Pharmacokinetics and pharmacodynamics of a long-acting monoclonal antibody against malaria in African adults.

BACKGROUNDCIS43LS is a long-acting mAb that targets the Plasmodium falciparum circumsporozoite protein. A phase II trial showed that a single dose of CIS43LS conferred > 85% sterile protection against infection in Malian adults over 6 months. Understanding the pharmacokinetics and pharmacodynamics (PK/PD) of CIS43LS is critical for the further development of CIS43LS and other antimalaria mAbs.METHODSUsing 3,777 serum samples collected from 348 trial participants over the 6-month study period, we performed a PK/PD analysis of CIS43LS that included assessments for antidrug antibodies and target-mediated drug disposition. A 2-compartment, nonlinear mixed effects population PK model that evaluated demographic, anthropometric, hematologic, baseline parasitemia, and endogenous IgG and IgG1 as potential covariates was used to estimate PK parameters and serum concentrations required to achieve 80% efficacy.RESULTSThe median CIS43LS t1/2 was 63.2 days (95% CI, 59.4-67.2 days). Serum concentrations ≥ 64 μg/mL (95% CI, 49-93 μg/mL) corresponded to ≥ 80% efficacy against infection over 6 months. A simulated dose of 30 mg/kg maintained serum concentrations > 64 μg/mL in > 97.5% of individuals for 4 months, the time frame for the WHO preferred product characteristics for antimalaria mAbs. There was no evidence of antidrug antibodies. Among infected individuals who received CIS43LS, no marked evidence of target-mediated drug disposition was observed.CONCLUSIONThis study indicates that protective CIS43LS levels can be maintained over the course of a single malaria season and provides guidance for PK/PD analyses of antimalaria mAbs in malaria-endemic populations.TRIAL REGISTRATIONClinicalTrials.gov NCT04329104.FUNDINGNIH and Gates Foundation.