Sarilumab is a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membrane-bound IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signalling which involves ubiquitous signal-transducing glycoprotein 130 (gp130) and the Signal Transducer and Activator of Transcription-3 (STAT-3).
In functional human cell-based assays, sarilumab was able to block the IL-6 signalling pathway, measured as STAT-3 inhibition, only in the presence of IL-6.
IL-6 is a pleiotropic cytokine that stimulates diverse cellular responses such as proliferation, differentiation, survival, and apoptosis and can activate hepatocytes to release acute-phase proteins, including C-reactive protein (CRP) and serum amyloid A. Elevated levels of IL-6 are found in the synovial fluid of patients with rheumatoid arthritis and play an important role in both the pathologic inflammation and joint destruction which are hallmarks of RA. IL-6 is involved in diverse physiological processes such as migration and activation of T-cells, B-cells, monocytes, and osteoclasts leading to systemic inflammation, synovial inflammation, and bone erosion in patients with RA.
The activity of sarilumab in reducing inflammation is associated with laboratory changes such as decrease in ANC and elevation in lipids.
Following single-dose subcutaneous (SC) administration of sarilumab 200 mg and 150 mg in patients with RA rapid reduction of CRP levels was observed. Levels were reduced to normal as early as 4 days after treatment initiation. Following single-dose sarilumab administration, in patients with RA, ANC decreased to the nadir between 3 to 4 days and thereafter recovered towards baseline. Treatment with sarilumab resulted in decreases in fibrinogen and serum amyloid A, and increases in haemoglobin and serum albumin.
The pharmacokinetics of sarilumab were characterised in 2186 patients with RA treated with sarilumab which included 751 patients treated with 150 mg and 891 patients treated with 200 mg subcutaneous doses every two weeks for up to 52 weeks.
The absolute bioavailability for sarilumab after SC injection was estimated to be 80% by population PK analysis. The median tmax after a single subcutaneous dose was observed in 2 to 4 days. After multiple dosing of 150 to 200 mg every two weeks, steady state was reached in 12 to 16 weeks with a 2- to 3-fold accumulation compared to single dose exposure. For the 150 mg every two weeks dose regimen, the estimated mean (± standard deviation, SD) steadystate area under curve (AUC), Cmin, and Cmax of sarilumab were 210 ± 115 mg.day/L, 6.95 ± 7.60 mg/L, and 20.4 ± 8.27 mg/L, respectively.
For the 200 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of sarilumab were 396 ± 194 mg.day/L, 16.7 ± 13.5 mg/L, and 35.4 ± 13.9 mg/L, respectively.
In a usability study sarilumab exposure after 200 mg Q2W was slightly higher (Cmax + 24-34%, AUC(0-2w) +7-21%) after use of a pre-filled pen compared to the pre-filled syringe.
In patients with RA, the apparent volume of distribution at steady state was 8.3 L.
The metabolic pathway of sarilumab has not been characterised. As a monoclonal antibody sarilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Sarilumab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear saturable target-mediated elimination predominates. These parallel elimination pathways result in an initial half-life of 8 to 10 days, and at steady-state an effective halflife of 21 days is estimated.
After the last steady state dose of 150 mg and 200 mg sarilumab, the median times to non-detectable concentration are 30 and 49 days, respectively. Monoclonal antibodies are not eliminated via renal or hepatic pathways.
A more than dose-proportional increase in pharmacokinetic exposure was observed in patients with RA. At steady state, exposure over the dosing interval measured by AUC increased approximately 2- fold with a 1.33-fold increase in dose from 150 to 200 mg every two weeks.
Simvastatin is a CYP3A4 and OATP1B1 substrate. In 17 patients with RA, one week following a single 200-mg subcutaneous administration of sarilumab, exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively.
Age, gender, ethnicity and body weight Population pharmacokinetic analyses in adult patients with RA (ranging in age from18 to 88 years with 14% over 65 years) showed that age, gender and race did not meaningfully influence the pharmacokinetics of sarilumab. Body weight influenced the pharmacokinetics of sarilumab. In patients with higher body weight (>100 Kg) both 150 mg and 200 mg doses demonstrated efficacy; however, patients weighing >100 Kg had greater therapeutic benefit with the 200 mg dose.
No formal study of the effect of renal impairment on the pharmacokinetics of sarilumab was conducted. Mild to moderate renal impairment did not affect the pharmacokinetics of sarilumab. No dosage adjustment is required in patients with mild to moderate renal impairment. Patients with severe renal impairment were not studied.
No formal study of the effect of hepatic impairment on the pharmacokinetics of sarilumab was conducted.
Non-clinical data reveal no special hazard for humans based on repeated-dose toxicity studies, carcinogenic risk assessment and reproductive and developmental toxicity studies.
No long-term animal studies have been performed to establish the carcinogenicity potential of sarilumab. The weight of evidence for IL-6Rα inhibition mainly indicates anti-tumour effects mediated by multiple mechanisms predominantly involving STAT-3 inhibition. In vitro and in vivo studies with sarilumab using human tumour cell lines showed inhibition of STAT-3 activation and inhibition of tumour growth in human tumour xenograft animal models.
Fertility studies conducted in male and female mice using a murine surrogate antibody against mouse IL-6Rα showed no impairment of fertility.
In an enhanced pre-/postnatal developmental toxicity study, pregnant Cynomolgus monkeys were administered sarilumab once-weekly intravenously from early gestation to natural birth (approximately 21 weeks) Maternal exposure up to approximately 83 times the human exposure based on AUC after subcutaneous doses of 200 mg every 2 weeks, did not cause any maternal or embryofetal effects. Sarilumab had no effect on maintenance of pregnancy or on the neonates evaluated up to 1 month after birth in body weight measurements, in parameters of functional or morphological development including skeletal evaluations, in immunophenotyping of peripheral blood lymphocytes, and in microscopic evaluations. Sarilumab was detected in the serum of neonates up to 1 month. The excretion of sarilumab in Cynomolgus monkey’s milk has not been studied.
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