Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals

AIDS-related Dementia Complex Clinical Trial

Official title:

Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02503462
• Other study ID #: DRVCOBI
• Status: Terminated
• Phase: Phase 4
• First received: July 9, 2015
• Last updated: February 1, 2017
• Start date: July 2015
• Est. completion date: January 2017

Study information

• Verified date: February 2017
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess whether a boosting by cobicistat results in similar concentrations of darunavir in the brain compared to a boosting by ritonavir.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7
• Est. completion date: January 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• AIDS Dementia Complex
• AIDS-related Dementia Complex
• Dementia

Intervention

Drug:
• Darunavir
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).
• ritonavir
ritonavir 100 mg once daily will be used to boost darunavir 800 mg once daily (period 1).
• cobicistat
cobicistat 150 mg once daily will be used to boost darunavir 800 mg once daily (period 2).

Locations

Country	Name	City	State
Switzerland	Division of Infectious Diseases, University Hospital Basel	Basel	BS

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cerebrospinal fluid/plasma concentrations (ng/ml) of darunavir/ritonavir versus darunavir/cobicistat	darunavir concentrations (ng/ml) in the cerebrospinal fluid when coadministered with ritonavir versus cobicistat relative to the corresponding concentrations of darunavir in the plasma	1 month
Secondary	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	darunavir concentrations (ng/ml) in the cerebrospinal fluid when coadministered with ritonavir versus cobicistat relative to darunavir concentrations (ng/ml) suppressing HIV replication by 50% and 90% (IC50 and IC90)	1 month
Secondary	Proportion of responders (HIV RNA < 50 copies/ml in CSF) for darunavir/ritonavir versus darunavir/cobicistat		1 month