Trial Outcomes & Findings for Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants (NCT NCT00833482)
NCT ID: NCT00833482
Last Updated: 2012-10-25
Results Overview
EM participants are those with functional CYP2C19 alleles.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
185 participants
Primary outcome timeframe
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
Results posted on
2012-10-25
Participant Flow
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.
Participant milestones
| Measure |
Voriconazole, 200 BID (EM)
Participants with functional CYP2C19 alleles (EM) received 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 meal.
|
Atazanavir/Ritonavir, 300/100 QD (EM)
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Participants who were poor metabolizers of CYP2C19 (PM)received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
Days 1-3
STARTED
|
24
|
0
|
0
|
8
|
0
|
0
|
|
Days 1-3
COMPLETED
|
24
|
0
|
0
|
8
|
0
|
0
|
|
Days 1-3
NOT COMPLETED
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Days 11-20
STARTED
|
0
|
24
|
0
|
0
|
0
|
8
|
|
Days 11-20
COMPLETED
|
0
|
21
|
0
|
0
|
0
|
8
|
|
Days 11-20
NOT COMPLETED
|
0
|
3
|
0
|
0
|
0
|
0
|
|
Days 21-30
STARTED
|
0
|
0
|
21
|
0
|
8
|
0
|
|
Days 21-30
COMPLETED
|
0
|
0
|
20
|
0
|
7
|
0
|
|
Days 21-30
NOT COMPLETED
|
0
|
0
|
1
|
0
|
1
|
0
|
Reasons for withdrawal
| Measure |
Voriconazole, 200 BID (EM)
Participants with functional CYP2C19 alleles (EM) received 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 meal.
|
Atazanavir/Ritonavir, 300/100 QD (EM)
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Participants who were poor metabolizers of CYP2C19 (PM)received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
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
Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants
Baseline characteristics by cohort
| Measure |
Extensive Metabolizers (EM)
n=24 Participants
Participants with functional CYP2C19 alleles (extensive metabolizers, or EM).
|
Poor Metabolizers (PM)
n=8 Participants
Participants without a functional CYP2C19 allele (poor metabolizers, or PM).
|
Total
n=32 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age Continuous
|
31 years
STANDARD_DEVIATION 10 • n=5 Participants
|
30 years
STANDARD_DEVIATION 7 • n=7 Participants
|
31 years
STANDARD_DEVIATION 9 • n=5 Participants
|
|
Sex: Female, Male
Female
|
4 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
20 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
28 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
2 participants
n=5 Participants
|
8 participants
n=7 Participants
|
10 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
1 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
20 participants
n=5 Participants
|
0 participants
n=7 Participants
|
20 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Not reported
|
0 participants
n=5 Participants
|
0 participants
n=7 Participants
|
0 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Other
|
1 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
1/1
|
11 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
1/2
|
5 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
1/17
|
6 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
2/2
|
0 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
2/3
|
0 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
2/17
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
17/17
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
CYP2C19 Genotype of Participants
3/3
|
0 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
EM participants are those with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=22 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
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
|
525 ng/mL
Geometric Coefficient of Variation 50
|
—
|
—
|
—
|
—
|
|
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
|
4076 ng/mL
Geometric Coefficient of Variation 23
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=22 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
Time to Maximum Concentration (Tmax) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
|
3.0 Hours
Interval 2.0 to 4.0
|
2.07 Hours
Interval 2.0 to 4.0
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=22 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
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
|
38276 ng*h/mL
Geometric Coefficient of Variation 28
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
Tmax=time to maximum concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
Tmax of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
|
1.50 Hours
Interval 0.5 to 3.0
|
1.25 Hours
Interval 1.0 to 3.0
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
Voriconazole Cmax
|
3416 ng/mL
Geometric Coefficient of Variation 49
|
3014 ng/mL
Geometric Coefficient of Variation 47
|
—
|
—
|
—
|
—
|
|
Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
Voriconazole Cmin
|
776 ng/mL
Geometric Coefficient of Variation 92
|
439 ng/mL
Geometric Coefficient of Variation 144
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
AUC(TAU)=area under the plasma concentration-time curve in 1 dosing interval; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
AUC(TAU)of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants
|
20284 ng.h/mL
Geometric Coefficient of Variation 65
|
12944 ng.h/mL
Geometric Coefficient of Variation 89
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
Cmax=maximum observed plasma concentration; Cmin=minimum observed plasma concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=22 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
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
|
1429 ng/mL
Geometric Coefficient of Variation 38
|
—
|
—
|
—
|
—
|
|
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
|
28.3 ng/mL
Geometric Coefficient of Variation 69
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
Tmax=time to maximum concentration; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=22 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
Tmax of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
|
4.0 Hours
Interval 1.5 to 5.0
|
4.0 Hours
Interval 2.0 to 4.0
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cyclePopulation: All participants who were healthy, who had functional CYP2C19 alleles, who received any study drug, and who had concentration-time data available.
