Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.
BACKGROUND
Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug.


METHODS
Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.


RESULTS
Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.


CONCLUSIONS
Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.
Yilmaz
Aylin
A
Department of Infectious Diseases, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. aylin.yilmaz@gu.se
Gisslén
Magnus
M
Spudich
Serena
S
Lee
Evelyn
E
Jayewardene
Anura
A
Aweeka
Francesca
F
Price
Richard W
RW
D000328:Adult; D000418:Albumins / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D019380:Anti-HIV Agents / Q000097:blood* / Q000134:cerebrospinal fluid*; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D011760:Pyrrolidinones / Q000097:blood* / Q000134:cerebrospinal fluid*; D000068898:Raltegravir Potassium; D015203:Reproducibility of Results
D000418:Albumins; D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium