Tezepelumab is a monoclonal antibody (IgG2λ) directed against thymic stromal lymphopoietin (TSLP), preventing its interaction with the heterodimeric TSLP receptor. In asthma, both allergic and non-allergic triggers induce TSLP production. Blocking TSLP with tezepelumab reduces a broad spectrum of biomarkers and cytokines associated with airway inflammation (e.g. blood eosinophils, airway submucosal eosinophils, IgE, FeNO, IL-5, and IL-13); however, the mechanism of action of tezepelumab in asthma has not been definitively established.
In clinical trials, administration of tezepelumab 210 mg subcutaneously every 4 weeks reduced blood eosinophils counts, FeNO, IL-5 concentration, IL-13 concentration and serum IgE concentration from baseline compared with placebo. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.
In a clinical trial, administration of tezepelumab 210 mg subcutaneously every 4 weeks reduced submucosal eosinophil counts by 89% compared with a 25% reduction with placebo. Reduction was consistent regardless of baseline inflammatory biomarkers.
In NAVIGATOR, anti-drug antibodies (ADA) were detected at any time in 26 (4.9%) out of 527 patients who received tezepelumab at the recommended dosing regimen during the 52-week study period. Of these 26 patients, 10 patients (1.9% of patients treated with tezepelumab) developed treatment-emergent ADA and 1 patient (0.2% of patients treated with tezepelumab) developed neutralising antibodies. ADA titres were generally low and often transient. No evidence of ADA impact on pharmacokinetics, pharmacodynamics, efficacy, or safety was observed.
The pharmacokinetics of tezepelumab were dose-proportional following subcutaneous administration over a dose range of 2.1 mg to 420 mg.
Following a single subcutaneous administration, the maximum serum concentration was reached in approximately 3 to 10 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 77%. There was no clinically relevant difference in bioavailability when administered to different injection sites (abdomen, thigh, or upper arm).
Based on population pharmacokinetic analysis, central and peripheral volume of distribution of tezepelumab were 3.9 L and 2.2 L, respectively, for a 70 kg individual. Metabolism Tezepelumab is a human monoclonal antibody (IgG2λ) that is degraded by proteolytic enzymes widely distributed in the body and not metabolised by hepatic enzymes.
As a human monoclonal antibody, tezepelumab is eliminated by intracellular catabolism and there is no evidence of target-mediated clearance. From population pharmacokinetic analysis, the estimated clearance for tezepelumab was 0.17 L/d for a 70 kg individual. The elimination half-life was approximately 26 days.
Based on population pharmacokinetic analysis, age, gender and race had no clinically meaningful effects on the pharmacokinetics of tezepelumab.
Based on population pharmacokinetic analysis, higher body weight was associated with lower exposure. However, the effect of body weight on exposure had no meaningful impact on efficacy or safety and does not require dose adjustment.
Based on the population pharmacokinetic analysis, there was no clinically meaningful age-related difference in the pharmacokinetics of tezepelumab between adults and adolescents aged 12 to 17 years. Tezepelumab has not been studied in children under 12 years of age.
Based on population pharmacokinetic analysis, there was no clinically meaningful difference in the pharmacokinetics of tezepelumab between patients 65 years of age or older and younger patients.
No formal clinical studies have been conducted to investigate the effect of renal impairment on tezepelumab. Based on population pharmacokinetic analysis, tezepelumab clearance was similar in patients with mild renal impairment (creatinine clearance 60 to <90 mL/min), moderate renal impairment (creatinine clearance 30 to <60 mL/min) and those with normal renal function (creatinine clearance ≥90 mL/min). Tezepelumab has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min); however, tezepelumab is not cleared renally.
No formal clinical studies have been conducted to investigate the effect of hepatic impairment on tezepelumab. IgG monoclonal antibodies are not primarily cleared via hepatic pathway; change in hepatic function is not expected to influence tezepelumab clearance. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (ALT, AST, and bilirubin) had no effect on tezepelumab clearance.
Non-clinical data revealed no special hazard for humans based on repeated dose toxicity studies including safety pharmacology and fertility evaluations, and an ePPND (enhanced Pre- and Post-Natal Development) reproductive toxicity study in cynomolgus monkeys at doses of up to 300 mg/kg/week (producing exposures of greater than 100-times the clinical exposure at maximum recommended human dose [MRHD]).
Tezepelumab is excreted in milk in monkeys, although at low concentrations (<1%).
Tezepelumab is a monoclonal antibody, as such genotoxicity and carcinogenicity studies have not been conducted.
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