HIV Infections, Human Immunodeficiency Virus Type 1 (HIV-1)
Conditions
Brief summary
This study assesses the effects of voriconazole, 200 mg, administered twice daily (BID), on the steady-state pharmacokinetics of atazanavir administered as atazanavir/ritonavir, 300/100 mg once daily (QD), in healthy participants with functional CYP2C19 alleles. The study also reviews the effects of atazanavir/ritonavir, 300/100 mg QD, on the pharmacokinetics of voriconazole, 200 mg, BID in healthy participants with functional CYP2C19 alleles.
Interventions
DRUGVoriconazole
Treatment A: Participants with functional CYP2C19 alleles (EM) received oral tablets of voriconazole, 400 mg, twice daily (BID), on Day 1, then 200 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a light meal. Treatment C: EM participants received atazanavir/ritonavir, 300/100 mg once daily (QD), plus voriconazole, 400 mg BID on Day 21 then 200 mg BID on Days 22-30. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal, and 1 hour before voriconazole morning dose. Treatment E: PM participants received atazanavir/ritonavir, 300/100 mg QD plus voriconazole, 100 mg BID, on Day 21, then 50 mg BID on Days 22-30.
DRUGAtazanavir
Treatment B in EM participants: EM participants received atazanavir/ritonavir, 300/100 mg once daily (QD), on Days 11 through 20. Treatment B in participants who were poor metabolizers of CYP2C19 (PMs): PM participants received oral tablets of atazanavir/ritonavir, 300/100 mg QD, on Days 11 through 20. Treatment C: EM participants received atazanavir/ritonavir, 300/100 mg QD, plus voriconazole, 400 mg BID on Day 21 then 200 mg BID on Days 22-30. Treatment E: PM participants received atazanavir/ritonavir, 300/100 mg QD plus voriconazole, 100 mg BID, on Day 21, then 50 mg BID on Days 22-30.
DRUGRitonavir
Treatment B: EM participants received atazanavir/ritonavir, 300/100 mg once daily (QD), on Days 11 through 20. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal. Treatment C: EM participants received atazanavir/ritonavir, 300/100 mg QD, plus voriconazole, 400 mg BID on Day 21 then 200 mg BID on Days 22-30. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal, and 1 hour before voriconazole morning dose.Treatment E: PM participants received atazanavir/ritonavir, 300/100 mg QD plus voriconazole, 100 mg BID, on Day 21, then 50 mg BID on Days 22-30. Treatment B in PM participants: PM participants received atazanavir/ritonavir, 300/100 mg QD, on Days 11 through 20. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal.
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy participants as determined by no clinically significant deviation from normal * Body Mass Index (BMI) of 18 to 32 kg/m\^2, inclusive. BMI=weight(kg)/height (m)\^2 * Women who are not of childbearing potential (WOCBP)(ie, who are postmenopausal or surgically sterile) and men, ages 18 to 45 years, inclusive
Exclusion criteria
* WOCBP * Sexually active fertile men not using effective birth control if their partners are WOCBP * Proven or suspected acute hepatitis (within 12 months prior to the 1st dose) * Any significant acute or chronic medical illness * Any gastrointestinal surgery that could impact on the absorption of study drug * Smoking more than 5 cigarettes per day * History of any hemolytic disorders (including drug-induced hemolysis) * History of acute or chronic pancreatitis * History of hypochlorhydria or achlorhydria * Men and women weighing \<40 kg * Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 or HIV-2 antibody * Patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM) | Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle | EM participants are those with functional CYP2C19 alleles. |
| Time to Maximum Concentration (Tmax) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle | EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| Area Under the Plasma Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] of Atazanavir Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle | EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| Tmax of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle | Tmax=time to maximum concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle | Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| AUC(TAU)of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle | AUC(TAU)=area under the plasma concentration-time curve in 1 dosing interval; EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Within 21 days of Day 1 and on Days -1, 21, and 31 (at discharge) | volt=voltage; LVH=left ventricular hypertrophy |
| Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle | Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| Number of Participants With Abnormalities in Vital Signs | Within 21 days of Day 1 and on Days -1, 1, 3, 11, 21, and 31 (at discharge) | — |
| Tmax of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle | Tmax=time to maximum concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| AUC(TAU) of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle | AUC(TAU)=area under the plasma concentration-time curve in 1 dosing interval; EM=extensive metabolizers, or participants with functional CYP2C19 alleles. |
