Antivirals/HIV
Conditions
Brief summary
The purpose of this study is to evaluate the exposure of rifabutin (RIB) when administered with atazanavir and ritonavir (ATV/RTV)
Interventions
DRUGRifabutin
Capsule, Oral, 150 mg, once daily, 11 Days
DRUGRifabutin + Atazanavir + Ritonavir
Capsules, Oral, 18 Days Rifabutin (150 mg, 2x/wk) Atazanavir (300 mg, once daily) Ritonavir (100 mg, once daily)
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Of 85 enrolled participants, 52 participants did not receive the study drug (49 did not meet the study criteria and 3 were not needed as study was fully enrolled).
Participants by arm
| Arm | Count |
|---|---|
| RIB 150 mg Once Daily (QD) Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. | 15 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. | 18 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 9 |
| Overall Study | Investigator discretion | 0 | 4 |
Baseline characteristics
| Characteristic | RIB 150 mg Once Daily (QD) | ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Total |
|---|---|---|---|
| Age Continuous | 36 years STANDARD_DEVIATION 5 | 37 years STANDARD_DEVIATION 9 | 36 years STANDARD_DEVIATION 7 |
| Age, Customized <65 years | 15 participants | 18 participants | 33 participants |
| Age, Customized >=65 years | 0 participants | 0 participants | 0 participants |
| Body Mass Index (BMI) | 26.1 kg/m^2 STANDARD_DEVIATION 3.2 | 26.6 kg/m^2 STANDARD_DEVIATION 3.5 | 26.4 kg/m^2 STANDARD_DEVIATION 3.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 14 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height Continuous | 173.7 cm STANDARD_DEVIATION 7.3 | 174.4 cm STANDARD_DEVIATION 10 | 174.1 cm STANDARD_DEVIATION 8.8 |
| Race/Ethnicity, Customized Asian | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 12 participants | 15 participants |
| Race/Ethnicity, Customized Caucasian | 9 participants | 5 participants | 14 participants |
| Race/Ethnicity, Customized Other Race | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
| Weight Continuous | 79.1 kg STANDARD_DEVIATION 12 | 81.3 kg STANDARD_DEVIATION 14.9 | 80.3 kg STANDARD_DEVIATION 13.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 18 | 5 / 15 |
| serious Total, serious adverse events | 2 / 18 | 0 / 15 |
Outcome results
Primary
AUC24avg for 25-O-Desacetyl-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
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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | AUC24avg for 25-O-Desacetyl-RIB | 117.7 ng*h/mL | Full Range 53.48 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | AUC24avg for 25-O-Desacetyl-RIB | 1283 ng*h/mL | Full Range 260.71 |
90% CI: [8.135, 14.61]ANOVA
Primary
Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (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.
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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB) | 1565 nanograms*hour /milliliters (ng*h/mL) | Full Range 528.49 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB) | 2311 nanograms*hour /milliliters (ng*h/mL) | Full Range 507.99 |
90% CI: [1.188, 1.835]ANOVA
Primary
Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-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.
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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB) | 13.44 ng/mL | Full Range 4.5 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB) | 104.36 ng/mL | Full Range 21.31 |
90% CI: [6.133, 9.833]ANCOVA
Primary
Cmin of 25-O-Desacetyl-RIB
Cmin was derived from plasma concentration versus time 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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Cmin of 25-O-Desacetyl-RIB | 2.79 ng/mL | Full Range 1.4 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Cmin of 25-O-Desacetyl-RIB | 31.97 ng/mL | Full Range 10.6 |
90% CI: [8.147, 16.095]ANOVA
Primary
Maximum Plasma Concentration (Cmax) of RIB
Cmax was derived from plasma concentration versus time for RIB and was recorded directly from experimental observations for each treatment period.
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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Maximum Plasma Concentration (Cmax) of RIB | 159.0 ng/mL | Full Range 50.52 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Maximum Plasma Concentration (Cmax) of RIB | 395.6 ng/mL | Full Range 54.32 |
90% CI: [2.025, 3.06]ANOVA
Primary
Minimum Plasma Concentration (Cmin) of RIB
Cmin was derived from plasma concentration versus time for 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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Minimum Plasma Concentration (Cmin) of RIB | 28.89 ng/mL | Full Range 14.08 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Minimum Plasma Concentration (Cmin) of RIB | 40.49 ng/mL | Full Range 11.27 |
90% CI: [1.052, 1.867]ANOVA
Primary
Total Area Under the Plasma Concentration-time Curve (AUCtot)
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.
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.
Population: All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. The RIB 300 mg arm represents an extrapolation of the RIB 150 mg arm and as such, does not have a value for Number of Participants Analyzed. AUCtot for RIB 300 mg QD was calculated as 2 × AUCtot for RIB 150 mg QD.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Total Area Under the Plasma Concentration-time Curve (AUCtot) | 2.00 µM*h | Full Range 0.68 |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Total Area Under the Plasma Concentration-time Curve (AUCtot) | 4.38 µM*h | Full Range 0.57 |
90% CI: [1.783, 2.691]ANOVA
Secondary
AUC(TAU) for ATV
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 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.
Population: All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | AUC(TAU) for ATV | 51795 ng*h/mL | Full Range 12680.65 |
90% CI: [0.723, 1.015]ANOVA
Secondary
AUC(TAU) for RTV
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.
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.
Population: All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | AUC(TAU) for RTV | 8699 ng*h/mL | Full Range 3002.89 |
90% CI: [0.563, 0.862]ANOVA
Secondary
Cmax of ATV
Cmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.
