Human Immunodeficiency Virus Type 1 (HIV-1)
Conditions
Brief summary
The purpose of the study is to compare the pharmacokinetics and bioequivalence of atazanavir in a fixed-dose combination with cobicistat with that of atazanavir coadministered with cobicistat as single agents.
Interventions
DRUGAtazanavir
300-mg capsule
DRUGCobicistat
150-mg tablet
DRUGAtazanavir/Cobicistat FDC
Atazanavir 300-mg/cobicistat 150-mg FDC tablet
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Healthy men and women, ages 18 to 49 years * Body mass index 18 to 32 kg/m\^2, inclusive * Women of childbearing potential (WOCBP) who were not pregnant or breastfeeding * WOCBP and men who are sexually active with WOCBP must use acceptable contraceptive methods Key
Exclusion criteria
* Any significant acute or chronic medical illness * Current or recent (within 3 months of study drug administration) gastrointestinal tract disease * Any major surgery within 4 weeks of study drug administration * Any gastrointestinal tract surgery (including cholecystectomy) that could have an impact on the absorption of study drug * Donation of blood to a blood bank or in a clinical study (except a screening visit) within 4 weeks of study drug administration (within 2 weeks for plasma only) * Blood transfusion within 4 weeks of study drug administration * Inability to tolerate oral medication, to be venipunctured, or to tolerate venous access * Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination or electrocardiogram (ECG) findings, vital sign measurements, or results of clinical laboratory tests, beyond what is consistent with the target population * Any of the following 12-lead ECG findings prior to study drug administration, confirmed by repeat testing * PR ≥210 msec * QRS ≥120 msec * QT ≥500 msec * QTcF ≥450 msec * 2nd- or 3rd-degree A-V block or clinically relevant abnormalities in ECG findings * Positive result on urine screening for drugs of abuse * Positive result on blood screening for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 or -2 antibody * Laboratory test results indicating levels outside of the ranges specified below: * Alanine aminotransferase \>upper limit of normal (ULN) * Aspartate aminotransferase \>ULN * Total bilirubin \>ULN * Serum creatinine \>ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Atazanavir | Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose) | Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data. |
| Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose) | Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | At screening; on Day -1; predose and 4 hours postdose on Days 1, 18, 15, 22, and 29; and at study discharge (Day 31) | A 12-lead ECG was recorded at predose and 4 hours post dose at screening, Days -1, 1, 8 15, 22, 29 and study discharge. ECGs were recorded after the patient had been supine for at least 5 minutes. All ECG readings post dosing (including unscheduled) were included. |
| Time of Maximum Observed Concentration (Tmax) of Atazanavir | Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose) | Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data. |
| Observed Concentration at 24 Hours (C24) of Atazanavir | Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose) | Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. C24 was derived from plasma concentration versus time data. |
| Apparent Terminal Half-life (T-HALF) of Atazanavir | Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose) | Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data. |
| Number of Participants Who Died and With Serious Adverse Events (SAEs) | On Day 24 or 31 | An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant who receives an investigational product and that does not necessarily have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. An SAE is any untoward medical occurrence that at any dose results in death; is life-threatening; or requires or prolongs inpatient hospitalization. |
| Time of Maximum Observed Concentration (Tmax) of Cobicistat | Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose) | Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data. |
| Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose) | Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data. |
| T-HALF of Cobicistat | Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose) | Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data. |
| Maximum Observed Plasma Concentration (Cmax) of Cobicistat | Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose) | Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data. |
| Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | At Screening and on Days -1,4, 11, 18, and 31 (study discharge) | LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment; h=high; hpf=high power field. Abnormal criteria: Leukocytes, low (\*10\^3 c/uL): \<0.85\*preRx if preRx\<LLN; \<0.9\*LLN if LLN≤preRx≤ULN;\< 0.9\*LLN if preRx=missing;\<LLN if preRX\>ULN. Neutrophils, low (\*10\^3 c/uL): \<0.85\*preRx if preRx\<1.5; \<1.5 if preRx=missing; \<1.5 if preRx ≥1.5. Bilirubin, h (mg/dL): \>1.1\* ULN if preRx≤ULN; \>1.1\*ULN if preRx=missing; \>1.25\*preRx if preRx\>ULN. Bilirubin, h (mg/dL): \>1.1\* ULN if preRx≤ULN; \>1.1\*ULN if preRx=missing; \>1.25\*preRx if preRx\>ULN. Blood, urine, h: ≥2\*preRx if preRx≥1; ≥2 if preRx \<1; ≥2 if preRx=missing. RBCs/WBCs, h (hpf): ≥2 if preRx=missing ≥2 if preRx\<2 ≥4 if preRx ≥2. Creatine kinase, h (U/L): \>1.5\*preRx if preRx\>ULN; \>1.5\*ULN if preRx≤ULN; \>1.5\*ULN if preRx=missing; AST, h (U/L): \>1.25\* preRx if preRx\>ULN; \>1.25\*ULN if preRx≤ULN; \>1.25\*ULN if preRx=missing. Lactate dehydrogenase, h (U/L): \>1.25\*ULN if preRx≤ULN; \>1.25\*ULN if preRx=missing; \>1.5\*preRx if preRx\>ULN. |
Countries
United States
Participant flow
Pre-assignment details
A total of 149 patients were enrolled and 64 randomized to 1 of 8 treatment sequences (ABCDE, ABDCE, BACDE, BADCE, ABCD, ABDC, BACD, or BADC), with a 7-day washout period between treatments. Approximately 32 were to be discharged after Period 4, based on treatment sequence. Those remaining were to continue to and be discharged at end of Period 5.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Who Received Treatment All participants who received atazanavir with cobicistat in 1 of 8 treatment sequences (ABCDE, ABDCE, BACDE, BADCE, ABCD, ABDC, BACD, or BADC). Treatment A: Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8. Treatment B: Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8. Treatment C: Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22. Treatment D: Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day15 or 29. Treatment E: Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29. | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2: Days 8-14 (Treatment B or A) | Withdrawal by Subject | 1 |
| Period 5: Days 29-31 (Treatment E) | Poor compliance/noncompliance | 1 |
Baseline characteristics
| Characteristic | All Participants Who Received Treatment |
|---|---|
| Age, Continuous | 32.5 Years STANDARD_DEVIATION 7.4 |
| Body mass index | 26.5 kg/m^2 STANDARD_DEVIATION 2.9 |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black | 33 Participants |
| Race/Ethnicity, Customized White | 29 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 64 | 3 / 64 | 0 / 63 | 0 / 63 | 0 / 31 |
| serious Total, serious adverse events | 0 / 64 | 0 / 64 | 0 / 63 | 0 / 63 | 0 / 31 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir
Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-T) | 32775 ng*h/mL | Geometric Coefficient of Variation 38 |
| Treatment A: Atazanavir + Cobicistat Coadministered | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-INF) | 33523 ng*h/mL | Geometric Coefficient of Variation 39 |
| Treatment B: Atazanavir/Cobicistat FDC | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-INF) | 35673 ng*h/mL | Geometric Coefficient of Variation 32 |
| Treatment B: Atazanavir/Cobicistat FDC | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-T) | 34905 ng*h/mL | Geometric Coefficient of Variation 32 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-INF) | 25547 ng*h/mL | Geometric Coefficient of Variation 47 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-T) | 25017 ng*h/mL | Geometric Coefficient of Variation 46 |
| Treatment D: Atazanavir/Cobicistat FDC | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-T) | 27875 ng*h/mL | Geometric Coefficient of Variation 41 |
| Treatment D: Atazanavir/Cobicistat FDC | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-INF) | 28378 ng*h/mL | Geometric Coefficient of Variation 42 |
| Treatment E: Atazanavir/Cobicistat FDC | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-INF) | 26510 ng*h/mL | Geometric Coefficient of Variation 40 |
| Treatment E: Atazanavir/Cobicistat FDC | Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir | AUC(0-T) | 25873 ng*h/mL | Geometric Coefficient of Variation 40 |
Comparison: Bioequivalence was concluded if the 90% confidence intervals for the ratios of geometric means of the test formulation (FDC tablet of 300/150 mg atazanavir/cobicistat) to the reference formulation (300-mg atazanavir capsule coadministered with 150-mg cobicistat) were contained within 0.80 to 1.25 for atazanavir Cmax, AUC(0-T) and AUC(INF).90% CI: [1.012, 1.12]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as a random effect was used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as an FDC90% CI: [1.166, 1.393]Mixed Models Analysis
