increasing in a greater than dose-proportional manner, and its elimination half-life depeding on the dose level. 21,22 Overall, the incidence of CNTO 7160-induced ADAs was low in this first-in-human study. The low CNTO 7160-induced ADAs was F I G U R E 4 Mean (standard deviation) percent predicted forced expiratory volume in the first second (FEV1) change from baseline-time profiles after biweekly CNTO 7160 IV infusions in patients with asthma F I G U R E 5 Mean (standard deviation) change from baseline in SCORing Atopic Dermatitis (SCORAD) scores after biweekly CNTO 7160 IV infusions in patients with atopic dermatitis consistent with that of other monoclonal antibodies (including omalizumab, mepolizumab, benralizumab and reslizumab) approved for the treatment of asthma.…”

“…The mean V z values across the 0.01 to 10 mg/kg groups were similar to blood volume and comparable to those reported for human IgG monoclonal antibodies. 21,22 These findings indicate that CNTO 7160 may be distributed mostly within the vascular compartment. The mean half-life of CNTO 7160 after 3 or 10 mg/kg multiple IV doses in asthma and atopic dermatitis patients ranged from approximately 13 to 18 days, which was comparable to that of benralizumab, a humanized monoclonal antibody of the IgG 1 class which binds IL-5Ra, with a mean elimination half-life of about 7-16 days at doses of 0.03 and 3 mg/kg IV and 25-200 mg SC in asthma patients.…”

“…However, mean CL values across the healthy subject CNTO 7160 1 to 10 mg/kg dose groups were similar and fell within the range of CL values for IgG-based monoclonal antibodies that are approved for treatment of asthma or atopic dermatitis such as omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. 21,22 It is possible that the relatively constant CL of CNTO 7160 at higher doses (3 and 10 mg/kg) is due to target (IL-33R) saturation. The mean V z values across the 0.01 to 10 mg/kg groups were similar to blood volume and comparable to those reported for human IgG monoclonal antibodies.…”

“…The mean half-life of CNTO 7160 after 3 or 10 mg/kg multiple IV doses in asthma and atopic dermatitis patients ranged from approximately 13 to 18 days, which was comparable to that of benralizumab, a humanized monoclonal antibody of the IgG 1 class which binds IL-5Ra, with a mean elimination half-life of about 7-16 days at doses of 0.03 and 3 mg/kg IV and 25-200 mg SC in asthma patients. 21,22 The PK of benralizumab was approximately doseproportional in patients with asthma following subcutaneous administration over a dose range of 20-200 mg. In contrast, dupilumab, a humanized anti-IL-4 receptor-α monoclonal antibody, exhibited nonlinear target-mediated PK similar to CNTO 7160, with exposures increasing in a greater than dose-proportional manner, and its elimination half-life depeding on the dose level.…”

How do biologicals and other novel therapies effect clinically used biomarkers in severe asthma?

“…If the level of a treatment-responsive biomarker has fallen on a targeted therapy, this confirms that the treatment is having its expected biological effect, and the lack of clinical improvement should prompt consideration of other factors responsible for treatment failure. In contrast, if the treatment-responsive biomarker has not fallen, this may indicate that drug doses are insufficient, 27 that blocking antibodies have developed, 28,29 or that other explanations need to be considered.…”