Satralizumab is a recombinant humanised immunoglobuline G2 (IgG2) monoclonal antibody (mAb) that binds to soluble and membrane-bound human IL-6 receptor (IL-6R) and thereby prevents IL-6 downstream signalling through these receptors.
IL-6 levels are increased in cerebrospinal fluid and serum of patients with NMO and NMOSD during periods of disease activity. IL-6 functions have been implicated in the pathogenesis of NMO and NMOSD, including B-cell activation, differentiation of B-cells to plasmablasts and production of pathological autoantibodies, e.g. against AQP4, a water channel protein mainly expressed by astrocytes in the CNS, Th17-cell activation and differentiation, T-regulatory cell inhibition, and changes in blood-brain-barrier permeability.
In clinical studies with satralizumab in NMO and NMOSD, decreases in C-reactive protein (CRP), fibrinogen and complement (C3, C4 and CH50) were observed.
The pharmacokinetics of satralizumab have been characterised both in Japanese and Caucasian healthy volunteers, and in NMO and NMOSD patients. The pharmacokinetics in NMO and NMOSD patients using the recommended dose were characterised using population PK analysis methods based on a database of 154 patients.
The concentration-time course of satralizumab in patients with NMO or NMOSD was accurately described by a two-compartment population PK model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order SC absorption. Satralizumab clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Bodyweight was shown to be a significant covariate, with clearance and Vc for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a 60 kg patient.
Steady state pharmacokinetics were achieved after the loading period (8 weeks) for Cmin, Cmax and AUC as follows (mean (±SD): Cmin: 19.7 (12.2) mcg/mL, Cmax: 31.5 (14.9) mcg/mL and AUC: 737 (386) mcg. mL/day.
The absorption rate constant of satralizumab was 0.0104/h equating to an absorption half-life of around 3 days (66 hours) at the recommended dose. The bioavailability was high (85.4%).
Satralizumab undergoes biphasic distribution. The central volume of distribution was 3.46 L, the peripheral volume of distribution was 2.07 L. The inter-compartmental clearance was 14 mL/h.
The metabolism of satralizumab has not been directly studied, as monoclonal antibodies are principally cleared by catabolism.
The total clearance of satralizumab is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMO and NMOSD patients) is estimated to be 2.50 mL/h. The associated terminal t1/2 is approximately 30 days (range 22-37 days) based on data pooled from the phase 3 studies.
Population pharmacokinetic analyses in adult patients with NMO or NMOSD showed that age, gender, and race did not meaningfully influence the pharmacokinetics of satralizumab. Although body weight influenced the pharmacokinetics of satralizumab, no dose adjustments are recommended for any of these demographics.
Data obtained in 8 adolescent patients [13-17 years of age] who received the adult dosing regimen show that population PK parameters for satralizumab are not significantly different from those in the adult population. Therefore, no dose adjustment is necessary.
No dedicated studies have been conducted to investigate the PK of satralizumab in patients ≥65 years of age, however patients with NMO or NMOSD between 65 and 74 years of age were included in the BN40898 and BN40900 clinical studies.
No formal study of the effect of renal impairment on the PK of satralizumab has been conducted. However, patients with mild renal impairment (creatinine clearance ≥50 mL/min and <80 mL/min) were included in the phase III studies. Based on population PK analysis there is no impact of renal impairment on the PK of satralizumab which is in line with the known mechanisms of clearance for satralizumab. Therefore no dose adjustment is required.
No formal study of the effect of hepatic impairment on the PK of satralizumab has been conducted.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity to reproduction and development.
No rodent carcinogenicity studies have been performed to establish the carcinogenic potential of satralizumab. Proliferative lesions have not been observed in a chronic cynomolgus monkey 6-month toxicity study.
No studies have been performed to establish the mutagenic potential of satralizumab. Antibodies are not expected to cause effects on DNA.
Prenatal treatment and postnatal exposure with satralizumab in pregnant monkeys and their offspring did not elicit any adverse effects on maternal animals, foetal development, pregnancy outcome or infant survival and development including learning ability.
The concentrations of satralizumab in breast milk were very low (<0.9% of the corresponding maternal plasma levels).
No effects on male or female reproductive organs were seen with chronic treatment of satralizumab in monkeys.
Based on in vitro studies with human blood, the risk of the release of pro-inflammatory cytokines with satralizumab is considered low in terms of incidence and increase in cytokines.
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