Comparison: To assess the relative bioavailability of atazanavir under fasted (Treatment D) versus fed (Treatment C) states, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-T) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect90% CI: [0.993, 1.248]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and participant as a random effect will be used to estimate the effect of a high fat meal and the fasted state on the natural logarithms of exposure of atazanavir when given as an FDC.90% CI: [0.804, 1.122]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and participant as a random effect will be used to estimate the effect of high fat and light meals on the natural logarithms of exposure of atazanavir when given as an FDC90% CI: [0.655, 0.849]Mixed Models Analysis
Comparison: To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-INF), with treatment period and sequence as fixed effects, and patient (sequence) as a random effect.90% CI: [1.011, 1.12]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and participant as a random effect was used to estimate the effect of a light meal and fthe fasted state on the natural logarithms of exposure of atazanavir when given as an FDC90% CI: [1.171, 1.398]Mixed Models Analysis
Comparison: To assess the relative bioavailability of atazanavir under fasted (Treatment D) versus fed (Treatment C) states, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-INF) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect90% CI: [0.991, 1.244]Mixed Models Analysis
90% CI: [0.81, 1.128]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and participant as a random effect was used to estimate the effect of high fat and light meals on the natural logarithms of exposure of atazanavir when administered as an FDC.90% CI: [0.658, 0.852]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax) of Atazanavir
Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Maximum Observed Plasma Concentration (Cmax) of Atazanavir | 3832 ng/mL | Geometric Coefficient of Variation 39 |
| Treatment B: Atazanavir/Cobicistat FDC | Maximum Observed Plasma Concentration (Cmax) of Atazanavir | 4104 ng/mL | Geometric Coefficient of Variation 32 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Maximum Observed Plasma Concentration (Cmax) of Atazanavir | 2585 ng/mL | Geometric Coefficient of Variation 45 |
| Treatment D: Atazanavir/Cobicistat FDC | Maximum Observed Plasma Concentration (Cmax) of Atazanavir | 2941 ng/mL | Geometric Coefficient of Variation 44 |
| Treatment E: Atazanavir/Cobicistat FDC | Maximum Observed Plasma Concentration (Cmax) of Atazanavir | 2545 ng/mL | Geometric Coefficient of Variation 43 |
Comparison: To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir Cmax, with treatment, period, and sequence as fixed effects, and participant (sequence) as a random effect.90% CI: [1.012, 1.137]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when given as an FDC90% CI: [1.273, 1.59]Mixed Models Analysis
Comparison: To assess the relative bioavailability of atazanavir under fasted (Treatment D) versus fed (Treatment C) states, a linear mixed-effects model was applied to the natural logarithms of atazanavir Cmax with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.90% CI: [1, 1.292]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and the fasted state on the natural logarithms of exposure of atazanavir when given as an FDC90% CI: [0.701, 1.059]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of high fat and light meals on the natural logarithms of exposure of atazanavir when given as an FDC90% CI: [0.545, 0.759]Mixed Models Analysis
Secondary
Apparent Terminal Half-life (T-HALF) of Atazanavir
Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Apparent Terminal Half-life (T-HALF) of Atazanavir | 7.54 Hours | Standard Deviation 2.91 |
| Treatment B: Atazanavir/Cobicistat FDC | Apparent Terminal Half-life (T-HALF) of Atazanavir | 7.50 Hours | Standard Deviation 2.6 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Apparent Terminal Half-life (T-HALF) of Atazanavir | 7.25 Hours | Standard Deviation 2.49 |
| Treatment D: Atazanavir/Cobicistat FDC | Apparent Terminal Half-life (T-HALF) of Atazanavir | 7.21 Hours | Standard Deviation 2.28 |
| Treatment E: Atazanavir/Cobicistat FDC | Apparent Terminal Half-life (T-HALF) of Atazanavir | 7.14 Hours | Standard Deviation 2.99 |
Secondary
Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat
Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis. n=evaluable participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(0-T) | 8738 ng*h/mL | Geometric Coefficient of Variation 42 |
| Treatment A: Atazanavir + Cobicistat Coadministered | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(INF) (n=63, 62, 63, 63, 28) | 9045 ng*h/mL | Geometric Coefficient of Variation 45 |
| Treatment B: Atazanavir/Cobicistat FDC | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(0-T) | 8866 ng*h/mL | Geometric Coefficient of Variation 38 |
