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CSF is not on-target marker of antiretroviral and fluconazole levels in brain
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19th International Workshop on Clinical Pharmacology of Antiviral Therapy
Mark Mascolini
Five postmortem brain tissue analyses indicated that cerebrospinal fluid (CSF) concentrations of efavirenz, tenofovir, lamivudine (3TC), and fluconazole did not accurately predict drug levels in brain tissue [1]. Tenofovir, 3TC, and fluconazole CSF levels overpredicted brain tissue penetration. Efavirenz CSF levels underpredicted brain penetration.
Researchers from the University of Minnesota and Makerere University in Kampala conducted this study to assess relative distribution of antiretrovirals and the antifungal fluconazole in plasma, CSF, and brain tissue collected shortly after death. They noted that HIV enters the brain within days of infection, with major neurologic consequences. The central nervous system is an important reservoir of HIV and other pathogens, including Cryptococcus. The researchers observed that current understanding of central nervous system penetration by drugs relies heavily on measuring their levels in CSF. But how closely CSF concentrations predict brain tissue levels remains poorly studied.
To address this issue, the Minnesota/Makerere team obtained next-of-kin permission to sample brain tissue from 5 people who had died with HIV infection and cryptococcal meningitis. They collected CSF, femoral artery blood, and samples from the cerebellum and pons. The researchers conducted postmortem analyses within 14 hours of death (median 5.2 hours). They measured drug levels with liquid chromatography coupled with triple quadrupole mass spectrometry.
Three people who had taken daily efavirenz/tenofovir/3TC (600/300/300 mg) had drug levels detectable in all compartments assessed. Four people who had taken fluconazole (400 to 1200 mg daily) also had detectable drug in all compartments.
CSF-to-plasma ratios for study drugs reflected those reported in the literature. But tissue-to-CSF ratios indicated discordance between the two measures: 0.09 to 1.48 for tenofovir, 0.09 to 0.32 for 3TC, 0.10 to 0.23 for fluconazole, and 8.25 to 16.77 for efavirenz. Tenofovir, 3TC, and fluconazole levels in CSF overpredicted brain tissue penetration about 7-fold. In contrast, efavirenz levels in CSF underpredicted brain penetration 9- to 14-fold.
The investigators concluded that "CSF is not a good surrogate for overall drug exposure in central nervous system tissues." Fluconazole in particular appeared to attain high levels in CSF but reached much lower levels in brain tissue. The Minnesota/Makerere researchers believe their findings support using postmortem tissues "to assess drug distribution to and within the central nervous system," a critical reservoir in the quest for HIV eradication.
Reference
1. Nicol M, Taylor J, Pastick K, et al. Differential brain tissue penetration of antiretrovirals and fluconazole. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy. May 22-24, 2018. Baltimore. Abstract 21.
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