069: Population Pharmacokinetics of Bictegravir in Pregnant & Postpartum Persons Living With HIV

Statement of Purpose, Innovation or Hypothesis: Bictegravir, a potent integrase strand transfer inhibitor, is widely used as part of antiretroviral treatment regimens for HIV-1. Many physiological changes occur with pregnancy and a better understanding of changes in bictegravir pharmacokinetics (PK) during pregnancy is needed. This study used population PK modeling to characterize changes in bictegravir disposition throughout pregnancy and postpartum in persons living with HIV.

Description of Methods & Materials: IMPAACT 2026 is an open-label, multi-center phase-IV prospective study of antiretroviral PK in pregnant persons living with HIV. Pregnant persons receiving bictegravir 50 mg once daily as part of standard of care were eligible to enroll. Intensive PK sampling was performed in the 2^nd trimester, 3^rd trimester, and postpartum. A population PK model was developed using non-linear mixed effects modeling (NONMEM v. 7.5).

Data & Results: Twenty-seven participants were included in the analysis with 508 plasma concentrations (96 2^nd trimester, 216 3^rd trimester, 196 postpartum). Median (range) weights were: 2^nd trimester: 87 kg (56-122), 3^rd trimester: 90 kg (46-149), and postpartum: 80 kg (44-141). Median (range) albumin concentrations were: 2^nd trimester: 3.6 g/dL (3.2-4.0), 3^rd trimester: 3.3 g/dL (2.9-4.1), and postpartum: 4.5 g/dL (3.6-4.8). Bictegravir concentrations in pregnant persons living with HIV were well fit with a one-compartment structural model. Albumin concentration and pregnancy were independent predictors of clearance (CL). Weight and Black/African American race were independent predictors of apparent volume of distribution (Vd/F). No differences were observed between bictegravir PK profiles during the second and third trimesters and pregnancy was thus treated as a categorical covariate. Bootstrap of the final model converged 99.3% of the time. The final population PK model parameters were: CL/F (L/hr) = 0.549 × (Albumin/3.7)^-1.13 × (1.61 if pregnant) V/F (L) = 12.6 × (Weight in kg/70)^0.64 × (1.32 if Race is Black or African American) Pregnancy was the most significant covariate in the model and was associated with a 61% increased CL compared to post-partum. Weight was associated with a 120% increase in Vd over the range of values seen in the study while albumin was associated with a 43% decrease in CL over the range of values seen in the study. Race (if Black or African American) led to a 32% increase in Vd. Monte Carlo simulations (n = 2000 virtual subjects receiving a 50 mg daily dose) demonstrated a median (IQR) pre-dose concentration of: 3^rd trimester: 920.2 ng/mL (587.8-1324.4) and postpartum: 3399.4 ng/mL (2377.0-4417.8), which were all above the protein-adjusted minimum target concentration of 162 ng/mL (Figure ).

Interpretation, Conclusion or Significance: The current analysis represents the first population PK model of bictegravir in pregnancy. Bictegravir CL increases during the 2^nd and 3^rd trimesters of pregnancy and is inversely related to albumin concentration, as expected because bictegravir is over 99% protein bound in plasma. Despite a higher bictegravir CL leading to lower exposure in pregnancy, a 50 mg daily dose is predicted to achieve therapeutic levels both during pregnancy and postpartum.

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