| Treatment B: Atazanavir/Cobicistat FDC | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(INF) (n=63, 62, 63, 63, 28) | 9178 ng*h/mL | Geometric Coefficient of Variation 41 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(0-T) | 6541 ng*h/mL | Geometric Coefficient of Variation 47 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(INF) (n=63, 62, 63, 63, 28) | 7884 ng*h/mL | Geometric Coefficient of Variation 45 |
| Treatment D: Atazanavir/Cobicistat FDC | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(INF) (n=63, 62, 63, 63, 28) | 7408 ng*h/mL | Geometric Coefficient of Variation 46 |
| Treatment D: Atazanavir/Cobicistat FDC | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(0-T) | 7204 ng*h/mL | Geometric Coefficient of Variation 44 |
| Treatment E: Atazanavir/Cobicistat FDC | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(0-T) | 7916 ng*h/mL | Geometric Coefficient of Variation 39 |
| Treatment E: Atazanavir/Cobicistat FDC | Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat | AUC(INF) (n=63, 62, 63, 63, 28) | 8298 ng*h/mL | Geometric Coefficient of Variation 39 |
Comparison: A linear mixed-effect model was applied to the natural logarithms of cobicistat AUC(0-T) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.90% CI: [0.983, 1.057]
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when given as an FDC90% CI: [1.141, 1.331]
Comparison: A linear mixed-effect model was applied to the natural logarithms of cobicistat AUC(0-T) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.90% CI: [0.929, 1.307]
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and the fasted state on the natural logarithms of exposure of cobicistat when given as an FDC.90% CI: [1.017, 1.248]
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and a light meal on the natural logarithms of exposure of cobicistat when given as an FDC90% CI: [0.825, 0.96]
Comparison: To demonstrate bioequivalence for atazanavir between the test (Treatment B) and reference (Treatment A) formulations, a linear mixed-effects model was applied to the natural logarithms of atazanavir AUC(0-INF), with treatment, period, and sequence as fixed effects, and participant (sequence) as a random effect.90% CI: [0.982, 1.058]
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when given as an FDC90% CI: [1.148, 1.34]
Comparison: A linear mixed-effect model was applied to the natural logarithms of cobicistat AUC(INF) with treatment, period, and sequence as fixed effects and participant (sequence) as a random effect.90% CI: [0.886, 1.075]
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and fasted on the natural logarithms of exposure of cobicistat when given as an FDC.90% CI: [1.012, 1.231]
Comparison: A linear mixed-effect model with treatment as fixed effects and participant as a random effect will be used to estimate the effect of a high fat meal and light meal on the natural logarithms of exposure of atazanavir when given as an FDC90% CI: [0.836, 0.978]
Secondary
Maximum Observed Plasma Concentration (Cmax) of Cobicistat
Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Maximum Observed Plasma Concentration (Cmax) of Cobicistat | 1321 ng/mL | Geometric Coefficient of Variation 32 |
| Treatment B: Atazanavir/Cobicistat FDC | Maximum Observed Plasma Concentration (Cmax) of Cobicistat | 1348 ng/mL | Geometric Coefficient of Variation 29 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Maximum Observed Plasma Concentration (Cmax) of Cobicistat | 952 ng/mL | Geometric Coefficient of Variation 39 |
| Treatment D: Atazanavir/Cobicistat FDC | Maximum Observed Plasma Concentration (Cmax) of Cobicistat | 1033 ng/mL | Geometric Coefficient of Variation 38 |
| Treatment E: Atazanavir/Cobicistat FDC | Maximum Observed Plasma Concentration (Cmax) of Cobicistat | 1060 ng/mL | Geometric Coefficient of Variation 32 |
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.90% CI: [0.991, 1.057]
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.90% CI: [1.215, 1.402]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir cobicistat90% CI: [0.925, 1.273]
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.90% CI: [0.937, 1.154]
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of cobicistat when administered as a fixed-dose combination.90% CI: [0.717, 0.858]Mixed Models Analysis
Secondary
Number of Participants Who Died and With Serious Adverse Events (SAEs)
An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant who receives an investigational product and that does not necessarily have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. An SAE is any untoward medical occurrence that at any dose results in death; is life-threatening; or requires or prolongs inpatient hospitalization.
