Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir

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Abstract

Objectives:

Cobicistat and ritonavir have different inhibitory profiles for drug transporters that could impact the distribution of co-administered drugs. We compared darunavir concentrations in CSF when boosted by cobicistat versus ritonavir relative to plasma concentrations and with WT HIV-1 IC50 and IC90.

Methods:

An open, single-arm, sequential clinical trial (NCT02503462) where paired CSF and blood samples were taken from seven HIV-infected patients presenting with HIV-associated neurocognitive disorders (HAND) and treated with a darunavir/ritonavir (800/100 mg) once-daily regimen. Ritonavir was subsequently replaced by cobicistat and paired CSF and blood samples were obtained from the same patients after treatment with the darunavir/cobicistat (800/150 mg) once-daily regimen. Darunavir concentrations at the end of the dosing interval were quantified by LC-MS/MS.

Results:

The median (IQR) darunavir concentrations in CSF with ritonavir and cobicistat boosting were 16.4 ng/mL (8.6–20.3) and 15.9 ng/mL (6.7–31.6), respectively (P = 0.58). The median (IQR) darunavir CSF:plasma ratios with ritonavir and cobicistat boosting were 0.007 (0.006–0.012) and 0.011 (0.007–0.015), respectively (P = 0.16). Darunavir concentrations in CSF exceeded the darunavir IC50 and IC90 by a median of 9.2- and 6.7-fold with ritonavir boosting, and by 8.9- and 6.5-fold with cobicistat boosting, respectively. All patients had darunavir CSF concentrations above the target inhibitory concentrations and remained virologically suppressed in the CSF and plasma.

Conclusions:

This small study shows that cobicistat and ritonavir give comparable effective darunavir concentrations in CSF, thus suggesting that these boosters can be used interchangeably in once-daily darunavir regimens.

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