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Days 1 to 31 (discharge), continuously | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. |
| Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge) | LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Safety criteria: AST and ALT: If \>1.25\*ULN, or if preRX\>ULN, use \>1.25\*preRX. Total and direct bilirubin: If \>1.1\*ULN or if preRX\>ULN, use \>1.25\*preRX. Creatinine: If \>1.33\*preRX. Serum glucose, fasting: If preRX\<LLN, use \<.8\*preRX or \>ULN; if preRX\>ULN, use \>2\*preRX or \<LLN. Creatinine kinase: If \>1.5\*ULN or preRX\>ULN, use \>1.5\*or preRX. Lactose dehydrogenase: If \>1.25\*ULN or preRX\>ULN, use \>1.5\*preRX. |
| Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge) | LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Safety criteria: Neutrophils + bands: If \<.85\*LLN or \>1.15\*ULN or ULN or if preRX\<LLN, use \<0.85\*preRX or \>ULN; if preRX\>ULN, use \>1.15\*preRX or \<LLN. Lymphocytes, relative: If \<0.85\*LLN or \>1.15\*ULN, or if preRX \<LLN, use \<0.85\*preRX or \>ULN; if preRX \>ULN, use \>1.15\*preRX or \<LLN. Blood, urine: If \>= 2+, or if preRX \>=1+, use \>=2\*preRX. White blood cells, urine: If \>=2+, or if preRX \>=2+, use \>=4+. Red blood cells, urine: If \>=2+ or if preRX \>=2+, use \>=4+. Not all categories were evaluated for each arm. |
Countries
Netherlands, United States
Participant flow
Pre-assignment details
A total of 185 participants were enrolled in the study, and 153 were not treated, because they no longer met study criteria, withdrew consent, or were alternate participants who were no longer needed. The remaining 32 participants received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Extensive Metabolizers (EM) Participants with functional CYP2C19 alleles (extensive metabolizers, or EM). | 24 |
| Poor Metabolizers (PM) Participants without a functional CYP2C19 allele (poor metabolizers, or PM). | 8 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Days 11-20 | Adverse Event | 0 | 2 | 0 | 0 | 0 | 0 |
| Days 11-20 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Days 21-30 | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Days 21-30 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Extensive Metabolizers (EM) | Poor Metabolizers (PM) | Total |
|---|---|---|---|
| Age Continuous | 31 years STANDARD_DEVIATION 10 | 30 years STANDARD_DEVIATION 7 | 31 years STANDARD_DEVIATION 9 |
| CYP2C19 Genotype of Participants 1/1 | 11 Participants | 0 Participants | 11 Participants |
| CYP2C19 Genotype of Participants 1/17 | 6 Participants | 0 Participants | 6 Participants |
| CYP2C19 Genotype of Participants 1/2 | 5 Participants | 0 Participants | 5 Participants |
| CYP2C19 Genotype of Participants 17/17 | 1 Participants | 0 Participants | 1 Participants |
| CYP2C19 Genotype of Participants 2/17 | 1 Participants | 0 Participants | 1 Participants |
| CYP2C19 Genotype of Participants 2/2 | 0 Participants | 6 Participants | 6 Participants |
| CYP2C19 Genotype of Participants 2/3 | 0 Participants | 1 Participants | 1 Participants |
| CYP2C19 Genotype of Participants 3/3 | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 participants | 8 participants | 10 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not reported | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 20 participants | 0 participants | 20 participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 20 Participants | 8 Participants | 28 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 24 | 24 / 24 | 2 / 8 | 17 / 21 | 0 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 8 | 0 / 21 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] of Atazanavir Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Area Under the Plasma Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] of Atazanavir Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 44634 ng*h/mL | Geometric Coefficient of Variation 35 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Area Under the Plasma Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] of Atazanavir Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 38276 ng*h/mL | Geometric Coefficient of Variation 28 |
Primary
AUC(TAU)of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
AUC(TAU)=area under the plasma concentration-time curve in 1 dosing interval; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | AUC(TAU)of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | 20284 ng.h/mL | Geometric Coefficient of Variation 65 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | AUC(TAU)of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | 12944 ng.h/mL | Geometric Coefficient of Variation 89 |
Primary
Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Voriconazole Cmax | 3416 ng/mL | Geometric Coefficient of Variation 49 |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Voriconazole Cmin | 776 ng/mL | Geometric Coefficient of Variation 92 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Voriconazole Cmax | 3014 ng/mL | Geometric Coefficient of Variation 47 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | Voriconazole Cmin | 439 ng/mL | Geometric Coefficient of Variation 144 |
Primary
Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM)
EM participants are those with functional CYP2C19 alleles.
Time frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM) | Atazanavir Cmin | 674 ng/mL | Geometric Coefficient of Variation 61 |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM) | Atazanavir Cmax | 4715 ng/mL | Geometric Coefficient of Variation 27 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM) | Atazanavir Cmin | 525 ng/mL | Geometric Coefficient of Variation 50 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM) | Atazanavir Cmax | 4076 ng/mL | Geometric Coefficient of Variation 23 |
Primary
Time to Maximum Concentration (Tmax) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Time to Maximum Concentration (Tmax) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 3.0 Hours |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Time to Maximum Concentration (Tmax) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 2.07 Hours |
Primary
Tmax of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
Tmax=time to maximum concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Tmax of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | 1.50 Hours |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Tmax of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants | 1.25 Hours |
Secondary
AUC(TAU) of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
AUC(TAU)=area under the plasma concentration-time curve in 1 dosing interval; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | AUC(TAU) of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 9572 ng.h/mL | Geometric Coefficient of Variation 37 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | AUC(TAU) of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 8280 ng.h/mL | Geometric Coefficient of Variation 32 |
Secondary
Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Ritonavir Cmax | 1597 ng/mL | Geometric Coefficient of Variation 40 |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Ritonavir Cmin | 37.1 ng/mL | Geometric Coefficient of Variation 61 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Ritonavir Cmax | 1429 ng/mL | Geometric Coefficient of Variation 38 |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | Ritonavir Cmin | 28.3 ng/mL | Geometric Coefficient of Variation 69 |
Secondary
Number of Participants With Abnormalities in Vital Signs
Time frame: Within 21 days of Day 1 and on Days -1, 1, 3, 11, 21, and 31 (at discharge)
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Abnormalities in Vital Signs | Respiratory rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Abnormalities in Vital Signs | Systolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Abnormalities in Vital Signs | Heart rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Abnormalities in Vital Signs | Diastolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Abnormalities in Vital Signs | Temperature | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Diastolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Respiratory rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Temperature | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Systolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Heart rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Temperature | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Respiratory rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Diastolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Heart rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Abnormalities in Vital Signs | Systolic blood pressure | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Abnormalities in Vital Signs | Heart rate | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Abnormalities in Vital Signs | Diastolic blood pressure | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Abnormalities in Vital Signs | Systolic blood pressure | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Abnormalities in Vital Signs | Respiratory rate | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Abnormalities in Vital Signs | Temperature | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Abnormalities in Vital Signs | Respiratory rate | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Abnormalities in Vital Signs | Diastolic blood pressure | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Abnormalities in Vital Signs | Temperature | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Abnormalities in Vital Signs | Systolic blood pressure | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Abnormalities in Vital Signs | Heart rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Abnormalities in Vital Signs | Diastolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Abnormalities in Vital Signs | Respiratory rate | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Abnormalities in Vital Signs | Systolic blood pressure | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Abnormalities in Vital Signs | Temperature | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Abnormalities in Vital Signs | Heart rate | 0 Participants |
