Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults

Abstract

The monoclonal antibody VRC01 targets the CD4 binding site of the human immunodeficiency virus (HIV)-1 envelope. In the clinical study HVTN 104 (NCT02165267), 84 HIV-uninfected adults received multiple-dose intravenous (IV) VRC01 (10, 20, 30 or 40 mg/kg) every 4 or 8 weeks or subcutaneous (SC) VRC01 (5 mg/kg) every 2 weeks, and were followed for 32 weeks. We conducted a population pharmacokinetics (popPK) analysis based on 1117 VRC01 serum concentrations using a 2-compartment PK model with first-order elimination; for SC VRC01 a depot compartment with a first-order absorption rate constant was also included. All PK parameters were estimated with acceptable precision. Estimated bioavailability of SC VRC01 was 74%, with peak concentrations occurring 2-3 d after administration. For both IV and SC VRC01, population mean estimates for clearance (CL), central volume of distribution (Vc), inter-compartmental distribution clearance (Q) and peripheral volume of distribution (Vp) were 0.40 L/day, 1.94 L, 0.84 L/day and 4.90 L, respectively; the estimated terminal half-life was 15 d and these were independent of VRC01 dose. Body weight significantly influenced CL (1.2% fold/kg), Vc (1.0% fold/kg), Q (0.69 log(L/day)/kg) and Vp (0.82 log(L)/kg). The developed popPK model, supporting weight-dependent dosing regimens, projected positive trough levels, 5.54 (95% prediction interval: 1.69, 14.5) mcg/mL and 15.9 (5.29, 46.63) mcg/mL, respectively, for the 10 mg/kg and 30 mg/kg 8-weekly regimens being evaluated in ongoing HIV prevention efficacy studies of IV VRC01. These results are critical for future dose-regimen selection and modeling research to identify VRC01 serum concentration levels sufficient for protection against HIV infection.

Potency and timing of antiviral therapy as determinants of duration of SARS CoV-2 shedding and intensity of inflammatory response

“…% . (45). In this model ) ad 8 represent the distribution and clearance rates of the bNAB whereas ) and 8 describe the coefficients associated with them.…”

Assessing pharmacokinetic marker correlates of outcome, with application to antibody prevention efficacy trials

“…This PK model assumes that the intravenous infusion administration time (about 20‐30 minutes) is brief relative to the half‐life of the mAb and that the PK of the mAb after a single dose is not altered by multiple doses, although cumulations of drug concentrations over multiple doses are accommodated. Both assumptions are reasonable based on the robust fit it provided to repeated‐dose PK data from recent Phase 1 studies of VRC01 …”

“…A, Observed VRC01 concentrations W at 0 and 3 days and 2, 4, and 8 weeks after each of the three infusions and at 1 hour and 10‐16 weeks after the last infusion for the 10 mg/kg (left) and 30 mg/kg (right) VRC01 dose arms in HVTN 104; B, Predicted and observed dose‐normalized VRC01 concentrations in HVTN 104 after a single intravenous (IV) infusion (left) and multiple IV infusions (right) based on the final population pharmacokinetic model described in the work of Huang et al; C, Simulated time‐concentration data under perfect study adherence. Solid lines are medians; shaded areas are 2.5th and 97.5th percentiles over 500 simulated data sets.…”

“…Both assumptions are reasonable based on the robust fit it provided to repeated-dose PK data from recent Phase 1 studies of VRC01. 8,9 As described in more detail in the work of Huang et al, 8 the population PK (popPK) model (that includes (5)) of the set of observed concentrations W considers both interindividual variabilities (IIVs) of the PK parameters (A, B, , and ) for S(t) and a combination proportional + additive residual error via nonlinear mixed effects (NLME) modeling. For IIV, an exponential interindividual random effects model is considered with PK parameters lognormally distributed and random effects normally distributed.…”

The pharmacological treatment of acute HIV infections in neonates

“…66 The study has also revised its protocol to make provision for the use of an anti-HIV monoclonal antibody (VCR01) that has had good success when used in prevention. 67 We eagerly await the results of this innovative new approach to facilitating remission in early-treated infants.…”