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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Raltegravir; Drug: Fosamprenavir; Drug: Ritonavir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A; Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 1400mg BID Period 3-Fosamprenavir 1400mg BID + Raltegravir 400mg BID	Drug: Raltegravir; 400mg BID; Other Names: Isentress MK-0518; Drug: Fosamprenavir; 1400mg BID, 700 mg BID or 1400 mg QD; Other Names: Lexiva
Active Comparator: Group B; Period 1-Raltegravir 400mg BID Period2-Fosamprenavir 1400mg BID + Raltegravir 400mg BID Period 3-Fosamprenavir 1400mg BID	Drug: Raltegravir; 400mg BID; Other Names: Isentress MK-0518; Drug: Fosamprenavir; 1400mg BID, 700 mg BID or 1400 mg QD; Other Names: Lexiva
Active Comparator: Group C; Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 700mg BID + Ritonavir 100mg BID Period 3-Fosamprenavir 700mg BID + Ritonavir 100mg BID + Raltegravir 400mg BID	Drug: Raltegravir; 400mg BID; Other Names: Isentress MK-0518; Drug: Fosamprenavir; 1400mg BID, 700 mg BID or 1400 mg QD; Other Names: Lexiva; Drug: Ritonavir; 100 mg BID or QD; Other Names: Norvir
Active Comparator: Group D; Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 700mg BID + Ritonavir 100mg BID + Raltegravir 400mg BID Period 3-Fosamprenavir 700mg BID + Raltegravir 100mg BID	Drug: Raltegravir; 400mg BID; Other Names: Isentress MK-0518; Drug: Fosamprenavir; 1400mg BID, 700 mg BID or 1400 mg QD; Other Names: Lexiva; Drug: Ritonavir; 100 mg BID or QD; Other Names: Norvir
Active Comparator: Group E; Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 1400mg QD + Ritonavir 100mg QD Period 3-Fosamprenavir 1400mg QD + Ritonavir 100mg QD + Raltegravir 400mg BID	Drug: Raltegravir; 400mg BID; Other Names: Isentress MK-0518; Drug: Fosamprenavir; 1400mg BID, 700 mg BID or 1400 mg QD; Other Names: Lexiva; Drug: Ritonavir; 100 mg BID or QD; Other Names: Norvir
Active Comparator: Group F; Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 1400mg QD + Ritonavir 100mg QD + Raltegravir 400mg BID Period 3-Fosamprenavir 1400mg QD + Ritonavir 100mg QD	Drug: Raltegravir; 400mg BID; Other Names: Isentress MK-0518; Drug: Fosamprenavir; 1400mg BID, 700 mg BID or 1400 mg QD; Other Names: Lexiva; Drug: Ritonavir; 100 mg BID or QD; Other Names: Norvir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmin/Cmax: Steady-state Plasma Amprenavir (APV) Pharmacokinetics (PK) Following Admin of Fosamprenavir (FPV) 1400mg BID, FPV 700mg/Ritonavir (RTV) 100 mg BID, or FPV 1400mg/RTV 100mg QD With and Without Concurrent Raltegravir (RTG) 400mg BID.	APV minimum concentration (Cmin), maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), and oral clearance (CL/F) as determined from APV concentrations observed in blood samples obtained at baseline, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours during the BID regimens (FPV 1400mg BID, FPV 700mg/RTV 100 mg BID), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours during the QD regimen (FPV 1400mg/RTV 100mg QD). As Groups A and B received the same regimens (albeit in different order), PK data for these two groups were collated, then assessed. For the same reason, PK data from Groups C and D regimens were collated before assessment, as were the PK data from Groups E and F	Day 14 of the FPV 1400mg BID, FPV 1400mg/RAL 400mg BID, FPV 700mg/RTV 100mg BID, FPV 700mg/RTV 100mg/RAL 400mg BID, FPV 1400mg/RTV 100mg QD, and FPV 1400mg/RTV 100mg QD plus RAL 400mg BID regimens
AUC: Steady-state Plasma Amprenavir (APV) Pharmacokinetics (PK) Following Admin of Fosamprenavir (FPV) 1400mg BID, FPV 700mg/Ritonavir (RTV) 100 mg BID, or FPV 1400mg/RTV 100mg QD With and Without Concurrent Raltegravir (RTG) 400mg BID.	APV minimum concentration (Cmin), maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), and oral clearance (CL/F) as determined from APV concentrations observed in blood samples obtained at baseline, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours during the BID regimens (FPV 1400mg BID, FPV 700mg/RTV 100 mg BID), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours during the QD regimen (FPV 1400mg/RTV 100mg QD). As Groups A and B received the same regimens (albeit in different order), PK data for these two groups were collated, then assessed. For the same reason, PK data from Groups C and D regimens were collated before assessment, as were the PK data from Groups E and F	Day 14 of the FPV 1400mg BID, FPV 1400mg/RAL 400mg BID, FPV 700mg/RTV 100mg BID, FPV 700mg/RTV 100mg/RAL 400mg BID, FPV 1400mg/RTV 100mg QD, and FPV 1400mg/RTV 100mg QD plus RAL 400mg BID regimens
CL/F: Steady-state Plasma Amprenavir (APV) Pharmacokinetics (PK) Following Administration of Fosamprenavir (FPV) 1400mg BID, FPV 700mg/Ritonavir (RTV) 100 mg BID, or FPV 1400mg/RTV 100mg QD With and Without Concurrent Raltegravir (RTG) 400mg BID.	APV minimum concentration (Cmin), maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), and oral clearance (CL/F) as determined from APV concentrations observed in blood samples obtained at baseline, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours during the BID regimens (FPV 1400mg BID, FPV 700mg/RTV 100 mg BID), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours during the QD regimen (FPV 1400mg/RTV 100mg QD). As Groups A and B received the same regimens (albeit in different order), PK data for these two groups were collated, then assessed. For the same reason, PK data from Groups C and D regimens were collated before assessment, as were the PK data from Groups E and F	Day 14 of the FPV 1400mg BID, FPV 1400mg/RAL 400mg BID, FPV 700mg/RTV 100mg BID, FPV 700mg/RTV 100mg/RAL 400mg BID, FPV 1400mg/RTV 100mg QD, and FPV 1400mg/RTV 100mg QD plus RAL 400mg BID regimens
Cmin/Cmax: Steady-state Plasma RTG PK Following Admin of FPV 1400mg BID, FPV 700mg/RTV 100 mg BID, or FPV 1400mg/RTV 100mg QD With and Without Concurrent RTG 400mg BID.	RAL minimum concentration (Cmin), maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), and oral clearance (CL/F) as determined from RAL concentrations observed in blood samples obtained at baseline, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours during the period when RAL 400mg BID was administered with the FPV-Containing BID regimens (FPV 1400mg BID, FPV 700mg/RTV 100 mg BID), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours during the period when RAL 400mg BID was administered with the FPV QD regimen (FPV 1400mg/RTV 100mg QD). As Groups A and B received the same regimens (albeit in different order), PK data for these two groups were collated, then assessed. For the same reason, PK data from Groups C and D regimens were collated before assessment, as were the PK data from Groups E and F.	Day 7 of the RAL 400mg BID regimen and Day 14 of the RAL 400mg/FPV 1400mg BID, RAL 400mg/FPV 700mg/RTV 100mg BID, and RAL 400mg BID Plus FPV 1400mg/RTV 100mg QD regimens
AUC: Steady-state Plasma Amprenavir (APV) Pharmacokinetics (PK) Following Administration of Fosamprenavir (FPV) 1400mg BID, FPV 700mg/Ritonavir (RTV) 100 mg BID, or FPV 1400mg/RTV 100mg QD With and Without Concurrent Raltegravir (RTG) 400mg BID.	APV minimum concentration (Cmin), maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), and oral clearance (CL/F) as determined from APV concentrations observed in blood samples obtained at baseline, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours during the BID regimens (FPV 1400mg BID, FPV 700mg/RTV 100 mg BID), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours during the QD regimen (FPV 1400mg/RTV 100mg QD). As Groups A and B received the same regimens (albeit in different order), PK data for these two groups were collated, then assessed. For the same reason, PK data from Groups C and D regimens were collated before assessment, as were the PK data from Groups E and F	Day 7 of the RAL 400mg BID regimen and Day 14 of the RAL 400mg/FPV 1400mg BID, RAL 400mg/FPV 700mg/RTV 100mg BID, and RAL 400mg BID Plus FPV 1400mg/RTV 100mg QD regimens
CL/F: Steady-state Plasma Amprenavir (APV) Pharmacokinetics (PK) Following Administration of Fosamprenavir (FPV) 1400mg BID, FPV 700mg/Ritonavir (RTV) 100 mg BID, or FPV 1400mg/RTV 100mg QD With and Without Concurrent Raltegravir (RTG) 400mg BID.	APV minimum concentration (Cmin), maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), and oral clearance (CL/F) as determined from APV concentrations observed in blood samples obtained at baseline, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours during the BID regimens (FPV 1400mg BID, FPV 700mg/RTV 100 mg BID), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours during the QD regimen (FPV 1400mg/RTV 100mg QD). As Groups A and B received the same regimens (albeit in different order), PK data for these two groups were collated, then assessed. For the same reason, PK data from Groups C and D regimens were collated before assessment, as were the PK data from Groups E and F	Day 7 of the RAL 400mg BID regimen and Day 14 of the RAL 400mg/FPV 1400mg BID, RAL 400mg/FPV 700mg/RTV 100mg BID, and RAL 400mg BID Plus FPV 1400mg/RTV 100mg QD regimens

