Low atazanavir concentrations in cerebrospinal fluid.
OBJECTIVE
Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF).


METHODS
Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005.


METHODS
Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml.


RESULTS
One hundred and seventeen participants (43 +/- 7.7 years, 79% men, 81 +/- 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5-17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525-2265) and 523 (283-1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5-21.1) and 7.9 (6.6-22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1-11 ng/ml.


CONCLUSIONS
Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.
Best
Brookie M
BM
Skaggs School of Pharmacy andPharmaceutical Sciences, School of Medicine, Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, MC 0719, La Jolla, CA 92093-0719, USA. brookie@ucsd.edu
Letendre
Scott L
SL
Brigid
Eileen
E
Clifford
David B
DB
Collier
Ann C
AC
Gelman
Benjamin B
BB
McArthur
Justin C
JC
McCutchan
J Allen
JA
Simpson
David M
DM
Ellis
Ronald
R
Capparelli
Edmund V
EV
Grant
Igor
I
D015526:AIDS Dementia Complex / Q000097:blood / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D000328:Adult; D000069446:Atazanavir Sulfate; D001812:Blood-Brain Barrier; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D011725:Pyridines / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D019562:Viral Load
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir