Population pharmacokinetics and pharmacodynamics of HFB30132A, a monoclonal antibody against SARS-CoV-2, in healthy Chinese and US subjects.

Development of neutralizing monoclonal antibodies (nAbs) is a strategy for treatment of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of HFB30132A, a fully human nAb targeting the SARS-CoV-2 spike protein receptor binding domain in healthy subjects. A randomized, double-blind, placebo-controlled phase I trial was performed in healthy Chinese and US subjects. The subjects (n=44) received a single ascending dose (400, 1000, 2000 mg) or placebo. Safety and PK data were analysed. PD were evaluated with a pseudovirus neutralization test in vitro using serum samples of Chinese subjects. A population PK/PD model was developed using non-linear mixed effects modelling. The effects of covariates were evaluated via covariate screening, Monte Carlo simulation and randomization tests. The PK profile was consistent with a three-compartment model. Clearance and V1 were 0.38 mL/h and 2.9 L, respectively. Ethnicity and body weight were factors affecting PK. Compared with subjects who were not Hispanic or Latino, area under the curve increased by 64% in subjects of Han nationality. PD were consistent with the effect-compartment model when 50% of neutralization dilution titre was used as the PD index. Maximal effect (E) reduced with time, consistent with the exponential model. The concentration of HFB30132A exerting 50% of E was 4590 mg/L. The half-life for reduction of E was 133 days. Albumin, lymphocytes, neutrophils and monocytes affected PD. Ethnic differences in PK and tolerance of PD were found for HFB30132A. The population PK/PD model characterized the dose-exposure-response relationship of HFB30132A in healthy subjects. These findings are useful for drug development in the future. Clinical trial registration: ClinicalTrial.gov NCT04590430, NCT05275660.