Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B cells.
CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells.
The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The capacity of B-cell reconstitution and preexisting humoral immunity are preserved. In addition, innate immunity and total T-cell numbers are not affected.
Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 14 days post treatment (first time-point of assessment) as an expected pharmacologic effect. This was sustained throughout the treatment period. For the B cell counts, CD19 is used, as the presence of ocrelizumab interferes with
the recognition of CD20 by the assay. In the Phase III studies, between each dose of ocrelizumab, up to 5% of patients showed B-cell repletion (> lower limit of normal (LLN) or baseline) at least at one time point. The extent and duration of B-cell depletion was consistent in the PPMS and RMS trials.
The longest follow up time after the last ocrelizumab infusion (Phase II study WA21493, N=51) indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 72 weeks (range 27-175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by approximately two and a half years after the last infusion.
The pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment model with time-dependent clearance, and with PK parameters typical for an IgG1 monoclonal antibody. The overall exposure (AUC over the 24 weeks dosing interval) was identical in the 2 × 300 mg in PPMS and 1 × 600 mg in RMS studies, as expected given an identical dose was administered. Area under the curve (AUCτ) after the 4th dose of 600 mg ocrelizumab was 3510 μg/mL•day, and mean maximum concentration (Cmax) was 212 μg/mL in RMS (600 mg infusion) and 141 μg/mL in PPMS (300 mg infusions).
Ocrelizumab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
The population pharmacokinetics estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 L and 0.294 L/day.
The metabolism of ocrelizumab has not been directly studied, as antibodies are cleared principally by catabolism (i.e. breakdown into peptides and amino acids).
Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.0489 L/day which declined with a half-life of 33 weeks. The terminal elimination half-life of ocrelizumab was 26 days.
No studies have been conducted to investigate the pharmacokinetics of ocrelizumab in children and adolescents <18 years of age.
There are no dedicated PK studies of ocrelizumab in patients ≥55 years due to limited clinical experience.
No formal pharmacokinetic study has been conducted. Patients with mild renal impairment were included in clinical trials and no change in the pharmacokinetics of ocrelizumab was observed in those patients. There is no PK information available in patients with moderate or severe renal impairment.
No formal pharmacokinetic study has been conducted. Patients with mild hepatic impairment were included in clinical trials, and no change in the pharmacokinetics was observed in those patients. There is no PK information available in patients with moderate or severe hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and embryo-foetal development. Neither carcinogenicity nor mutagenicity studies have been conducted with ocrelizumab.
In a pre- and post-natal development study in cynomolgus monkeys, administration of ocrelizumab from gestation day 20 to approximately 5 weeks postpartum was associated with glomerulopathy, lymphoid follicle formation in bone marrow, lymphoplasmacytic renal inflammation, and decreased testicular weight in offspring. The maternal doses administered in this study resulted in maximum mean serum concentrations (Cmax) that were 4.5- and 21-fold above those anticipated in the clinical setting.
There were two cases of moribundityone attributed to weakness due to premature birth accompanied by opportunistic infection and the other to an infective meningoencephalitis involving the cerebellum of the neonate from a maternal dam with an active infection (mastitis). The course of both neonatal infections could have potentially been impacted by B-cell depletion. Newborn offspring of maternal animals exposed to ocrelizumab were noted to have depleted B cell populations during the post natal phase. Measurable levels of ocrelizumab were detected in milk (approximated 0.2% of steady state trough serum levels) during the lactation period.
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