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Adverse Events	Safety/tolerability data included all adverse events (AEs) reported within the time frame of each regimen evaluated. The intent was to compare adverse events for each sequence and not for each regimen. The regimens for which AE information was culled were: RAL 400mg BID alone; FPV 1400mg BID alone; FPV 700mg/RTV 100 mg BID alone; FPV 1400mg/RTV 100mg QD alone; FPV 1400mg BID combined with RAL 400mg BID; FPV 700mg/RTV 100 mg BID combined with RAL 400mg BID; FPV 1400mg/RTV 100mg QD combined with RAL 400mg BID The severity of reported AEs was graded according to DAIDS criteria, Version 1.0 (National Institute of Allergy and Infectious Diseases (NIAID). Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0. Division of Acquired Immunodeficiency Syndrome (DAIDS), Washington D.C.; 2004.	Day 0 through Day 49

Collaborators and Investigators

• Sponsor: Garden State Infectious Disease Associates, PA
• Collaborators: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): March 1, 2008
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: February 1, 2008
• First Submitted That Met QC Criteria: February 13, 2008
• First Posted (Estimate): February 14, 2008

Study Record Updates

• Last Update Posted (Estimate): January 29, 2016
• Last Update Submitted That Met QC Criteria: January 27, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Healthy Subjects; Pharmacokinetics study; Pharmacokinetics of medications
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Raltegravir Potassium; Ritonavir; Fosamprenavir
• Other Study ID Numbers: COL111242

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No