Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir.
BACKGROUND
Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study's objective was to determine tenofovir's penetration into cerebrospinal fluid (CSF).


METHODS
CNS HIV Antiretroviral Therapy Effects Research is a multicenter observational study to determine the effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL.


RESULTS
One hundred eighty-three participants (age 44 ± 8 years; 83 ± 32 kg; 33 females; CSF protein 44 ± 16 mg/dL) had plasma and CSF samples drawn 12.2 ± 6.9 and 11 ± 7.8 hours post dose, respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL [interquartile range (IQR) 47-153 ng/mL] and 5.5 ng/mL (IQR 2.7-11.3 ng/mL), respectively. Thirty-four of 231 plasma (14.7%) and 9 of 77 CSF samples (11.7%) were below detection. CSF to plasma concentration ratio from paired samples was 0.057 (IQR 0.03-0.1; n = 38). Median CSF to wild-type 50% inhibitory concentration ratio was 0.48 (IQR 0.24-0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type 50% inhibitory concentration. More subjects had detectable CSF HIV with lower (≤ 7 ng/mL) versus higher (>7 ng/mL) CSF tenofovir concentrations (29% versus 9%; P = 0.05).


CONCLUSIONS
Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093-0719, USA. brookie@ucsd.edu
Brookie M
BM
Best
Scott L
SL
Letendre
Peter
P
Koopmans
Steven S
SS
Rossi
David B
DB
Clifford
Ann C
AC
Collier
Benjamin B
BB
Gelman
Christina M
CM
Marra
Justin C
JC
McArthur
J Allen
JA
McCutchan
Susan
S
Morgello
David M
DM
Simpson
Edmund V
EV
Capparelli
Ronald J
RJ
Ellis
Igor
I
Grant
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D000328:Adult; D015331:Cohort Studies; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D000068698:Tenofovir
D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine