Drug Interaction Study

Phase 1

Completed

• Conditions: Antivirals/HIV
• Interventions: Drug: Rifabutin + Atazanavir + Ritonavir; Drug: Rifabutin

• Registration Number: NCT00646776
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2008-03-26
• Study First Submitted QC: 2008-03-26
• Study First Posted: 2008-03-31
• Study Start: 2008-04
• Primary Completion: 2008-08
• Study Completion: 2008-08
• Results First Submitted: 2010-09-03
• Results First Submitted QC: 2010-12-09
• Results First Posted: 2011-01-05
• Status Verified: 2013-01
• Last Update Submitted: 2013-01-23
• Last Update Posted: 2013-01-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 85

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
B	Rifabutin + Atazanavir + Ritonavir	-
A	Rifabutin	-

Primary Outcome Measures

Name	Time	Method
Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB)	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.	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	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.	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	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.	Cmin was derived from plasma concentration versus time for RIB.
AUC24avg for 25-O-Desacetyl-RIB	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.	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)	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.	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	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.	Cmin was derived from plasma concentration versus time for 25-O-Desacetyl-RIB.
Total Area Under the Plasma Concentration-time Curve (AUCtot)	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.	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

Name	Time	Method
Cmax of RTV	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.	Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.
Cmax of ATV	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.	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	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.	Cmin was derived from the plasma concentration versus time for ATV.
AUC(TAU) for ATV	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.	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	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.	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	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.	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.
Cmin of RTV	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.	Cmin was derived from the plasma concentration versus time for RTV.
AUC(TAU) for RTV	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.	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	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.	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	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.	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.	From Day 1 to 30 days after the last dose of study drug.	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	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.	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)	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.	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)	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.	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)	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.	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)	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.	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	Pre-dose on Day -1, Day 7 and discharge.	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	Pre-dose on Day -1 and study discharge.	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	Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge	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.

Trial Locations

Locations (1)

Bristol-Myers Squibb Clinical Pharmacology Unit; 🇺🇸 Hamilton, New Jersey, United States