Drug Interaction Study

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00646776
First received: March 26, 2008
Last updated: January 23, 2013
Last verified: January 2013
  Purpose

The purpose of this study is to evaluate the exposure of rifabutin (RIB) when administered with atazanavir and ritonavir (ATV/RTV)


Condition Intervention Phase
Antivirals/HIV
Drug: Rifabutin
Drug: Rifabutin + Atazanavir + Ritonavir
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Study to Evaluate the Exposure of Rifabutin Administered in an Alternate Regimen in Combination With Atazanavir and Ritonavir Healthy Subjects

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB) [ Time Frame: Pre-dose (0 hours [h]) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150mg once daily (QD); AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7.

  • Maximum Plasma Concentration (Cmax) of RIB [ Time Frame: Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmax was derived from plasma concentration versus time for RIB and was recorded directly from experimental observations for each treatment period.

  • Minimum Plasma Concentration (Cmin) of RIB [ Time Frame: Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmin was derived from plasma concentration versus time for RIB.

  • AUC24avg for 25-O-Desacetyl-RIB [ Time Frame: Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150 mg QD; AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7

  • Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB) [ Time Frame: Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmax was derived from the plasma concentration versus time for 25-O-Desacetyl-RIB (a metabolite of RIB) and was recorded directly from experimental observations for each treatment period.

  • Cmin of 25-O-Desacetyl-RIB [ Time Frame: Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmin was derived from plasma concentration versus time for 25-O-Desacetyl-RIB.

  • Total Area Under the Plasma Concentration-time Curve (AUCtot) [ Time Frame: Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    AUCtot represents the total free RIB plus 25-O-Desacetyl-RIB output. It is calculated as: AUCtot (micromolar[µM]*h) = AUC24avg(RIB)(ng*h/mL)/847.016 (g/mole) + AUC24avg(25-O-Desacetyl-RIB)(ng*h/mL)/804.979(g/mole). The 300 mg RIB arm represents an extrapolation from the 150 mg RIB group.


Secondary Outcome Measures:
  • Cmax of ATV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.

  • Cmin of ATV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmin was derived from the plasma concentration versus time for ATV.

  • AUC(TAU) for ATV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    AUC(TAU) was derived from the plasma concentration versus time for ATV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Tmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.

  • Terminal Elimination Half-life (T-half) of ATV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    T-half was obtained directly from the concentration-time data. T-half following doses administered for treatment ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly.

  • Cmax of RTV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.

  • Cmin of RTV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Cmin was derived from the plasma concentration versus time for RTV.

  • AUC(TAU) for RTV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    AUC(TAU) was derived from the plasma concentration versus time for RTV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm.

  • Tmax of RTV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    Tmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.

  • T-half of RTV [ Time Frame: Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. ] [ Designated as safety issue: No ]
    T-half was obtained directly from the concentration-time data.

  • Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. [ Time Frame: From Day 1 to 30 days after the last dose of study drug. ] [ Designated as safety issue: Yes ]
    AEs were defined as new, untoward medical occurrences/worsening of pre-existing medical condition, whether drug-related or not. SAEs were defined as any AE that: resulted in death; was life threatening; resulted in a persistent or significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was a cancer; or was an overdose. Discontinuation from the study was due either to an AE or was conducted at the investigator's discretion.

  • Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes [ Time Frame: Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin/hematocrit: <0.85 x pre-treatment (pre-Rx) value. Platelet count: <0.85 x lower limit of normal (LLN) (or, if pre-Rx value <LLN, then <0.85 x pre-Rx value) or >1.5 x upper limit of normal (ULN). Leukocytes: <0.9 x LLN or >1.2 x ULN (or, if pre-Rx value <LLN, then <0.85 x pre-Rx or >ULN. If pre-Rx value >ULN, then >1.15 x pre-Rx or <LLN).

  • Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) [ Time Frame: Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils+bands (absolute): <=1.50 x 10^3 cells/microliter (uL). Lymphocytes (absolute): <0.75 x 10^3 cells/uL or >7.50 x 10^3 cells/uL. Monocytes (absolute): >2.00 x 10^3 cells/uL. Basophils (absolute): >0.40 x 10^3 cells/uL. Eosinophils (absolute): >0.75 x 10^3 cells/uL.

  • Number of Participants With MAs in Serum Chemistry: Alkaline Phosphatase (ALP),Aspartate Aminotransferase (AST),Alanine Aminotransferase (ALT),Bilirubin (Total),Bilirubin (Direct),Blood Urea Nitrogen (BUN),Creatinine,Sodium (Serum),Potassium (Serum) [ Time Frame: Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. ] [ Designated as safety issue: Yes ]
    MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, AST, ALT:>1.25xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Bilirubin (total), bilirubin (direct), BUN:>1.1xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Creatinine:>1.33xpre-Rx. Sodium (serum):<0.95xLLN or >1.05xULN (if pre-Rx <LLN, then <0.95xpre-Rx or >ULN. If pre-Rx >ULN, then >1.05xpre-Rx or <LLN). Potassium (serum):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN).

  • Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) [ Time Frame: Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. ] [ Designated as safety issue: Yes ]
    MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Chloride (serum), calcium (total), protein (total):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN). Bicarbonate:<0.8xLLN or >1.2xULN (if pre-Rx value <LLN, then <0.8xpre-Rx value or >ULN. If pre-Rx >ULN, then >1.2xpre-Rx value or <ULN). Phosphorous (inorganic):<0.85xLLN or >1.25xULN (if pre-Rx <ULN, then <0.85xpre-Rx or <ULN. If pre-Rx >ULN, then >1.25x re-Rx or <LLN).

  • Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) [ Time Frame: Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. ] [ Designated as safety issue: Yes ]
    MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 x LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8 x pre-Rx or >ULN. If pre-Rx >ULN, then >2.0 x pre-Rx or <LLN. Albumin: <0.9 x LLN (if pre-Rx <LLN, then <0.9 x pre-Rx). Creatine kinase: >1.5 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). Uric acid: >1.2 x ULN (if pre-Rx >ULN, then >1.25 x pre-Rx). LDH: >1.25 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx).

  • Number of Participants With MAs in Urinalysis [ Time Frame: Pre-dose on Day -1, Day 7 and discharge. ] [ Designated as safety issue: Yes ]
    MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs. Protein, glucose and blood: >=2+ (or, if pre-treatment value >=1+, then >= 2 x pre-treatment value).

  • Number of Participants With Identified Electrocardiogram (ECG) Abnormalities [ Time Frame: Pre-dose on Day -1 and study discharge. ] [ Designated as safety issue: Yes ]
    ECG abnormalities were defined as findings that are clinically meaningful as judged by the investigator. A 12-lead ECG was recorded at least 5 minutes after the participant had been lying down and all ECG recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed.

  • Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings [ Time Frame: Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge ] [ Designated as safety issue: Yes ]
    Vital signs assessments and physical examination were conducted throughout the study. Vital signs assessments included body temperature, respiratory rate, blood pressure (systolic and diastolic), and heart rate. Physical examination included a neurological examination (if ocular signs or symptoms occurred, a reflex to slit lamp exam was performed by an ophthalmologist). The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs or physical examination were clinically meaningful.


Enrollment: 85
Study Start Date: April 2008
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: A Drug: Rifabutin
Capsule, Oral, 150 mg, once daily, 11 Days
Active Comparator: B Drug: Rifabutin + Atazanavir + Ritonavir

Capsules, Oral, 18 Days

Rifabutin (150 mg, 2x/wk)

Atazanavir (300 mg, once daily)

Ritonavir (100 mg, once daily)

Other Name: Reyataz

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male and female subjects between the ages of 18 to 50 years old with a body mass index (BMI) of 18 to 32 kg/m²
  • Prior to enrollment, subjects must have physical and laboratory test findings within the normal limits, and women of childbearing potential (WOCBP) must have a negative pregnancy test

Exclusion Criteria:

  • Any significant acute or chronic medical illness
  • Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, electrocardiogram (ECG) or clinical laboratory determinations
  • Use of any prescription drugs or over-the-counter acid controllers within 4 weeks prior to study drug administration
  • Use of any other drugs, including over-the-counter medications of herbal preparations within 1 week prior to study drug administration
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00646776

Locations
United States, New Jersey
Bristol-Myers Squibb Clinical Pharmacology Unit
Hamilton, New Jersey, United States, 08690
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00646776     History of Changes
Other Study ID Numbers: AI424-360
Study First Received: March 26, 2008
Results First Received: September 3, 2010
Last Updated: January 23, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Atazanavir
Rifabutin
Ritonavir
Anti-Bacterial Agents
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antibiotics, Antitubercular
Antitubercular Agents
Antiviral Agents
Enzyme Inhibitors
HIV Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014