An Interaction Study to Assess Drug Levels in Healthy Adult Subjects

Steady-State Plasma Amprenavir (APV) and Raltegravir (RTG) Pharmacokinetics After Fosamprenavir (FPV) and Raltegravir (RTG) Are Each Administered Alone Versus in Combination With or Without Ritonavir (RTV) Boosting in Healthy Adult Subjects

To date, no study has investigated whether there is a drug interaction between the protease inhibitor fosamprenavir and the integrase inhibitor raltegravir. COL111242 is a randomized, open-label, 6-arm, 3-period, drug interaction study to assess steady-state plasma amprenavir (APV) and raltegravir (RTG) pharmacokinetics in 48 healthy, HIV-negative adults after administration of a 7-day regimen of RTG 400mg twice a day (BID) alone and after 14-day regimens of unboosted fosamprenavir (FPV) 1400mg twice daily (BID), FPV 700mg/Ritonavir (RTV) 100mg BID, or FPV 1400mg/ritonavir (RTV) 100mg once daily (QD) with and without concurrent RTG 400mg BID. Blood samples for drug concentration measurement will be collected over 12 hours at the end of each dosing period. Subjects will undergo a physical examination, complete blood count (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

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 FPV 1400mg BID

• RTG 400mg BID

C 8 RTG 400mg BID FPV 700mg BID FPV 700mg BID

• RTV 100mg BID + RTV 100mg BID
• RTG 400mg BID

D 8 RTG 400mg BID FPV 700mg BID FPV 700mg BID

• RTV 100mg BID + RTV 100mg BID
• RTG 400mg BID

E 8 RTG 400mg BID FPV 1400mg QD FPV 1400mg QD

• RTV 100mg QD + RTV 100mg QD
• RTG 400mg BID

F 8 RTG 400mg BID FPV 1400mg QD FPV 1400mg QD

• RTV 100mg QD + RTV 100mg QD
• RTG 400mg BID

Study subjects will enter the clinic in the morning prior to dosing 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:

• Age > 18 years
• 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
• Willingness and ability to adhere to treatment and follow-up procedures;
• The ability to understand and sign a written informed consent form.

Exclusion Criteria:

• They fail to meet the above inclusion 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
• Are receiving medications that are contraindicated or result in significant drug-drug interactions with RTV (including, but not limited to, triazolam, astemizole, ergot medications, cisapride, midazolam, bepridil, or rifampin)
• Have a significant documented sulfa allergy (e.g., Stevens-Johnson Syndrome)
• HIV, Hepatitis B or C positive
• Cigarette/cigar/pipe smokers
• They are pregnant or lactating. All other women of childbearing potential must use effective method(s) of contraception throughout the study participation and for 30 days following the end of the study.