CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Poster and Themed Discussion Abstracts

415 PHARMACOKINETICS ANALYSIS OF VRC01, A BROADLY NEUTRALIZING HIV-1 MONOCLONAL ANTIBODY Yunda Huang 1 , Lily Zhang 1 , Nicole Grunenberg 1 , Robert Bailor 2 , Abby Isaacs 1 , Julie Ledgerwood 3 , Kelly Seaton 4 , Kenneth Mayer 5 , Larry Corey 1 , Peter Gilbert 1 1 Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA, 2 NIAID, Gaithersburg, MD, USA, 3 NIAID, Bethesda, MD, USA, 4 Duke Human Vaccine Inst, Durham, NC, USA, 5 The Fenway Inst, Boston, MA, USA Background: VRC01 is a monoclonal antibody targeting the CD4 binding site of the HIV envelope. Eighty-four HIV-uninfected adults received multiple-dose intravenous (IV) VRC01 at 10, 20, 30 or 40 mg/Kg every 4 or 8 weeks, or subcutaneous (SC) VRC01 at 5 mg/Kg every 2 weeks, and were followed for 8 months in HVTN 104. We conducted the first population pharmacokinetics (popPK) analysis of VRC01, providing important understanding of the inter-individual variability (IIV) of the drug disposition process and the effects of covariates on systemic drug exposure for ongoing and planned HIV prevention efficacy trials of VRC01. Methods: VRC01 serum concentration-time data were described using an open 2-compartment disposition model with first-order elimination from the central compartment. A depot compartment with a first-order absorption rate constant was included for SC VRC01. Nonlinear mixed effect models with exponential random effects and combined proportion/ constant residual error were used. Baseline demographic and safety laboratory values were screened and considered as potential covariates of different functional forms in the popPK model via a stepwise model selection procedure. The PK model was parameterized in terms of clearance (CL), central volume of distribution (Vc), peripheral volume of distribution (Vp), distribution clearance (Q), and absorption rate constant (Ka). Results: All available 1117 serum concentrations were modeled. Dose-normalized area under the time-concentration curve showed linearity of PK following IV VRC01. IIV of the PK parameters was moderate (23-31% CV) except for that of Vp (40% CV) and Ka (48% CV) in the base model that did not account for covariates (Table). Relative to IV administration, bioavailability (F1) after SC administration was 71%. Population mean estimates for CL and Vc were 0.39 Liter/day and 1.83 Liter, with an estimated terminal half-life of 15 days. The correlations between the individual-level PK parameters ranged from 0.12 (Vc and Q) to 0.97 (Vp and Q). In the final model, body weight was identified to have a significant influence on CL (0.7% fold increase per Kg) and Vc (1.1% per Kg). All parameters were estimated with acceptable precision. Conclusion: A robust popPK model for VRC01 was developed, supporting the weight-dependent dosing regimens. This model could be used to simulate concentration data for correlates research, and with given protective VRC01 levels to guide dose and target population selections in efficacy trials.

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EFFECT OF CYP3A4*22 ON ORAL RILPIVIRINE PLASMA CONCENTRATIONS Rana Abutaima 1 , Marta Boffito 2 , Andrea Calcagno 3 , Jessica Cusato 3 , Antonio D’Avolio 3 , Laura Else 1 , Chris Higgs 2 , Saye Khoo 1 , Marco Siccardi 1 , Andrew Owen 1

CROI 2017 171