Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants

Phase 1

Completed

Conditions: Human Immunodeficiency Virus Type 1 (HIV-1)
HIV Infections

Interventions: Drug: Voriconazole
Drug: Atazanavir
Drug: Ritonavir

Registration Number: NCT00833482

Lead Sponsor: Bristol-Myers Squibb

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 185

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Voriconazole, 200 mg BID (EM)	Voriconazole	-
Atazanavir/Ritonavir, 300/100 QD (EM & PM)	Atazanavir	-
Atazanavir/Ritonavir, 300/100 QD (EM & PM)	Ritonavir	-
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)	Voriconazole	-
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)	Atazanavir	-
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)	Ritonavir	-
Voriconazole, 50 mg BID (PM)	Voriconazole	-
Atazanavir/ritonavir, 300/100mgQD+voriconazole, 50mgBID (PM)	Voriconazole	-
Atazanavir/ritonavir, 300/100mgQD+voriconazole, 50mgBID (PM)	Atazanavir	-
Atazanavir/ritonavir, 300/100mgQD+voriconazole, 50mgBID (PM)	Ritonavir	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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
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)