AUC(TAU)=area under the plasma concentration-time curve in 1 dosing interval; EM=extensive metabolizers, or participants with functional CYP2C19 alleles.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=22 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=20 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
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.
|
Voriconazole, 50 mg BID (PM)
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
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.
|
|---|---|---|---|---|---|---|
|
AUC(TAU) of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants
|
9572 ng.h/mL
Geometric Coefficient of Variation 37
|
8280 ng.h/mL
Geometric Coefficient of Variation 32
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Days 1 to 31 (discharge), continuouslyPopulation: All participants who received study drug.
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.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=21 Participants
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.
|
Voriconazole, 50 mg BID (PM)
n=8 Participants
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
n=8 Participants
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
n=8 Participants
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.
|
|---|---|---|---|---|---|---|
|
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE
SAEs
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
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
|
2 Participants
|
1 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE
Any AE
|
22 Participants
|
24 Participants
|
21 Participants
|
0 Participants
|
3 Participants
|
2 Participants
|
|
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE
Deaths
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)Population: All participants who received study drug.
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.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=21 Participants
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.
|
Voriconazole, 50 mg BID (PM)
n=8 Participants
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
n=8 Participants
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
n=8 Participants
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.
|
|---|---|---|---|---|---|---|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Aspartate aminotransferase (AST) (U/L): High
|
0 Participants
|
0 Participants
|
1 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Alanine aminotransferase (ALT) (U/L): High
|
0 Participants
|
1 Participants
|
1 Participants
|
0 Participants
|
1 Participants
|
1 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Total bilirubin (mg/dL): High
|
4 Participants
|
22 Participants
|
21 Participants
|
0 Participants
|
8 Participants
|
7 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Creatinine (mg/dL): High
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
1 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Direct bilirubin (mg/dL): High
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
2 Participants
|
2 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Serum glucose, fasting (mg/dL): Low
|
1 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Creatine kinase (U/L): High
|
0 Participants
|
1 Participants
|
3 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Marked Abnormalities in Serum Chemistry Test Results
Lactase dehydrogenase (U/L): High
|
1 Participants
|
1 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)Population: All participants who received study drug.
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.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=21 Participants
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.
|
Voriconazole, 50 mg BID (PM)
n=8 Participants
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
n=8 Participants
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
n=8 Participants
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.
|
|---|---|---|---|---|---|---|
|
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
Lymphocytes, relative (*10*3 cells/uL): Low
|
1 Participants
|
1 Participants
|
1 Participants
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
|
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
Blood, urine: High
|
1 Participants
|
1 Participants
|
2 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
White blood cells (WBC), urine: High
|
1 Participants
|
0 Participants
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
|
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
Lymphocytes, relative (*10*3 cells/uL): High
|
5 Participants
|
1 Participants
|
1 Participants
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
|
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
Neutrophils + bands(absolute)(*10^3 cells/uL): Low
|
1 Participants
|
0 Participants
|
1 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
Red blood cells (RBC), urine: High
|
1 Participants
|
0 Participants
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
NA Participants
Not evaluated
|
SECONDARY outcome
Timeframe: Within 21 days of Day 1 and on Days -1, 21, and 31 (at discharge)Population: All participants who received study drug.
volt=voltage; LVH=left ventricular hypertrophy
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=21 Participants
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.
|
Voriconazole, 50 mg BID (PM)
n=8 Participants
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
n=8 Participants
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
n=8 Participants
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.
