Lopinavir Cerebrospinal Fluid Steady-State Trough Concentrations in HIV-Infected Adults

BACKGROUND: The central nervous system may act as a sanctuary site for viral replication in the setting of low antiretroviral penetration. Data on lopinavir cerebrospinal fluid (CSF) trough concentration (C-trough) values have yet to be reported. OBJECTIVE: To describe lopinavir CSF C-trough values and compare them with a measure of HIV susceptibility. METHODS: In a prospective, open-label design, HIV-infected adults whose regimen included lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily for at least 4 weeks were enrolled. Each subject had 8 plasma lopinavir concentrations determined over a 12-hour dosing interval and 1 CSF lopinavir C-trough value determined at the end of the study. Linear regression methods tested for associations between CSF or CSF to plasma concentration ratio and covariates including pharmacokinetic parameters and CSF protein. RESULTS: Ten patients (7 male; median [range] +/- SD age 45.3 +/- 2.8 y) completed the study. Median (intraquartile range [IQR]) lopinavir plasma 0- to 12-hour area under the curve (AUC(0-12)) and minimum concentrations were 71.3 h.mu g/mL (48.4-87.6) and 3.82 mu g/mL (2.76-5.34). Median (IQR) CSF C-trough, paired plasma concentration, and time since last dose were 11,200 pg/mL (6760-16,400), 5.42 mu g/mL (3.88-5.85), and 9.9 hours (9.7-10.2), respectively. Median (IQR) CSF to plasma concentration ratio was 0.225% (0.194-0.324). Lopinavir CSF C-trough was above the median 50% inhibitory concentration (IC50) for wildtype HIV-1 (wtHIV-1) (1900 pg/mL) in all subjects. Lopinavir plasma AUC(0-12) (r(2) = 0.65; p = 0.009) and CSF protein (r(2) = 0.26; p = 0.006) were associated with lopinavir CSF concentration, while CSF protein (r(2) = 0.66; p = 0.008) was associated with CSF to plasma concentration ratio. CONCLUSIONS: Lopinavir CSF C-trough was above the median IC50 for wtHIV-1 replication in all patients receiving lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily.