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Raltegravir penetration in the cerebrospinal fluid of HIV-positive patients
27 March 2010 - Volume 24 - Issue 6 - p 931-932
Calcagno, Andrea; Bonora, Stefano; Bertucci, Roberto; Lucchini, Anna; D'Avolio, Antonio; Di Perri, Giovanni Department of Infectious Diseases, University of Torino, Torino, Italy.
ICAAC: Raltegravir in CSF: "Raltegravir Concentrations in CSF Exceed The Median Inhibitory Concentration" - (09/20/09)
ICAAC: Darunavir in the CSF: "Darunavir Concentrations in CSF Exceed The Median Inhibitory Concentration" - (09/20/09)
Recent data highlighted the association between penetration of antiretrovirals in the central nervous system (CNS) and neurocognitive impairment in HIV-positive patients. Existing antiretrovirals have been ranked according to a score of neuropenetration, which was shown to be a predictor of anti-HIV activity in the CNS and improvement of neurocognitive disorders [1]. Main factors affecting drug penetration are known to be protein binding, lipophilicity and molecular weight [2]. Moreover, active translation by membrane transporters (such as p-glycoprotein) could be a key mechanism of passage [3]. The use of raltegravir (RGV), a novel antiretroviral drug targeted to inhibit the HIV preintegrase complex, is increasing worldwide due to its efficacy and tolerability. However, penetration of RGV in the CNS has not been yet elucidated. In fact, prediction of RGV neuropenetration according to molecular characteristics is controversial. Intermediate protein binding (83%) and large volume of distribution (273 l) could suggest a high distribution beyond extracellular spaces [4]. On the contrary, low lipophilicity (oil/water partition coefficient at pH 7.4 of 2.80) and intermediate molecular weight (482.51 Da) suggest a limited diffusion. Furthermore, in-vitro studies suggest that RGV is substrate of p-glycoprotein, although this efflux pump has not been identified to significantly affect plasma pharmacokinetics [5]. In any case, no data concerning RGV passage into cerebrospinal fluid of animals or humans have yet been published.
We describe three patients starting an RGV-containing regimen who, for clinical reasons, underwent two sequential lumbar punctures: the first at the baseline of the new regimen and the second after 2 weeks. After informed consent was given, 1 ml cerebrospinal fluid (CSF) from the second lumbar puncture and a concomitant blood sample were collected. Samples were obtained at a median of 12.5 h after last intake of drugs (evening doses). The CSF sample was immediately frozen and stored at -20°C. Plasma and CSF drug concentrations were measured by a validated HPLC-photo diode array [6] and a liquid chromatography/mass spectrometry (LC/MS) method, respectively (modified from [7]).
Patient 1 was a naive, 19-year-old, Romanian boy diagnosed with subacute HIV-related encephalopathy. A regimen with high CSF penetration, including zidovudine (AZT), lamivudine (3TC), nevirapine (NVP) and RGV, was started. He had a hypersensitivity reaction on day 22 and NVP was switched to a boosted atazanavir-containing regimen.
Patient 2 was a 39-year-old Italian man presenting with visual deficit and whose brain MRI showed a hyperintensity of the white matter; a PCR positive for John Cunningham virus supported a diagnosis of multiple progressive leukoencephalopathy. He started the same regimen as patient 1 and had a transient improvement, but eventually died on day 60.
Patient 3 was a 39-year-old Italian man presenting with pancytopenia and fever while on a successful HAART containing tenofovir, emtricitabine and lopinavir/ritonavir. Bone marrow histological examination showed granulomes with necrosis and yielded growth of Mycobacterium tuberculosis, supporting a diagnosis of disseminated tuberculosis. The standard four drugs-based and rifampin-containing antituberculosis treatment was started, and HAART was modified to abacavir (ABC), 3TC, RGV (400 mg twice daily) and enfuvirtide due to drug-drug interactions and previous failure with nonnucleoside reverse transcriptase inhibitors (NNRTIs). After 4 months, the patient is still on those medications and showing a marked improvement in his general conditions and pancytopenia without toxicities.
At day 14, all patients showed a marked virological response as a rapid decrease in plasma viral load, whereas the magnitude of such a response was more variable at the CSF level (Table 1). Patient 3, switching from a lopinavir-containing suppressive regimen, showed a slight increase of CSF viral load (Table 1). Although samples have been obtained at the end of the dosing interval in all patients the drug concentrations measured are generally low (in patient 1, AZT was not detectable in either sample), NRTIs and NVP were confirmed to have high penetration in CSF (Table 1). More interestingly, RGV also showed significant penetration in this compartment (Table 1). In the three patients, RGV CSF trough concentrations were above or very close to in-vitro 95% inhibitory concentration (IC95) (14.6 ng/ml). In patients 1 and 2, an RGV plasma-to-CSF ratio of more than 0.3 was found, a value higher than those reported for boosted protease inhibitors and close to median values of most NRTIs and NNRTIs. Patient 3 showed a ratio of 0.09; in addition to the RGV wide interpatient and intrapatient variability, concomitant administration of rifampicin could explain the lower value as compared with the other two patients. Rifampin, in fact, is known to be an inducer of p-glycoprotein, efflux pump actively involved in limiting drug passage through blood-brain barrier and RGV was considered its substrate [8]. However, the drug concentration exceeded IC95 for HIV also in this patient.
In conclusion, to the best of our knowledge, these are the first data concerning the penetration of RGV in the CNS. The promising profile observed deserves further clinical evaluation in order to define the activity of the drug in such compartment.
Table 1. Early immunovirological changes and pharmacokinetics results expressed as trough concentrations (ng/ml) and ratios.

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