|
|---|---|---|---|---|---|---|
|
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
|
0 Participants
|
0 Participants
|
0 Participants
|
2 Participants
|
0 Participants
|
|
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
|
0 Participants
|
0 Participants
|
0 Participants
|
1 Participants
|
0 Participants
|
|
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
|
0 Participants
|
0 Participants
|
0 Participants
|
1 Participants
|
0 Participants
|
|
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
|
0 Participants
|
0 Participants
|
0 Participants
|
1 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=24 Participants
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=21 Participants
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.
|
Voriconazole, 50 mg BID (PM)
n=8 Participants
Treatment D: Participants who were poor metabolizers of CYP2C19 (PM) received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
n=8 Participants
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.
|
Atazanavir/Ritonavir, 300/100 QD (PM)
n=8 Participants
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.
|
|---|---|---|---|---|---|---|
|
Number of Participants With Abnormalities in Vital Signs
Temperature
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Abnormalities in Vital Signs
Diastolic blood pressure
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Abnormalities in Vital Signs
Systolic blood pressure
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Abnormalities in Vital Signs
Heart rate
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Abnormalities in Vital Signs
Respiratory rate
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
Adverse Events
Voriconazole, 200 BID (EM)
Serious events: 0 serious events
Other events: 22 other events
Deaths: 0 deaths
Atazanavir/Ritonavir, 300/100 QD (EM)
Serious events: 0 serious events
Other events: 24 other events
Deaths: 0 deaths
Atazanavir/Ritonavir, 300/100 QD (PM)
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
Serious events: 0 serious events
Other events: 17 other events
Deaths: 0 deaths
Voriconazole, 50 mg BID (PM)
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Atazanazvir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Voriconazole, 200 BID (EM)
n=24 participants at risk
Participants with functional CYP2C19 alleles (EM) received 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 meal.
|
Atazanavir/Ritonavir, 300/100 QD (EM)
n=24 participants at risk
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
|
Atazanavir/Ritonavir, 300/100 QD (PM)
n=8 participants at risk
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.
|
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)
n=21 participants at risk
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.
|
Voriconazole, 50 mg BID (PM)
n=8 participants at risk
Participants who were poor metabolizers of CYP2C19 (PM)received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
|
Atazanazvir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)
n=8 participants at risk
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.
|
|---|---|---|---|---|---|---|
|
Eye disorders
Lacrimation increased
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
9.5%
2/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Ocular icterus
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
33.3%
8/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Chromatopsia
|
8.3%
2/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
9.5%
2/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Eye irritation
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
9.5%
2/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Skin and subcutaneous tissue disorders
Rash maculo-papular
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
3/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Investigations
Blood bilirubin increased
|
4.2%
1/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
25.0%
6/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
1/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.8%
1/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Investigations
Blood creatine phosphokinase increased
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
8.3%
2/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
14.3%
3/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Psychiatric disorders
Hallucination
|
4.2%
1/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
9.5%
2/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Nervous system disorders
Headache
|
50.0%
12/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
3/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
9.5%
2/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Photophobia
|
41.7%
10/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
19.0%
4/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
General disorders
Fatigue
|
8.3%
2/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
16.7%
4/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
14.3%
3/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
8.3%
2/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.8%
1/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Vision blurred
|
33.3%
8/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.2%
1/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
23.8%
5/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Visual impairment
|
20.8%
5/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.2%
1/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
14.3%
3/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Nervous system disorders
Dizziness
|
25.0%
6/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.2%
1/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
14.3%
3/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Gastrointestinal disorders
Dyspepsia
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
1/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Hepatobiliary disorders
Hyperbilirubinaemia
|
8.3%
2/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
62.5%
15/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.2%
1/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
4.8%
1/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
1/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Hepatobiliary disorders
Jaundice
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
33.3%
8/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Scleral discolouration
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
20.8%
5/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Skin and subcutaneous tissue disorders
Dry skin
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
1/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Eye disorders
Photopsia
|
16.7%
4/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
28.6%
6/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
|
Gastrointestinal disorders
Abdominal pain lower
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/24 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/21 • Days 1 through 30, continuously, of a 30-day cycle.
|
0.00%
0/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
12.5%
1/8 • Days 1 through 30, continuously, of a 30-day cycle.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
- Publication restrictions are in place
Restriction type: OTHER