Time frame: On Day 24 or 31
Population: All participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants Who Died and With Serious Adverse Events (SAEs) | Deaths | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants Who Died and With Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants Who Died and With Serious Adverse Events (SAEs) | Deaths | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants Who Died and With Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants Who Died and With Serious Adverse Events (SAEs) | Deaths | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants Who Died and With Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants Who Died and With Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants Who Died and With Serious Adverse Events (SAEs) | Deaths | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants Who Died and With Serious Adverse Events (SAEs) | Deaths | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants Who Died and With Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests
LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment; h=high; hpf=high power field. Abnormal criteria: Leukocytes, low (\*10\^3 c/uL): \<0.85\*preRx if preRx\<LLN; \<0.9\*LLN if LLN≤preRx≤ULN;\< 0.9\*LLN if preRx=missing;\<LLN if preRX\>ULN. Neutrophils, low (\*10\^3 c/uL): \<0.85\*preRx if preRx\<1.5; \<1.5 if preRx=missing; \<1.5 if preRx ≥1.5. Bilirubin, h (mg/dL): \>1.1\* ULN if preRx≤ULN; \>1.1\*ULN if preRx=missing; \>1.25\*preRx if preRx\>ULN. Bilirubin, h (mg/dL): \>1.1\* ULN if preRx≤ULN; \>1.1\*ULN if preRx=missing; \>1.25\*preRx if preRx\>ULN. Blood, urine, h: ≥2\*preRx if preRx≥1; ≥2 if preRx \<1; ≥2 if preRx=missing. RBCs/WBCs, h (hpf): ≥2 if preRx=missing ≥2 if preRx\<2 ≥4 if preRx ≥2. Creatine kinase, h (U/L): \>1.5\*preRx if preRx\>ULN; \>1.5\*ULN if preRx≤ULN; \>1.5\*ULN if preRx=missing; AST, h (U/L): \>1.25\* preRx if preRx\>ULN; \>1.25\*ULN if preRx≤ULN; \>1.25\*ULN if preRx=missing. Lactate dehydrogenase, h (U/L): \>1.25\*ULN if preRx≤ULN; \>1.25\*ULN if preRx=missing; \>1.5\*preRx if preRx\>ULN.
Time frame: At Screening and on Days -1,4, 11, 18, and 31 (study discharge)
Population: All participants who received at least 1 dose of study drug and had laboratory test results available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, total (high) | 1 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Lactate dehydrogenase (high) | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, direct | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Aspartate aminotransferase (AST) (high) | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Creatine kinase (high) | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Neutrophils, absolute (low) | 2 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Leukocytes (low) | 3 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | White blood cells (WBC), urine (high) | 2 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Red blood cells (RBC), urine (high) | 1 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood, urine (high) | 1 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Neutrophils, absolute (low) | 4 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Leukocytes (low) | 2 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, total (high) | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, direct | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood, urine (high) | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Red blood cells (RBC), urine (high) | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | White blood cells (WBC), urine (high) | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Creatine kinase (high) | 1 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Aspartate aminotransferase (AST) (high) | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Lactate dehydrogenase (high) | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Red blood cells (RBC), urine (high) | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Aspartate aminotransferase (AST) (high) | 1 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, total (high) | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, direct | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Neutrophils, absolute (low) | 3 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood, urine (high) | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | White blood cells (WBC), urine (high) | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Leukocytes (low) | 3 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Lactate dehydrogenase (high) | 1 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Creatine kinase (high) | 1 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Neutrophils, absolute (low) | 2 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Lactate dehydrogenase (high) | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Leukocytes (low) | 1 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, total (high) | 3 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Red blood cells (RBC), urine (high) | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Creatine kinase (high) | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Aspartate aminotransferase (AST) (high) | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | White blood cells (WBC), urine (high) | 3 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, direct | 1 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood, urine (high) | 1 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, direct | 1 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Aspartate aminotransferase (AST) (high) | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood, urine (high) | 1 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Red blood cells (RBC), urine (high) | 1 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Lactate dehydrogenase (high) | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | White blood cells (WBC), urine (high) | 2 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Leukocytes (low) | 1 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Creatine kinase (high) | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Bilirubin, total (high) | 4 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Neutrophils, absolute (low) | 1 Participants |
Secondary
Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings
A 12-lead ECG was recorded at predose and 4 hours post dose at screening, Days -1, 1, 8 15, 22, 29 and study discharge. ECGs were recorded after the patient had been supine for at least 5 minutes. All ECG readings post dosing (including unscheduled) were included.