Secondary
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
Time frame: Days 1 to 31 (discharge), continuously
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Deaths | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | SAEs | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | AEs leading to discontinuation | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Any AE | 22 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | AEs leading to discontinuation | 2 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | SAEs | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Deaths | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Any AE | 24 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Any AE | 21 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | AEs leading to discontinuation | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | SAEs | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Deaths | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Deaths | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Any AE | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | SAEs | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | AEs leading to discontinuation | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | AEs leading to discontinuation | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Any AE | 3 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | SAEs | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Deaths | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | SAEs | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | AEs leading to discontinuation | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Any AE | 2 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE | Deaths | 0 Participants |
Secondary
Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator
volt=voltage; LVH=left ventricular hypertrophy
Time frame: Within 21 days of Day 1 and on Days -1, 21, and 31 (at discharge)
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Sinus bradycardia | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | ST elevation and fusion complexes | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | T-wave abnormality + minimum volt criteria for LVH | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Nonspecific T-wave abnormality | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | T-wave abnormality + minimum volt criteria for LVH | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | ST elevation and fusion complexes | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Sinus bradycardia | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Nonspecific T-wave abnormality | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Nonspecific T-wave abnormality | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | T-wave abnormality + minimum volt criteria for LVH | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | ST elevation and fusion complexes | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Sinus bradycardia | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Sinus bradycardia | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Nonspecific T-wave abnormality | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | ST elevation and fusion complexes | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | T-wave abnormality + minimum volt criteria for LVH | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | T-wave abnormality + minimum volt criteria for LVH | 1 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Nonspecific T-wave abnormality | 1 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | ST elevation and fusion complexes | 1 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Sinus bradycardia | 2 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | ST elevation and fusion complexes | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | T-wave abnormality + minimum volt criteria for LVH | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Nonspecific T-wave abnormality | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator | Sinus bradycardia | 0 Participants |
Secondary
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Safety criteria: Neutrophils + bands: If \<.85\*LLN or \>1.15\*ULN or ULN or if preRX\<LLN, use \<0.85\*preRX or \>ULN; if preRX\>ULN, use \>1.15\*preRX or \<LLN. Lymphocytes, relative: If \<0.85\*LLN or \>1.15\*ULN, or if preRX \<LLN, use \<0.85\*preRX or \>ULN; if preRX \>ULN, use \>1.15\*preRX or \<LLN. Blood, urine: If \>= 2+, or if preRX \>=1+, use \>=2\*preRX. White blood cells, urine: If \>=2+, or if preRX \>=2+, use \>=4+. Red blood cells, urine: If \>=2+ or if preRX \>=2+, use \>=4+. Not all categories were evaluated for each arm.