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.
Population: All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Cmax of ATV | 5633 ng/mL | Full Range 940.84 |
90% CI: [0.817, 1.098]ANOVA
Secondary
Cmax of RTV
Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.
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.
Population: All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Cmax of RTV | 1466 ng/mL | Full Range 467.23 |
90% CI: [0.538, 0.809]ANOVA
Secondary
Cmin of ATV
Cmin was derived from the plasma concentration versus time 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.
Population: All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Cmin of ATV | 920.69 ng/mL | Full Range 497.07 |
p-value: 0.096390% CI: [0.5569, 0.9967]ANOVA
Secondary
Cmin of RTV
Cmin was derived from the plasma concentration versus time 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.
Population: All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Cmin of RTV | 40.54 ng/mL | Full Range 34.78 |
90% CI: [0.43, 0.986]ANOVA
Secondary
Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation.
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.
Time frame: From Day 1 to 30 days after the last dose of study drug.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | Other SAEs | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | AE leading to discontinuation | 1 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | Discontinuation due to investigator discretion | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | AEs | 5 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | Deaths | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | AE leading to discontinuation | 9 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | Deaths | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | Other SAEs | 2 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | AEs | 13 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | Discontinuation due to investigator discretion | 4 Participants |
Secondary
Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings
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.
Time frame: Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge
Population: All treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings | 0 Participants |
Secondary
Number of Participants With Identified Electrocardiogram (ECG) Abnormalities
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.
Time frame: Pre-dose on Day -1 and study discharge.
Population: All participants who received the study drug on Day 1 were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With Identified Electrocardiogram (ECG) Abnormalities | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With Identified Electrocardiogram (ECG) Abnormalities | 3 Participants |
Secondary
Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes
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).
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.
Population: All treated participants. If a value had not evaluable in the dataset, then these participants were not counted (hemoglobin and hematocrit).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Hemoglobin | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Hematocrit | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Platelet count | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Leukocytes | 1 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Leukocytes | 7 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Hemoglobin | 1 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Platelet count | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | Hematocrit | 1 Participants |
Secondary
Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute)
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.
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.
Population: All treated participants. If a value had not evaluable in the dataset, then these participants were not counted(neutrophils + bands \[absolute\], monocytes \[absolute\], basophils \[absolute\] and eosinophils \[absolute\]).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Neutrophils+bands (absolute) | 1 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Lymphocytes (absolute) | 1 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Monocytes (absolute) | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Basophils (absolute) | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Eosinophils (absolute) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Eosinophils (absolute) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Neutrophils+bands (absolute) | 10 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Basophils (absolute) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Lymphocytes (absolute) | 5 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | Monocytes (absolute) | 0 Participants |
Secondary
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)
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).
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.
Population: All treated participants. If a value had not evaluable in the dataset, then these participants were not counted (ALP, AST, ALT, bilirubin \[total\], bilirubin \[direct\], BUN and creatinine).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | 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) | AST | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | BUN | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | Bilirubin (total) | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | Creatinine | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | ALT | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | Sodium (serum) | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | Bilirubin (direct) | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | Potassium (serum) | 0 Participants |
| RIB 150 mg Once Daily (QD) | 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) | ALP | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | Potassium (serum) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | ALP | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | AST | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | ALT | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | Bilirubin (total) | 17 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | Bilirubin (direct) | 16 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | BUN | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | Creatinine | 1 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | 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) | Sodium (serum) | 0 Participants |
Secondary
Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic)
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).
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.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Chloride (serum) | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Calcium (total) | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Protein (total) | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Bicarbonate | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Phosphorous (inorganic) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Protein (total) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Chloride (serum) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Phosphorous (inorganic) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Calcium (total) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | Bicarbonate | 0 Participants |
Secondary
Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH)
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).
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.
Population: All treated participants. If a value had not evaluable in the dataset, then these participants were not counted(albumin, creatine kinase, uric acid and LDH).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Creatine Kinase | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Albumin | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Uric Acid | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | LDH | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Glucose (Fasting Serum) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Albumin | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | LDH | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Creatine Kinase | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Glucose (Fasting Serum) | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | Uric Acid | 0 Participants |
Secondary
Number of Participants With MAs in Urinalysis
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).
Time frame: Pre-dose on Day -1, Day 7 and discharge.
Population: All participants who received the study drug on Day 1 were included in the analysis. If a value had not evaluable in the dataset, then these participants were not counted (for all parameters: protein, glucose and blood).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Urinalysis | Protein | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Urinalysis | Glucose | 0 Participants |
| RIB 150 mg Once Daily (QD) | Number of Participants With MAs in Urinalysis | Blood | 0 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Urinalysis | Protein | 1 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Urinalysis | Blood | 1 Participants |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Number of Participants With MAs in Urinalysis | Glucose | 0 Participants |
Secondary
Terminal Elimination Half-life (T-half) of ATV
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.
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.
Population: All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Terminal Elimination Half-life (T-half) of ATV | 11.89 Hour | Standard Deviation 3.65 |
Secondary
T-half of RTV
T-half was obtained directly from the concentration-time data.
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.
Population: All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | T-half of RTV | 4.45 Hour | Standard Deviation 0.65 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV
Tmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period.
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.
Population: All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV | 2.00 Hour | Full Range 0.88 |
Secondary
Tmax of RTV
Tmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period.
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.
Population: All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| RIB 150 mg Once Daily (QD) | Tmax of RTV | 4.00 Hour | Full Range 0.87 |