A Phase IB, Open Label Study to Examine the Safety, Pharmacokinetic Characteristics and Anti-Inflammatory Effects of the NK-1R Antagonist, Aprepitant, In HIV-Infected Subjects Receiving Atazanavir/Ritonavir Or Darunavir/Ritonavir
Overview
- Phase
- Phase 1
- Intervention
- Aprepitant
- Conditions
- HIV Infection
- Sponsor
- University of Pennsylvania
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Inflammatory
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This is an open-label, single arm, phase I study to determine the safety, PK characteristics and anti-inflammatory effects of the NK-R1 coadministered with ritonavir-containing antiretroviral therapy in individuals with well-controlled viral replication.
Our hypothesis is that Aprepitant will be safe, well tolerated, and will have anti-inflammatory properties when administered concomitantly with the protease inhibitor ritonavir.
Detailed Description
This is an open-label, single arm, phase I study to determine the safety, PK characteristics and anti-inflammatory effects of the NK-R1 coadministered with ritonavir-containing antiretroviral therapy in individuals with well-controlled viral replication. Our hypothesis is that Aprepitant will be safe, well tolerated, and will have anti-inflammatory properties when administered concomitantly with the protease inhibitor ritonavir. The study will recruit 12 participants receiving either darunavir/ritonavir or atazanavir/ritonavir
Investigators
Eligibility Criteria
Inclusion Criteria
- •HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
- •Antiretroviral treatment with a regimen that includes either atazanavir 300 mg daily with ritonavir 100 mg daily or darunavir/ritonavir on a combination of 800/100 mg daily for at least 6 months prior to enrollment.
- •CD4+ cell count ≥ 350/mm3 for at least 6 months prior to enrollment and performed at any CLIA-certified laboratory.
- •Plasma HIV-1 RNA below the limit of quantification of an ultrasensitive assay as measured by any standard assay (the Roche Amplicor, the UltraSensitive HIV-1 Monitor assay (Roche Molecular Systems), or Version 3 bDNA assay or other) for at least 6 months prior to enrollment by any laboratory that is CLIA-certified (or its equivalent) for the assay.
- •Laboratory values obtained within 30 days prior to study entry, as follows:
- •Absolute neutrophil count (ANC) greater or equal than 750/mm3
- •Hemoglobin greater or equal than 10.0 g/dL
- •Platelet count greater or equal than 100,000/mm3
- •Creatinine less or equal than 2 x ULN (fasting)
- •AST (SGOT), ALT (SGPT), and alkaline phosphatase less or equal than 2 x ULN
Exclusion Criteria
- •Diabetes requiring treatment with oral hypoglycemics or insulin therapy.
- •Pregnancy within 90 days prior to study entry.
- •Use of inhibitors of metabolism by the cytochrome P450 3A4 with the exception of ritonavir, atazanavir and darunavir (i.e. Diltiazem, Ketoconazole, Clarithromycin, Nelfinavir, Itraconazole, Nefazodone, Troleandomycin)
- •Use of inducers of metabolism by the cytochrome P450 3A4 (i.e.: Rifampin, Carbamazepine, Phenytoin) with the exception of the protease inhibitors considered in this trial.
- •Breast-feeding.
- •Use of systemic corticosteroids or hormonal agents within 90 days prior to study entry.
- •Use of any immunomodulator, HIV vaccines, or investigational therapy within 90 days prior to study entry. However, if the experimental agent has a short half life, as determined by the Principal Investigator, the required wash out period can be reduced to 30 days.
- •Any vaccination within 30 days prior to study entry.
- •Use of systemic cytotoxic chemotherapy within 90 days prior to study entry.
- •History of allergy to aprepitant or its formulations.
Arms & Interventions
Aprepitant
Subjects will add 375 mg daily dosing of aprepitant (Emend®) to their current antiretroviral therapy for 28 days. * 6 participants will be receiving an antiretroviral regimen containing atazanavir/ritonavir (300/100 mg) daily plus two other antiretrovirals. * 6 participants will be receiving an antiretroviral regimen containing darunavir/ritonavir (800/100 mg) daily plus two other antiretrovirals.
Intervention: Aprepitant
Outcomes
Primary Outcomes
Inflammatory
Time Frame: 14 days
Change in levels of Soluble CD163 from baseline to Day 14.
Safety
Time Frame: 28 days
Incidence of Grade 2, 3, and 4 adverse events (using the DAIDS grading scale) by body system and by type. Lack of virologic control is considered a safety event for the purpose of this trial.
Pharmacokinetic Cmin:
Time Frame: day 1, 14 and 28
Trough plasma aprepitant concentration.
Pharmacokinetic Cmax
Time Frame: day 1, 14 and 28
Maximum plasma concentration.
Pharmacokinetic Tmax
Time Frame: day 1, 14 and 28
Time to maximum plasma concentration
Pharmacokinetic AUCss
Time Frame: day 1, 14 and 28
Area under the plasma concentration-time curve at steady-state (based on steady-state assessment of trough concentrations or via modeling).
Secondary Outcomes
- Lipids(28 days)
- Neurological(28 days)
- Inflammatory markers(28 days)