Antiretroviral Drug Interaction Study in Volunteers With HIV

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.

- INCLUSION CRITERIA:

A subject will be considered eligible for this study only if all of the following criteria
are met:

1. Between the ages of 18 and 70 years.

2. HIV-infected patients stabilized (greater than or equal to 90 days) on ARV regimens
containing efavirenz 600 mg daily, or atazanavir/ritonavir 300/100 mg daily or
HIV-infected patients not receiving ARV therapy.

3. CD4 cells greater than or equal to 350 cells/mm3 for HIV-infected patients not
receiving ARV therapy.

4. CD4 cells >200 cells/mm3 for HIV-infected patients receiving ARV therapy.

5. Virologically suppressed patients receiving ARV therapy (<200 copies/mL on at least 2
consecutive occasions, within 6 months prior to enrollment).

6. Females of child bearing potential who are able and willing to prevent pregnancy by
(a) practicing abstinence or (b) using effective methods of birth control, such as
condoms, during the study period and for 1 month after study completion.

7. Subject agrees to storage of specimens for future research.

EXCLUSION CRITERIA:

A subject will be ineligible for this study if 1 or more of the following criteria are
met:

1. Concomitant routine therapy with any prescription, over-the- counter, herbal, or
holistic medications that are known or suspected to alter atovaquone including
rifampin, rifabutin, and metoclopramide for 14 days prior to study participation.

2. Subjects receiving primary or secondary prophylaxis for PCP or toxoplasmosis.

3. ARV regimens containing both EFV and ATV/r.

4. Subjects receiving hormonal contraceptives within 90 days of Study Day 1.

5. Inability to obtain venous access for sample collection.

6. Laboratory and/or physical evidence of any active opportunistic infection.

Diabetes mellitus requiring treatment with insulin, active tuberculosis, cardiac
disease (uncontrolled hypertension and/or heart failure etc.), renal disease (chronic
or acute renal failure or insufficiency resulting in baseline serum creatinine
greater than 1.5 times upper limit of normal [ULN]), untreated/uncontrolled thyroid
disease, untreated/uncontrolled psychiatric disease, active hepatitis (liver failure
resulting in liver function tests greater than 3 times the ULN, ascites, or jaundice
in the absence of ATV), or any other condition that may interfere with the
interpretation of the study results or not be in the best interest of the subject in
the opinion of the Investigator.

7. Positive pregnancy test or breastfeeding female.

8. The presence of persistent diarrhea or malabsorption that could interfere with the
subject s ability to absorb drugs.

9. Drug or alcohol use that may impair safety or adherence.

10. History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty
breathing) to atovaquone.

11. Bleeding disorders (hemophilia, G.I., or intracranial bleeding).

12. Organ transplant recipient.

13. Documented ongoing problems with medication adherence.

14. High likelihood of switching ARV regimen within 12 weeks of the start of the study.