Population Pharmacokinetics of Dolutegravir in Plasma and Cerebrospinal Fluid in Adults Living With HIV

ABSTRACT Characterizing dolutegravir penetration into the central nervous system is important for optimizing human immunodeficiency virus treatment outcomes, yet population‐specific pharmacokinetic data describing cerebrospinal fluid disposition and equilibration kinetics remain lacking. This study characterizes dolutegravir pharmacokinetics in plasma and cerebrospinal fluid to describe the plasma‐to‐cerebrospinal fluid equilibration rate constant and cerebrospinal fluid‐to‐plasma pseudo‐partition coefficient. Sparse pharmacokinetics samples were collected from 121 antiretroviral therapy‐experienced adults who are predominantly overweight or obese (body mass index: 32.2 ± 8.7 kg/m 2 ) receiving daily dolutegravir (50 mg)‐based therapy. The model was developed using nonlinear mixed‐effects modeling in NONMEM. Plasma dolutegravir pharmacokinetics were best described by a one‐compartment model with first‐order absorption and elimination. The population estimate for apparent oral clearance was 1.38 L/h/70 kg. Cerebrospinal fluid data were modeled using a sequential approach with a hypothetical effect compartment linked to plasma to estimate equilibration kinetics and relative cerebrospinal fluid exposure at steady‐state. Key cerebrospinal fluid penetration parameters included a plasma‐to‐cerebrospinal fluid equilibration rate constant of 0.38 h −1 , corresponding to an equilibration half‐life of 1.82 h, and a cerebrospinal fluid‐to‐plasma pseudo‐partition coefficient of 0.0015, indicating 0.15% cerebrospinal fluid penetration relative to plasma. Post hoc estimated area under the concentration‐time curve (0–24) demonstrated a moderate inverse correlation with body mass index ( r  = −0.34), indicating that dolutegravir exposure decreases with increasing body mass index. The model revealed rapid plasma‐to‐cerebrospinal fluid equilibration kinetics with low steady‐state cerebrospinal fluid penetration in this predominantly overweight and obese population.