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 x microg/mL (48.4-87.6) and 3.82 microg/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 microg/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 (IC(50)) for wild-type 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 IC(50) for wtHIV-1 replication in all patients receiving lopinavir/ritonavir 400/100-mg soft-gel capsules twice daily.
DiCenzo
Robert
R
Wegmans School of Pharmacy, St. John Fisher College, Rochester, NY 14618, USA. rdicenzo@sjfc.edu
DiFrancesco
Robin
R
Cruttenden
Kim
K
Donnelly
Julie
J
Schifitto
Giovanni
G
D000328:Adult; D019540:Area Under Curve; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D016014:Linear Models; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011744:Pyrimidinones / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid*; D019438:Ritonavir / Q000008:administration & dosage; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir