Ravulizumab is a monoclonal antibody IgG2/4K that specifically binds to the complement protein C5, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the C5b-9. Ravulizumab preserves the early components of complement activation that are essential for opsonisation of microorganisms and clearance of immune complexes.
Following ravulizumab treatment in both adult and paediatric complement inhibitor-naïve patients and eculizumab-experienced patients with PNH in Phase 3 studies, immediate, complete and sustained inhibition of serum free C5 (concentration of <0.5 µg/mL) was observed by the end of the first infusion and sustained throughout the entire 26-week treatment period in all patients. Immediate and complete inhibition of serum free C5 was also observed in adult and paediatric patients with aHUS by the end of the first infusion and throughout the 26-week treatment period.
The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure dependent for ravulizumab. Free C5 levels less than 0.5 µg/mL were correlated with maximal intravascular haemolysis control and complete terminal complement inhibition.
Because the route of ravulizumab administration is an intravenous infusion and the dosage form is a solution, 100% of the administered dose is considered bioavailable. The time to maximum observed concentration (tmax) is expected at the end of infusion (EOI) or soon after EOI. Therapeutic steady-state drug concentrations are reached after the first dose.
The mean (standard deviation [SD]) volume of distribution at steady state for adult patients with PNH and adult and paediatric patients with aHUS on the studied weight-based dose regimen was 5.35 (0.92) L and 5.22 (1.85) L respectively.
As an immunoglobulin gamma (IgG) monoclonal antibody, ravulizumab is expected to be metabolized in the same manner as any endogenous IgG (degraded into small peptides and amino acids via catabolic pathways), and is subject to similar elimination. Ravulizumab contains only natural occurring amino acids and has no known active metabolites. The mean (SD) values for terminal elimination half-life and clearance of ravulizumab in adult patients with PNH and adult and paediatric patients with aHUS are 49.7 (8.9) days and 0.08 (0.022) L/day and 51.8 (16.2) days and 0.08 (0.04) L/day, respectively.
Over the studied dose and regimen range, ravulizumab exhibited dose proportional and time linear pharmacokinetics (PK).
Weight: Body weight is a significant covariate in patients with PNH and aHUS, resulting in lower exposures in heavier patients.
No formal trial of the effect of sex, race, age (geriatric), hepatic or renal impairment on the pharmacokinetics of ravulizumab was conducted. However, based on population-PK assessment no impact of sex, age, race and hepatic or renal function on ravulizumab PK was identified in the studied healthy volunteers, subjects and patients with PNH or aHUS, and as a result, no dosing adjustment is considered necessary.
The pharmacokinetics of ravulizumab have been studied in aHUS patients with a range of renal impairment including patients receiving dialysis. There have been no observed differences in pharmacokinetic parameters noted in these subpopulations of patients including patients with proteinuria.
Animal reproductive toxicology studies have not been conducted with ravulizumab, but were conducted in mice with a murine surrogate complement inhibitory antibody, BB5.1. No clear treatment-related effects or adverse effects were observed in the murine surrogate reproductive toxicology studies in mice. 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 ravulizumab 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 ravulizumab.
Non-clinical data reveal no special hazard for humans based on nonclinical studies using a murine surrogate molecule, BB5.1, in mice.
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