Pharmacokinetic approaches to standardize antiviral exposure in cerebrospinal fluid
Year: 2025
Type: article
Abstract: Objectives HIV has been shown to persist in the central nervous system (CNS) in persons on antiretroviral therapy (ART). Our objective was to use pharmacokinetic (PK) modeling to estimate cerebrospinal fluid (CSF) exposure from time‐variant concentrations of various antiretrovirals of ART regimens and to standardize CSF metrics, including maximum concentration [C MAX ], area under the curve [AUC], and trough [C Trough ]. Methods Advancing Clinical Therapeutics Globally (ACTG) A5321 is a prospective cohort study of HIV‐1 reservoirs in persons with HIV. Plasma and CSF antiretroviral (ARV) concentrations were measured in 74 participants who were receiving ART. PK modeling (Pmetrics) was performed for nine ARVs. Relative CSF penetration for each ARV was estimated by comparing CSF C MAX and AUC to plasma C MAX and AUC (i.e., C MAXmethod and AUC method ). The CSF C Trough for each ARV was compared with in vitro literature values of HIV inhibitory concentration values (IC 50, 90, or 95 ). Results Emtricitabine exhibited the highest median relative CSF penetration (C MAXmethod , 46.3%; AUC method , 72%) and dolutegravir had the lowest CSF penetration (C MAXmethod , 0.57%; AUC method , 0.57%). Tenofovir, lamivudine, atazanavir, and raltegravir had median estimated CSF C Trough concentrations less than IC 50, 90, or 95 . Interparticipant variability of relative CSF penetration based on exposures ranged from 160% for lamivudine to approximately 9% for dolutegravir. Conclusions PK modeling successfully standardized ARV CSF concentrations to a given time point (i.e., C MAX or C Trough ) to allow estimation of CSF penetration. This approach provides uniformity for the assessment of exposure, for the estimation of whether desired therapeutic drug goals are obtained in the CSF, and for further studies to investigate whether CSF exposure metrics calculated using this method are associated with measures of HIV persistence.
DOI: 10.1002/phar.70013
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1428073803, G2127051194, G3922356, G4553935269, G5186286648, G574326724, G6186512954, G6692172508, G681742546, G749074515, The Lymphoid Tissue Pharmacology of Antiretroviral Drugs, G781020096, G857487509, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, Investigations of antiretroviral therapy penetration in cerebrospinal fluid, AIDS Clinical Trial Group Laboratory Center, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), The University of North Carolina Center for AIDS Research, G90079629
OpenAlex ID: W4408957169