Reslizumab is a humanised monoclonal antibody (IgG4, κ) against the human interleukin-5 (IL-5). Reslizumab binds specifically to IL-5 and interferes with IL-5 binding to its cell-surface receptor. IL-5 is a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. Reslizumab binds human IL-5 with picomolar affinity blocking its biological function; consequently survival and activity of eosinophils are reduced.
The effect of reslizumab in patients with asthma and elevated sputum eosinophil counts (at least 3%) was evaluated in a 15-week, phase 2, randomised, double-blind, placebo-controlled clinical study with reslizumab 3 mg/kg. Sputum eosinophils were measured in a subset of 38 adult patients at the end of therapy. In this study, the percentage of sputum eosinophils was reduced from a mean baseline value of 17.4% (standard deviation: 15.9%) by 82% at end of therapy in the reslizumab group.
In clinical Studies I and II with reslizumab 3 mg/kg, decreases in blood eosinophil counts were seen following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. In pooled data, mean eosinophil counts were 655 µL-1 (n=476) and 654 µL-1 (n=477) for the placebo and reslizumab treatment groups at baseline and were 514 µL-1 (n=405) and 61 µL-1 (n=407) at week 52. Eosinophils began to return towards baseline in those reslizumab patients completing a 90-day follow-up assessment (394 µL-1, n=36). Decreases in blood eosinophils were related to reslizumab levels.
The reduction in blood eosinophil counts by reslizumab in anti-reslizumab antibody-positive patients was not different from patients who were anti-reslizumab antibody-negative.
Peak serum concentrations of approximately 80 µg/mL are typically observed at the end of the infusion. Serum reslizumab concentrations generally decline from peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulate approximately 1.5- to 1.9-fold. No apparent deviation from dose-proportional reslizumab pharmacokinetics was noted over the dose range of 0.3 mg/kg to 3.0 mg/kg. Inter-individual variability in peak and overall exposure is approximately 20-30%.
Based on population pharmacokinetic analysis, systemic exposure to reslizumab appears to be unaffected by circulating anti-reslizumab antibodies.
Reslizumab has a volume of distribution of approximately 5 L, suggesting minimal distribution to the extravascular tissues.
In common with other monoclonal antibodies, reslizumab is believed to be degraded by enzymatic proteolysis into small peptides and amino acids. As reslizumab binds to a soluble target, linear non-target-mediated clearance is expected.
Reslizumab clearance is approximately 7 mL/hour. Reslizumab has a half-life of about 24 days.
The pharmacokinetics of reslizumab was similar in adults (18-65 years of age; n=759) and elderly patients (greater than 65 years of age; n=30).
The range of systemic exposures in patients from 12 to less than 18 years of age (n=15) overlapped that in the other groups although the median value was slightly lower than in adult patients (18-65 years of age; n=759) and elderly patients (greater than 65 years of age; n=30).
The pharmacokinetics of reslizumab was not significantly different between males and females.
Reslizumab has not been studied in patients with hepatic impairment. No direct effect of hepatic function on the pharmacokinetics of reslizumab is expected because antibodies are principally cleared by catabolism. In a population pharmacokinetic analysis, patients were classified by baseline liver function levels. Most patients had normal liver function tests (n=766, approximately 95%) or mildly increased liver function tests (either, in the first case, total bilirubin above the upper limit of normal [ULN] but less than or equal to 1.5 times the ULN or, in the second case, aspartate aminotransferase greater than the ULN and total bilirubin less than or equal to the ULN; n=35, approximately 4%). No significant difference in the pharmacokinetics of reslizumab was observed across these groups.
Reslizumab is an antibody with a molecular mass of 147 kDaltons and is therefore not expected to be excreted in urine. Most patients in the population pharmacokinetic analysis had normal renal function (estimated glomerular filtration rate [eGFR]) greater than or equal to 90 mL/min/1.73 m²; n=294, approximately 37%), mild renal impairment (eGFR 60-89 mL/min/1.73 m²; n=446, approximately 56%), or moderate renal impairment (eGFR 30-59 mL/min/1.73 m²; n=63, approximately 8%). No noteworthy differences in the pharmacokinetics of reslizumab were observed across these renal function groups. Reslizumab has not been studied in patients with severe renal impairment or end stage renal disease.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
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