An Interaction Study to Assess Drug Levels in Fasting Healthy Adult Subjects

This randomized, open-label, six-arm, three-period drug interaction study will recruit 48
healthy volunteers so as to obtain a minimum of 36 evaluable subjects at a single study
center in the U.S. The study will have a screening visit, 3 treatment visits for
pharmacokinetics (PK) sampling and a follow-up visit. The screening visit will be conducted
within 30 days prior to receiving the first dose. Subjects will then be randomized into 1 of
6 treatment groups as shown below:

Cohort Size Period 1 Period 2 Period 3 Sample Days 1 to 7 Days 1-14 Days 1-14

A 8 RTG 400mg BID, FPV 1400mg BID, FPV 1400mg BID + RTG 400mg BID

B 8 RTG 400mg BID, FPV 1400mg BID + RTG 400mg BID , FPV 1400mg BID

C 8 RTG 400mg BID, FPV 700mg BID + RTV 100mg BID, FPV 700mg BID + RTV 100mg BID + RTG 400mg
BID

D 8 RTG 400mg BID, FPV 700mg BID + RTV 100mg BID + RTG 400mg BID, FPV 700mg BID + RTV 100mg
BID

E 8 RTG 400mg BID, FPV 1400mg QD + RTV 100mg QD, FPV 1400mg QD + RTV 100mg QD + RTG 400mg
BID

F 8 RTG 400mg BID, FPV 1400mg QD + RTV 100mg QD + RTG 400mg BID, FPV 1400mg QD + RTV 100mg
QD

Study subjects will enter the clinic in the morning prior to dosing in a fasting state and
remain at the center for 12 hours following each dose. Fourteen to 21 days following
completion of the third dosing period, study subjects will return to the clinic for
follow-up assessment. The total duration of the study will be approximately 86 days from
screening through follow up. Blood samples for drug concentration measurement of amprenavir
(APV) and raltegravir (RTG) concentrations will be collected over 12 hours at the end of
each dosing period (at 0 [baseline], 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose).
Subjects will undergo a physical examination, CBC with differential, HIV test, hepatitis B/C
test, liver function test, renal function analysis, and lipid panel at screening, and all of
these tests except those for HIV and hepatitis B/C will be repeated at follow-up post-study.
Adverse events and adherence (by pill count and medication diary) will be assessed by the
investigator/study personnel at the end of each dosing period. Evaluable patients will be
required to have adhered to at least 95% of their study drug doses. Plasma APV
concentrations will be analyzed using a validated high-performance liquid chromatography
method with tandem mass spectrometric detection (HPLC/MS/MS) and plasma RTG concentrations
by triple quadruple mass spectrometry. Plasma APV and RTG pharmacokinetic parameters
measured will include maximum concentration (Cmax), time to maximum concentration (Tmax),
minimum concentration (Cmin), and area under the concentration-time curve (AUC). All these
parameters, except Tmax, will be log-transformed before statistical analysis. Analysis of
variance, considering treatment as a fixed effect and subject as a random effect will be
performed using Statistical Analysis Software (SAS), and assuming a treatment ratio for
steady-state APV PK parameters as 1.0, the 90% confidence intervals will be within the range
0.81-1.24

Inclusion Criteria:

- Healthy subjects with no clinically significant abnormality identified by physician
by evaluation of medical history, physical examination, clinical laboratory tests or
vital signs.

- Between 18 and 64 years.

- A female subject is eligible to participate if she is neither pregnant nor lactating,
and falls into one of the following categories:

- non-childbearing potential including females with documented (medical report
verification) hysterectomy or bilateral oophorectomy, or post-menopausal females
defined as being amenorrheic for greater than 1 year and having estradiol and
follicle stimulating hormone (FSH) levels consistent with menopause.

- childbearing potential with a negative serum pregnancy test at screen and who
agrees to use one of the following methods of contraception from screening or at
least two weeks prior to the first dose (whichever is earlier) until the
follow-up visit (any contraception method must be used consistently and
correctly, i.e., in accordance with both the product label and the instructions
of a physician).

- Agreement for complete abstinence from intercourse.

- Double barrier contraception (male condom/spermicide, male condom/diaphragm,
diaphragm/spermicide).

- Any intrauterine device (IUD) with published data showing that the expected failure
rate is less than 1% per year (not all IUDs meet this criterion)

- Any other method with published data showing that the lowest expected failure rate
for that method is less than 1% per year.

- Adequate renal function (calculated creatinine clearance via Cockcroft and Gault
method (CrCl) > 50 mL/min).

- Adequate hepatic function (total bilirubin < 2.5mg/dL; hepatic transaminases < 5x
normal).

- Adequate hematologic function (absolute neutrophil count [ANC] > 750
neutrophils/mm^3; platelets > 50,000/mm^3; hematocrit > 25%).

- Non-smoker, defined as not having used nicotine-containing products within the past 6
months.

- Willingness and ability to adhere to treatment and follow-up procedures.

- The ability to understand and sign a written informed consent form.

- Body weight > or =50 kg for males and > or=45 kg for females and body mass index
(BMI) in the range of 19 to 30 kg/m^2 (BMI = weight [kg]/(height [m])^2).

Exclusion Criteria:

- Have an active infection that required parenteral antibiotics or hospitalization
within 2 weeks prior to enrollment.

- A history of or documented gastrointestinal diseases that impact drug absorption.

- Have a significant documented sulfa allergy (e.g., Stevens-Johnson Syndrome) or a
history of sensitivity to any of the study medications, or components thereof.

- HIV, Hepatitis B or C positive .

- Cigarette/cigar/pipe smokers.

- History of alcohol/drug abuse or dependence within 12 months of the study, or a
history of alcohol consumption in the past six months exceeding 7 units/week for
women and 14 units/week for men (where 1 unit = 5 ounces of wine or 12 ounces of beer
or 1.5 ounces of hard liquor).

- Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) preceding the first dose of study medication.

- Use of prescription or non-prescription drugs (including aspirin and nonsteroidal
anti-inflammatory drug (NSAIDs), vitamins, herbal and dietary supplements within 7
days (or 14 days if the drug is a potential enzyme inducer, such as St. John's Wort)
or 5 half-lives (whichever is longer) prior to the first dose of study medication,
unless in the opinion of the investigator the medication will not interfere with the
study procedures or compromise subject safety.

- Subjects who have donated plasma within 7 days prior to the screening visit or where
participation in this study would result in donation of blood in excess of 500 mL of
blood within 56 day period.