Time frame: Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Neutrophils + bands(absolute)(*10^3 cells/uL): Low | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): Low | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): High | 5 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Blood, urine: High | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | White blood cells (WBC), urine: High | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Red blood cells (RBC), urine: High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): Low | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Blood, urine: High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Red blood cells (RBC), urine: High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Neutrophils + bands(absolute)(*10^3 cells/uL): Low | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | White blood cells (WBC), urine: High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Red blood cells (RBC), urine: High | NA Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | White blood cells (WBC), urine: High | NA Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Blood, urine: High | 2 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Neutrophils + bands(absolute)(*10^3 cells/uL): Low | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): Low | 1 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Blood, urine: High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): Low | NA Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): High | NA Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Red blood cells (RBC), urine: High | NA Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | White blood cells (WBC), urine: High | NA Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Neutrophils + bands(absolute)(*10^3 cells/uL): Low | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Neutrophils + bands(absolute)(*10^3 cells/uL): Low | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | White blood cells (WBC), urine: High | NA Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): Low | NA Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): High | NA Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Blood, urine: High | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Red blood cells (RBC), urine: High | NA Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Blood, urine: High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): High | NA Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | White blood cells (WBC), urine: High | NA Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Red blood cells (RBC), urine: High | NA Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Lymphocytes, relative (*10*3 cells/uL): Low | NA Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results | Neutrophils + bands(absolute)(*10^3 cells/uL): Low | 0 Participants |
Secondary
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Safety criteria: AST and ALT: If \>1.25\*ULN, or if preRX\>ULN, use \>1.25\*preRX. Total and direct bilirubin: If \>1.1\*ULN or if preRX\>ULN, use \>1.25\*preRX. Creatinine: If \>1.33\*preRX. Serum glucose, fasting: If preRX\<LLN, use \<.8\*preRX or \>ULN; if preRX\>ULN, use \>2\*preRX or \<LLN. Creatinine kinase: If \>1.5\*ULN or preRX\>ULN, use \>1.5\*or preRX. Lactose dehydrogenase: If \>1.25\*ULN or preRX\>ULN, use \>1.5\*preRX.
Time frame: Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)
Population: All participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Total bilirubin (mg/dL): High | 4 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Alanine aminotransferase (ALT) (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Aspartate aminotransferase (AST) (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Direct bilirubin (mg/dL): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatinine (mg/dL): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Lactase dehydrogenase (U/L): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Serum glucose, fasting (mg/dL): Low | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatine kinase (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatinine (mg/dL): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Direct bilirubin (mg/dL): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Aspartate aminotransferase (AST) (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatine kinase (U/L): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Lactase dehydrogenase (U/L): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Total bilirubin (mg/dL): High | 22 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Alanine aminotransferase (ALT) (U/L): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Serum glucose, fasting (mg/dL): Low | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Alanine aminotransferase (ALT) (U/L): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Total bilirubin (mg/dL): High | 21 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Direct bilirubin (mg/dL): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Lactase dehydrogenase (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatinine (mg/dL): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Serum glucose, fasting (mg/dL): Low | 0 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatine kinase (U/L): High | 3 Participants |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Aspartate aminotransferase (AST) (U/L): High | 1 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Total bilirubin (mg/dL): High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Alanine aminotransferase (ALT) (U/L): High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Serum glucose, fasting (mg/dL): Low | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatinine (mg/dL): High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Aspartate aminotransferase (AST) (U/L): High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatine kinase (U/L): High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Direct bilirubin (mg/dL): High | 0 Participants |
| Voriconazole, 50 mg BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Lactase dehydrogenase (U/L): High | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Serum glucose, fasting (mg/dL): Low | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Total bilirubin (mg/dL): High | 8 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Aspartate aminotransferase (AST) (U/L): High | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatinine (mg/dL): High | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Lactase dehydrogenase (U/L): High | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatine kinase (U/L): High | 0 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Alanine aminotransferase (ALT) (U/L): High | 1 Participants |
| Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Direct bilirubin (mg/dL): High | 2 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Serum glucose, fasting (mg/dL): Low | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Direct bilirubin (mg/dL): High | 2 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatine kinase (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Total bilirubin (mg/dL): High | 7 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Aspartate aminotransferase (AST) (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Creatinine (mg/dL): High | 1 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Lactase dehydrogenase (U/L): High | 0 Participants |
| Atazanavir/Ritonavir, 300/100 QD (PM) | Number of Participants With Marked Abnormalities in Serum Chemistry Test Results | Alanine aminotransferase (ALT) (U/L): High | 1 Participants |
Secondary
Tmax of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
Tmax=time to maximum concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Time frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle
Population: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atazanavir/Ritonavir, 300/100 QD (EM) | Tmax of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 4.0 Hours |
| Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) | Tmax of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants | 4.0 Hours |