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

HIV Infections Clinical Trial

Official title:

Study to Assess the Pharmacokinetic Drug - Drug Interactions Between Atazanavir Plus Ritonavir Coadministered With Voriconazole in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00833482
• Other study ID #: AI424-383
• Secondary ID: 2009-009095-13
• Status: Completed
• Phase: Phase 1
• First received: January 30, 2009
• Last updated: September 24, 2012
• Start date: September 2009
• Est. completion date: February 2011

Study information

• Verified date: September 2012
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationEurope, Middle East, Africa: Committee for Medicinal Products for Human Use
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 185
• Est. completion date: February 2011
• Est. primary completion date: July 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

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

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus Type 1 (HIV-1)
• Immunologic Deficiency Syndromes

Intervention

Drug:
• Voriconazole
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.
• Atazanavir
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.
• Ritonavir
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.

Locations

Country	Name	City	State
Netherlands	Local Institution	Nijmegen
United States	West Coast Clinical Trials, Llc	Cypress	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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	No
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.	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	No
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.	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	No
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.	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	No
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.	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	No
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.	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	No
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.	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	No
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.	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	No
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.	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	No
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.	Days 1 to 31 (discharge), continuously	No
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	Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)	No
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	Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)	No
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	Within 21 days of Day 1 and on Days -1, 21, and 31 (at discharge)	No
Secondary	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)	No

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
•   Investigator Inquiry form