Sotrovimab

Sotrovimab is a human IgG1 mAb that binds to a conserved epitope on the spike protein receptor binding domain of SARS-CoV-2.

Antiviral activity

Sotrovimab neutralised wild-type SARS-CoV-2 virus in vitro with a half maximal effective concentration (EC₅₀) of 100.1 ng/mL.

Table 1. Sotrovimab neutralisation data for SARS-CoV-2 variants:

^a Based on EC₅₀ fold change compared to wild-type. No change: ≤5-fold change in EC₅₀ compared to wild-type.
^b Variant has not been named by the WHO.
^c The BA.2.86, BN.1 and JN.1 variants contain the K356T substitution.

Antiviral resistance

Cell culture studies

No viral breakthrough was observed when virus was passaged for 10 passages (34 days) in the presence of fixed concentration of antibody at the lowest concentration tested (~10x EC₅₀). Forcing the emergence of resistance variants through an increasing concentration selection method identified E340A as a sotrovimab mAb resistance mutant (MARM). An E340A substitution emerged in cell culture selection of resistant virus and had a >100-fold reduction in activity in a pseudotyped virus-like particle (VLP) assay.

Table 2 shows the activity data for sotrovimab against epitope sequence polymorphisms evaluated in pseudotyped VLP assessments in cell culture using the Wuhan-Hu-1 and Omicron BA.1, BA.2 and BA.5 spike proteins.

Table 2. Sotrovimab pseudotyped VLP assessments in cell culture against epitope substitutions:

^a Based on EC₅₀ fold change relative to each spike viral variant. No change: ≤5-fold change; –: depicts not tested.
^b Wuhan-Hu-1 strain
^c Omicron lineages

Absorption

Based on population pharmacokinetic analyses, following a 15 minute to 1 hour intravenous infusion of 500 mg, the geometric mean C_max was 170 μg/mL (N=1188, CVb% 53.4), and the geometric mean Day 28 concentration was 39.7 μg/mL (N=1188, CVb% 37.6).

Distribution

Based on population pharmacokinetic analysis, the geometric mean steady-state volume of distribution was 7.9 L.

Biotransformation

Sotrovimab is degraded by proteolytic enzymes which are widely distributed in the body.

Elimination

Based on population pharmacokinetic analysis, the mean systemic clearance (CL) was 95 mL/day, with a median terminal half-life of approximately 61 days.

Special populations

Elderly patients

Based on population pharmacokinetic analyses, there was no difference in sotrovimab pharmacokinetics in elderly patients.

Renal impairment

Sotrovimab is too large to be excreted renally, thus renal impairment is not expected to have any effect on elimination. Furthermore, based on population pharmacokinetic analyses there was no difference in sotrovimab pharmacokinetics in patients with mild or moderate renal impairment.

Hepatic impairment

Sotrovimab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, therefore changes in hepatic function are not expected to have any effect on elimination. Furthermore, based on population pharmacokinetic analyses there was no difference in sotrovimab pharmacokinetics in patients with mild to moderate elevations in alanine aminotransferase (1.25 to <5 x ULN).

Paediatric population

Limited data on the pharmacokinetics of sotrovimab in patients aged less than 18 years, has been obtained from the COMET-TAIL study and the COMET-PACE study. The COMET-PACE study is an open-label, non-conparator paediatric study, that was terminated prior to completion of recruitment. The recommended dose for adolescents aged from 12 years and from 40 kg body weight was based on an allometric scaling approach, which accounted for effect of body weight changes associated with age on clearance and volume of distribution. This approach is supported by a population pharmacokinetic analysis, which shows comparable serum exposures of sotrovimab in adolescents as those observed in adults. Following intravenous infusion of 500 mg sotrovimab in 7 adolescents, the geometric mean C_max was 180 μg/mL (geometric CV% 25.6) and the geometric mean Day 29 concentration was 47.4 μg/mL (geometric CV% 17.0).

Data (n=3) in children (aged 6 to less than 12 years and weighing at least 15 kg), are too limited to establish pharmacokinetics of sotrovimab in this age group.

Other special populations

Based on population pharmacokinetic analyses, the pharmacokinetics of sotrovimab following intravenous infusion were not affected by age, sex or BMI. No dose adjustment is warranted based on these characteristics. Body weight was a significant covariate, but the magnitude of effect does not warrant dose adjustment.

Carcinogenesis/mutagenesis

Genotoxicity and carcinogenicity studies have not been conducted with sotrovimab.

Reproductive toxicology

Nonclinical reproductive and developmental toxicity studies have not been conducted with sotrovimab.

Animal toxicology and pharmacology

No toxicity with sotrovimab was identified in a cynomolgus monkey 2-week repeat-dose IV infusion toxicology study with 105-day recovery period at doses up to 500 mg/kg, the no observed adverse effect level (NOAEL) and highest dose tested. The C_max and total exposure AUC [sum of AUC_0-168h after Dose 1 and AUC_0-last after Dose 2 (Day 8)] values at the NOAEL of 500 mg/kg were 13500 μg/mL and 216000 day*μg/mL, respectively.