Antiretroviral Drug Interaction Study in Volunteers With HIV
Condition: HIV; PCP; Toxoplasmosis
MeSH terms: Toxoplasmosis
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - People who are infected with the human immunodeficiency virus (HIV) are at risk of getting
      certain diseases. Two of these diseases are a type of pneumonia known as PCP and a brain
      infection called toxoplasmosis. Most people with HIV take antiretroviral (ARV) drugs to treat
      HIV and lower the risk of infections. However, some ARV drugs may make other drugs used to
      treat PCP and toxoplasmosis less effective. Researchers want to test specific ARV drugs to
      see if they affect atovaquone, a drug used to treat PCP and toxoplasmosis.

      Objectives:

      - To see if ARV drugs atazanavir-ritonavir or efavirenz lower the blood levels of atovaquone.

      Eligibility:

        -  Individuals between 18 and 70 years of age who have HIV.

        -  Participants must be taking efavirenz or atazanavir-ritonavir, or not taking any ARV
           drugs.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will also
           have blood and urine tests.

        -  This study has a screening visit and five study visits. Two of the study visits will
           last about 12 hours; the other three visits will last about 1 hour each.

        -  Participants will receive either a low dose or high dose of atovaquone to take for 14
           days. They will record doses and any symptoms on a diary card at home.

        -  After 14 days, participants will have a 12-hour visit to provide blood samples. There
           will be a wash-out period with no doses for up to 6 weeks.

        -  After the wash-out period, participants will switch dose levels to either the high or
           low dose.

        -  After 14 days, participants will have a 12-hour visit to provide blood samples.
    

Detailed description: 
      The incidence of opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP) and
      Toxoplasma gondii have substantially declined in patients with HIV infection due to potent
      combination antiretroviral (ARV) therapy and effective prophylaxis. The drug of choice for
      prophylaxis and treatment of PCP and toxoplasmosis is trimethoprim-sulfamethoxazole (TMP-SMX)
      and sulfadiazine, respectively. In patients who cannot tolerate these first line therapies,
      atovaquone is a common alternative. While generally considered safe and effective, a recent
      drug interaction study involving a single dose of combination tablet of atovaquone/proguanil
      (Malarone ) in HIV-infected patients showed that atovaquone plasma concentrations were
      significantly lowered (compared to healthy volunteers) by 75%, 74%, and 46% in patients
      taking the ARV medications efavirenz (EFV), lopinavir-ritonavir (LPV/r), and
      atazanavir-ritonavir (ATV/r), respectively. The mechanism of this drug interaction is unknown
      but is presumably due to induction of uridine diphosphate glucuronsosyltransferase (UGT)
      enzymes responsible for the metabolism of atovaquone. The magnitude of this interaction is
      such that it strongly suggests a clinically relevant drug interaction between atovaquone and
      the aforementioned ARVs. The purpose of this study is to determine whether HIV-infected
      subjects receiving ATV/r or EFV-containing ARV regimens, experience reductions in atovaquone
      exposure under steady state conditions compared to HIV-infected patients not receiving ARV
      therapy.

      In this open-label study, 30 HIV-infected subjects will participate in 1 of 3 groups of 10
      (Groups A, B, and C). Group A will consist of 10 subjects who are already receiving
      combination ARV therapy containing ATV/r; Group B will consist of 10 subjects already
      receiving combination ARV therapy containing EFV; and Group C will consist of 10 subjects who
      are not currently receiving ARV therapy. All subjects in Groups A, B, and C will be randomly
      assigned to either receive atovaquone 750 mg twice daily for 14 days (Phase 1) followed by a
      2-6 week washout period, followed by atovaquone 1500 mg twice daily for 14 days (Phase 2), or
      vice versa. Pharmacokinetic (PK) sampling for atovaquone will occur on Day 14 of Phase 1 and
      2.

      Atovaquone PK parameters will be determined using non-compartmental methods with the
      WinNonlin professional computer program (version 5.2; Pharsight Corporation, Mountain View,
      CA). The following PK parameters will be compared among the groups: area under the
      concentration vs. time curve (AUC ?), maximum concentration (Cmax), apparent oral clearance
      (Cl/F), time to reach maximum concentration (Tmax), and half-life (T (Omega)). Data from this
      investigation will determine whether ATV/r and/or EFV alter the steady state PK of atovaquone
      in HIV-infected subjects. This information will assist clinicians in choosing appropriate
      alternative therapies for the treatment of PCP and toxoplasmosis in patients who are not
      candidates for first line therapies.
    

Intervention name(s): Atovaquone 750 mg twice daily; Atovaquone 1500 mg twice daily
Intervention type(s): Drug; Drug
Intervention MeSH terms: Atovaquone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Atovaquone; Drug Interaction; Pharmacokinetics; Efavirenz; Atazanavir-Ritonavir; HIV