Pharmacokinetic approaches to standardize antiviral exposure in cerebrospinal fluid.

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], area under the curve [AUC], and trough [C].

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 and AUC to plasma C and AUC (i.e., C and AUC). The CSF C for each ARV was compared with in vitro literature values of HIV inhibitory concentration values (IC).

RESULTS

Emtricitabine exhibited the highest median relative CSF penetration (C, 46.3%; AUC, 72%) and dolutegravir had the lowest CSF penetration (C, 0.57%; AUC, 0.57%). Tenofovir, lamivudine, atazanavir, and raltegravir had median estimated CSF C concentrations less than IC. 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 or C) 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.