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Similar Darunavir Levels in CSF With RTV or COBI Boost
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18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Darunavir attained similar cerebrospinal fluid (CSF) levels with ritonavir (RTV) and cobicistat (COBI) boosting in a study of 7 people with HIV-associated neurocognitive disorder (HAND) [1].
Researchers from university hospitals in Basel and Lausanne noted that RTV and COBI do not have an identical impact on inhibition of drug transporters that could affect drug distribution to the brain and other sites. For example, in vitro studies show weaker inhibition of the transporters P-gp and BCRP with COBI than RTV. The researchers hypothesized that weaker inhibition of the efflux transporters P-gp and BCRP by COBI "could result in less darunavir crossing the blood-brain barrier" when boosted by COBI versus RTV.
This open one-arm trial collected paired blood and CSF samples from patients with HAND who needed lumbar puncture for clinical reasons and who were taking a regimen including darunavir/RTV at a dose of 800/100 mg once daily for at least 30 days The study excluded people with conditions or medications that might affect drug penetration of the central nervous system.
After paired plasma and CSF sampling at the end of a dosing interval, participants switched to darunavir/COBI at 800/150 mg once daily for at least 30 days and had a second paired sampling at the end of a dosing interval. The need for two lumbar punctures made recruitment for this trial difficult and limited participation to 7 people, 2 of them women, 1 African, 1 Asian, and 5 Caucasian.
Median darunavir trough concentrations in plasma stood at 1761 ng/mL (interquartile range [IQR] 1614 to 2473) with RTV and 1275 ng/mL (IQR 657 to 3240) with COBI, a nonsignificant difference (P = 0.94). Respective darunavir CSF troughs with RTV and COBI boosting were 16.4 ng/mL (IQR 8.6 to 20.3) and 15.9 ng/mL (IQR 6.7 to 31.6) (P = 0.58).
The median CSF-to-plasma ratio was slightly lower with RTV boosting (0.007, IQR 0.006 to 0.012) than with COBI boosting (0.011, IQR 0.007 to 0.015), a difference still shy of statistical significance (P = 0.16).
Every darunavir trough in CSF exceeded 50% and 90% inhibitory concentrations (IC50 and IC90) with either RTV or COBI boosting--by 9.2-fold and 6.7-fold with RTV, and by 8.9-fold and 6.5-fold with COBI. All study participants maintained virologic suppression in plasma and CSF throughout the study.
The Swiss team concluded that RTV and COBI boost darunavir to similar levels in CSF "and therefore can be used interchangeably as boosters in patients with HAND." They noted that COBI boosting led to higher interpatient variability of darunavir levels in both CSF and plasma, yet everyone in this small study attained adequate CSF darunavir concentrations with COBI.
References
1. Marzolini C, Bartels H, Decosterd L, Battegay M. Darunavir concentrations in CSF in HIV-infected individuals when boosted with cobicistat versus ritonavir. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_06.
2. ClinicalTrials.gov. Effect of cobicistat versus ritonavir boosting on the brain permeation of darunavir in HIV-infected individuals. ClinicalTrial.gov identifier NCT02503462. https://clinicaltrials.gov/ct2/show/NCT02503462
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