Time frame: At screening; on Day -1; predose and 4 hours postdose on Days 1, 18, 15, 22, and 29; and at study discharge (Day 31)
Population: All participants who received at least 1 dose of study medication and were evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | PR interval >210 msec | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QRS interval >120 msec | 1 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QT interval >500 msec | 0 Participants |
| Treatment A: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QTcF>450 msec | 1 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | PR interval >210 msec | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QTcF>450 msec | 0 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QRS interval >120 msec | 1 Participants |
| Treatment B: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QT interval >500 msec | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QTcF>450 msec | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QRS interval >120 msec | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QT interval >500 msec | 0 Participants |
| Treatment C: Atazanavir + Cobicistat Coadministered | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | PR interval >210 msec | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | PR interval >210 msec | 1 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QRS interval >120 msec | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QTcF>450 msec | 0 Participants |
| Treatment D: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QT interval >500 msec | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QTcF>450 msec | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QT interval >500 msec | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | QRS interval >120 msec | 0 Participants |
| Treatment E: Atazanavir/Cobicistat FDC | Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings | PR interval >210 msec | 0 Participants |
Secondary
Observed Concentration at 24 Hours (C24) of Atazanavir
Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. C24 was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Observed Concentration at 24 Hours (C24) of Atazanavir | 416 ng/mL | Geometric Coefficient of Variation 58 |
| Treatment B: Atazanavir/Cobicistat FDC | Observed Concentration at 24 Hours (C24) of Atazanavir | 449 ng/mL | Geometric Coefficient of Variation 52 |
| Treatment C: Atazanavir + Cobicistat Coadministered | Observed Concentration at 24 Hours (C24) of Atazanavir | 295 ng/mL | Geometric Coefficient of Variation 63 |
| Treatment D: Atazanavir/Cobicistat FDC | Observed Concentration at 24 Hours (C24) of Atazanavir | 337 ng/mL | Geometric Coefficient of Variation 56 |
| Treatment E: Atazanavir/Cobicistat FDC | Observed Concentration at 24 Hours (C24) of Atazanavir | 398 ng/mL | Geometric Coefficient of Variation 45 |
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.90% CI: [1.014, 1.158]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.90% CI: [1.215, 1.498]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as an FDC90% CI: [1.006, 1.3]Mixed Models Analysis
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.90% CI: [1.023, 1.483]
Comparison: A linear mixed-effect model with treatment as fixed effect and patient as random effect will be used to estimate the effect of a light meal and the fasted state on the natural logarithms of exposure of atazanavir when administered as a fixed-dose combination.90% CI: [0.789, 1.054]Mixed Models Analysis
Secondary
T-HALF of Cobicistat
Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | T-HALF of Cobicistat | 4.34 Hours | Standard Deviation 1.45 |
| Treatment B: Atazanavir/Cobicistat FDC | T-HALF of Cobicistat | 4.33 Hours | Standard Deviation 1.42 |
| Treatment C: Atazanavir + Cobicistat Coadministered | T-HALF of Cobicistat | 4.23 Hours | Standard Deviation 1.32 |
| Treatment D: Atazanavir/Cobicistat FDC | T-HALF of Cobicistat | 4.09 Hours | Standard Deviation 1.2 |
| Treatment E: Atazanavir/Cobicistat FDC | T-HALF of Cobicistat | 4.27 Hours | Standard Deviation 1.39 |
Secondary
Time of Maximum Observed Concentration (Tmax) of Atazanavir
Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Time of Maximum Observed Concentration (Tmax) of Atazanavir | 3.00 Hours | Full Range 39 |
| Treatment B: Atazanavir/Cobicistat FDC | Time of Maximum Observed Concentration (Tmax) of Atazanavir | 2.50 Hours | — |
| Treatment C: Atazanavir + Cobicistat Coadministered | Time of Maximum Observed Concentration (Tmax) of Atazanavir | 2.00 Hours | — |
| Treatment D: Atazanavir/Cobicistat FDC | Time of Maximum Observed Concentration (Tmax) of Atazanavir | 2.00 Hours | — |
| Treatment E: Atazanavir/Cobicistat FDC | Time of Maximum Observed Concentration (Tmax) of Atazanavir | 3.54 Hours | — |
Secondary
Time of Maximum Observed Concentration (Tmax) of Cobicistat
Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data.
Time frame: Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)
Population: All participants who received any study medication and had any available concentration-time data. All available derived pharmacokinetic (PK) parameter values were included in the PK data set and reported, but only those with adequate PK profiles were included in the summary statistics and statistical analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Atazanavir + Cobicistat Coadministered | Time of Maximum Observed Concentration (Tmax) of Cobicistat | 2.52 Hours |
| Treatment B: Atazanavir/Cobicistat FDC | Time of Maximum Observed Concentration (Tmax) of Cobicistat | 2.52 Hours |
| Treatment C: Atazanavir + Cobicistat Coadministered | Time of Maximum Observed Concentration (Tmax) of Cobicistat | 2.00 Hours |
| Treatment D: Atazanavir/Cobicistat FDC | Time of Maximum Observed Concentration (Tmax) of Cobicistat | 2.00 Hours |
| Treatment E: Atazanavir/Cobicistat FDC | Time of Maximum Observed Concentration (Tmax) of Cobicistat | 4.00 Hours |