Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals
Keywords
Abstract
Description
Cobicistat is a new pharmacokinetic enhancer or booster of the HIV protease inhibitor darunavir. Cobicistat is distinct from the conventional booster ritonavir in that cobicistat presents a more selective inhibition of the enzymes metabolizing drugs. In addition, cobicistat is a weaker inhibitor of the efflux drug transporters expressed at the level of the blood-brain barrier (i.e. P-glycoprotein (P-gp) and breast cancer resistance Protein (BCRP)). A weaker inhibition of these efflux transporters could possibly result in less darunavir entering the brain when boosted by cobicistat as compared to a boosting by ritonavir. Such a difference could potentially be critical in patients with HIV-associated neurocognitive disorders as sufficient drug levels are needed to efficiently inhibit HIV replication inside the brain.
The aim of this study is to determine whether the boosting of darunavir by cobicistat results effectively in lower darunavir concentrations in the CSF as compared to a boosting by ritonavir. The study will be performed in HIV infected patients presenting HIV associated neurocognitive disorders (HAND) and requiring a lumbar puncture for clinical reasons. In addition, the patients will be only eligible if the are treated or if they qualify for a darunavir/ritonavir (800/100 mg once daily) containing regimen. Darunavir concentrations will be measured simultaneously in the CSF and plasma (CSF/plasma ratio) first with the ritonavir boosting and subsequently with the cobicistat boosting.
Dates
| Last Verified: | 01/31/2017 |
| First Submitted: | 07/08/2015 |
| Estimated Enrollment Submitted: | 07/16/2015 |
| First Posted: | 07/20/2015 |
| Last Update Submitted: | 01/31/2017 |
| Last Update Posted: | 02/01/2017 |
| Actual Study Start Date: | 06/30/2015 |
| Estimated Primary Completion Date: | 12/31/2016 |
| Estimated Study Completion Date: | 12/31/2016 |
Condition or disease
Intervention/treatment
Drug: darunavir/ritonavir vs cobicistat
Drug: darunavir/ritonavir vs cobicistat
Drug: darunavir/ritonavir vs cobicistat
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: darunavir/ritonavir vs cobicistat All HIV infected patients will be treated with a darunavir/ritonavir (800/100 mg) once daily containing regimen. Darunavir/ritonavir concentrations will be measured simultaneously in CSF and plasma after 1 month of treatment. The treatment will be switched to darunavir/cobicistat (800/150 mg) once daily and darunavir/cobicistat levels will be measured in CSF and plasma after 1 month of treatment. | Drug: darunavir/ritonavir vs cobicistat darunavir 800 mg once daily will be first given together with ritonavir 100 mg once daily for one month (period 1) and then darunavir 800 mg once daily will be given together with cobicistat 150 mg once daily for one month (period 2). Afterwards, all patients will be switched back to darunavir/ritonavir (800/100 mg once daily). |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - documented HIV infection - presence of HIV associated neurocognitive disorders requiring a lumbar puncture for clinical reasons - treatment or qualifying to be treated with a HIV therapy including darunavir/r (800/100 mg once daily) - ability to comply with the study requirements - informed consent Exclusion Criteria: - conditions which disrupt the blood-brain barrier and thereby impact the entry of drugs in the brain (meningitis, meningoencephalitis, multiple sclerosis, progressive multifocal leucoencephalopathy) - co-medications inhibiting/inducing P-glycoprotein and BCRP - co-medications inhibiting/inducing cytochrome P450 isoenzyme 3A4 (CYP3A4) - non adherence to Treatment - pregnancy |
Outcome
Primary Outcome Measures
1. Cerebrospinal fluid/plasma concentrations (ng/ml) of darunavir/ritonavir versus darunavir/cobicistat [1 month]
Secondary Outcome Measures
1. Cerebrospinal fluid concentrations (ng/ml) of darunavir/ritonavir versus darunavir/cobicistat relative to the concentration of darunavir (ng/ml) inhibiting 50% (IC50) or 90% (IC90) of the viral replication [1 month]
2. Proportion of responders (HIV RNA < 50 copies/ml in CSF) for darunavir/ritonavir versus darunavir/cobicistat [1 month]
