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Clinical Trial
. 2021 Feb:64:103203.
doi: 10.1016/j.ebiom.2020.103203. Epub 2021 Jan 23.

Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials

Yunda Huang  1 , Logashvari Naidoo  2 , Lily Zhang  3 , Lindsay N Carpp  3 , Erika Rudnicki  3 , April Randhawa  3 , Pedro Gonzales  4 , Adrian McDermott  5 , Julie Ledgerwood  5 , Margarita M Gomez Lorenzo  6 , David Burns  6 , Allan DeCamp  7 , Michal Juraska  7 , John Mascola  5 , Srilatha Edupuganti  8 , Nyaradzo Mgodi  9 , Myron Cohen  10 , Lawrence Corey  11 , Philip Andrew  12 , Shelly Karuna  3 , Peter B Gilbert  13 , Kathryn Mngadi  14 , Erica Lazarus  15
Affiliations
Clinical Trial

Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials

Yunda Huang et al. EBioMedicine. 2021 Feb.

Abstract

The phase 2b AMP trials are testing whether the broadly neutralising antibody VRC01 prevents HIV-1 infection in two cohorts: women in sub-Saharan Africa, and men and transgender persons who have sex with men (MSM/TG) in the Americas and Switzerland. We used nonlinear mixed effects modelling of longitudinal serum VRC01 concentrations to characterise pharmacokinetics and predict HIV-1 neutralisation coverage. We found that body weight significantly influenced clearance, and that the mean peripheral volume of distribution, steady state volume of distribution, elimination half-life, and accumulation ratio were significantly higher in MSM/TG than in women. Neutralisation coverage was predicted to be higher in the first (versus second) half of a given 8-week infusion interval, and appeared to be higher in MSM/TG than in women overall. Study cohort differences in pharmacokinetics and neutralisation coverage provide insights for interpreting the AMP results and for investigating how VRC01 concentration and neutralisation correlate with HIV incidence.

Keywords: Antibody mediated prevention trials; Broadly neutralising antibodies; HIV-1; Population pharmacokinetics; VRC01.

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Conflict of interest statement

Declaration of Competing Interest Dr. Huang, Ms. Zhang, Dr. Carpp, Ms. Rudnicki, Dr. Randhawa, Dr. DeCamp, Dr. Juraska, Dr. Corey, Dr. Karuna, and Dr. Gilbert report grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health during the conduct of the study. Dr. Edupuganti reports grants from Fred Hutch/NIH during the conduct of the study. Dr. Mascola has a patent E-300–2009: Isolation of Novel Broadly Neutralizing Monoclonal Antibodies Against HIV-1 Using Epitope Specific Glycoprotein Probes to Identify HIV-1 Specific B-Cells, VRC01 issued. Dr. Cohen reports Advisory Board travel expenses from Merck, outside the submitted work. Dr. Mngadi reports grants from The Aurum Institute during the conduct of the study and grants from the HIV Vaccine Trial Network Research and Mentorship Programme outside the submitted work. Dr. Mngadi is a non-voting member of the HVTN Scientific Governance Committee. Review editor for Frontiers Reproductive Health, HIV and STI's Journal, a member of the Trial Steering Committee for the PrEPVACC study, a member of the Safety Monitoring Committee for the IAVI C100 study, and Protocol Co-Chair for the HVTN 705/VAC89220HPX2008 and HVTN 107 studies. All other authors have nothing to disclose.

Figures

Fig 1
Fig. 1
Individual-level VRC01 serum concentration (log10-scale) over time in HVTN 703/HPTN 081 (women) (n = 23), and HVTN 704/HPTN 085 (MSM/TG) (n = 24). “+” indicates the observed concentration at a 4-week post infusion visit, an open circle indicates the observed concentration at an infusion visit, and a triangle indicates the observed concentration at the 5-day post infusion #2 visit.
Fig 2
Fig. 2
Distributions of individual-level PK parameter estimates of VRC01 over the 10 infusions in HVTN 703/HPTN 081 (women) and HVTN 704/HPTN 085 (MSM/TG). a) Clearance (CL), and b) volume of the peripheral compartment (Vp), c) distribution half-life, and d) elimination half-life estimates are shown. Estimates are based on the inter-occasion variability-included base model described in Table S1. Panels a and b are shown on a log10 scale since both CL and Vp show a log-normal distribution, while panels c and d are shown on a linear scale.
Fig 3
Fig. 3
Predicted VRC01 neutralisation coverage and serum concentration by time since first infusion. a (30 mg/kg), c (10 mg/kg) in HVTN 703/HPTN 081 (women): Percent of 315 clade C isolates on CATNAP that would be sensitive to VRC01 neutralisation if the geometric mean serum concentration at the given time-point was at least 100-fold greater than the viral in vitro inhibitory concentration 50% (IC50), i.e., ID50 serum neutralisation titre is ≥100. b (30 mg/kg), d (10 mg/kg) in HVTN 704/HPTN 085 (MSM/TG): Percent of 118 clade B isolates on CATNAP that would be sensitive to VRC01 neutralisation if the geometric mean serum concentration at the given time-point was at least 100-fold greater than the viral in vitro inhibitory concentration 50% (IC50), i.e., ID50 serum neutralisation titre is ≥100. Within each plot, the left-most bolded percentage corresponds to the average coverage in the first 4 weeks post-first infusion and the right-most bolded percentage corresponds to the average coverage in the second 4 weeks post-first infusion.
Fig 4
Fig. 4
Distributions of covariate-adjusted individual-level PK parameters of VRC01 in HVTN 703/HPTN 081 (women) and HVTN 704/HPTN 085 (MSM/TG). a) Clearance (CL) and b) volume of the peripheral compartment (Vp). All estimates were adjusted for dose, age, body weight, race, and creatinine clearance via targeted minimum loss-based estimation (TMLE) as presented in Table 2. **, two-sided adjusted p-value < 0.001.
Fig 5
Fig. 5
Distributions of covariate-adjusted individual-level PK parameters of VRC01 in HVTN 703/HPTN 081 (women) and HVTN 704/HPTN 085 (MSM/TG). a) Steady state AUC, b) steady state volume of distribution, c) distribution half-life, d) elimination half-life, and e) accumulation ratio. All estimates were adjusted for dose, age, body weight, race, and creatinine clearance via TMLE as presented in Table 2. *, two-sided adjusted p-value < 0.05; **, two-sided adjusted p-value < 0.001.
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