Eculizumab is a monoclonal antibody, a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.
In PNH patients, uncontrolled terminal complement activation and the resulting complement-mediated intravascular haemolysis are blocked with eculizumab treatment. In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/mL are sufficient for essentially complete inhibition of terminal complement-mediated intravascular haemolysis. In PNH, chronic administration of eculizumab resulted in a rapid and sustained reduction in complement-mediated haemolytic activity.
In aHUS patients, uncontrolled terminal complement activation and the resulting complement-mediated thrombotic microangiopathy are blocked with eculizumab treatment. All patients treated with eculizumab when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In all aHUS patients, eculizumab serum concentrations of approximately 50-100 microgram/mL are sufficient for essentially complete inhibition of terminal complement activity.
In aHUS, chronic administration of eculizumab resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy.
In refractory gMG patients, uncontrolled terminal complement activation causes membrane attack complex (MAC) dependent lysis and C5a-dependent inflammation at the Neuromuscular Junction (NMJ) leading to failure of neuromuscular transmission. Chronic administration of eculizumab results in immediate, complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥116 microgram/ml).
In patients with NMOSD, uncontrolled terminal complement activation caused by autoantibodies against AQP4 leads to the formation of the MAC and C5a-dependent inflammation which results in astrocyte necrosis and increased permeability of the blood brain barrier, as well as death of the surrounding oligodendrocytes and neurons. Chronic administration of eculizumab results in immediate, complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥116 microgram/ml).
Human antibodies undergo endocytotic digestion in the cells of the reticuloendothelial system. Eculizumab contains only naturally occurring amino acids and has no known active metabolites. Human antibodies are predominately catabolized by lysosomal enzymes to small peptides and amino acids.
No specific studies have been performed to evaluate the hepatic, renal, lung, or gastrointestinal routes of excretion/elimination for eculizumab. In normal kidneys, antibodies are not excreted and are excluded from filtration by their size.
In 40 patients with PNH, a 1-compartmental model was used to estimate pharmacokinetic parameters after multiple doses. Mean clearance was 0.31 ± 0.12 mL/hr/kg, mean volume of distribution was 110.3 ± 17.9 mL/kg, and mean elimination half-life was 11.3 ± 3.4 days. The steady state is achieved by 4 weeks using the PNH adult dosing regimen.
In PNH patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels above ≥ 35 microgram/mL results in essentially complete blockade of haemolytic activity in the majority of PNH patients.
A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 37 aHUS patients receiving the recommended eculizumab regimen in studies C08-002A/B and C08-003A/B. In this model, the clearance of eculizumab for a typical aHUS patient weighing 70 kg was 0.0139 L/hr and the volume of distribution was 5.6 L. The elimination half-life was 297 h (approximately 12.4 days).
The second population PK model was applied to the multiple dose PK data from 22 paediatric aHUS patients receiving the recommended eculizumab regimen in aHUS C10-003. The clearance and volume of distribution of eculizumab are weight dependent, which forms the basis for a weight categorical based dose regimen in paediatric patients. Clearance values of eculizumab in paediatric aHUS patients were 10.4, 5.3, and 2.2 mL/hr with body weight of 70, 30, and 10 kg, respectively; and the corresponding volume of distribution values were 5.23, 2.76, and 1.21 L, respectively. The corresponding elimination half-life remained almost unchanged within a range of 349 to 378 h (approximately 14.5 to 15.8 days).
The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange resulted in an approximately 50% decline in eculizumab concentrations following a 1 hour intervention and the elimination half-life of eculizumab was reduced to 1.3 hours. Supplemental dosing is recommended when eculizumab is administered to aHUS patients receiving plasma infusion or exchange.
All aHUS patients treated with eculizumab when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In aHUS patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels of approximately 50-100 microgram/ml results in essentially complete blockade of terminal complement activity in all aHUS patients.
PK parameters are consistent across PNH, aHUS, refractory gMG and NMOSD patient populations.
Pharmacodynamic activity measured by free C5 concentrations of <0.5 ug/mL, is correlated with essentially complete blockade of terminal complement activity in PNH, aHUS, refractory gMG and NMOSD patients.
Dedicated studies have not been conducted to evaluate the pharmacokinetics of eculizumab in special patient populations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment. Population PK analysis on data collected across studies in PNH, aHUS, gMG and NMOSD patients showed that gender, race, age (geriatric), or the presence of renal or hepatic impairment.function do not influence the PK of eculizumab. Body weight was a significant covariate resulting in a lower eculizumab clearance in pediatric patients requiring body weight based dosing in pediatric patients.
The pharmacokinetics of eculizumab was evaluated in Study M07-005 in PNH paediatric patients (aged from 11 to less than 18 years) and in Studies C08-002, C08-003, C09-001r and C10-003 in aHUS pediatric patients (aged 2 months to less than 18 years) with body-weight based dose regimen.
Weight was a significant covariate resulting in a lower eculizumab clearance 0.0105 L/h in the adolescent PNH patients. Dosing for paediatric patients <40 kg is based on paediatric patients with aHUS.
The specificity of eculizumab for C5 in human serum was evaluated in two in vitro studies.
The tissue cross-reactivity of eculizumab was evaluated by assessing binding to a panel of 38 human tissues. C5 expression in the human tissue panel examined in this study is consistent with published reports of C5 expression, as C5 has been reported in smooth muscle, striated muscle, and renal proximal tubular epithelium. No unexpected tissue cross-reactivity was observed.
Animal reproduction studies have not been conducted with eculizumab due to lack of pharmacologic activity in non-human species.
In a 26 week toxicity study performed in mice with a surrogate antibody directed against murine C5, treatment did not affect any of the toxicity parameters examined. Haemolytic activity during the course of the study was effectively blocked in both female and male mice.
No clear treatment-related effects or adverse effects were observed in reproductive toxicology studies in mice with a surrogate terminal complement inhibitory antibody, which was utilized to assess the reproductive safety of C5 blockade. These studies included assessment of fertility and early embryonic development, developmental toxicity, and pre and post-natal development.
When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (approximately 4 times the maximum recommended human eculizumab dose, based on a body weight comparison); however, the exposure did not increase foetal loss or neonatal death.
No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential of eculizumab.
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