Bioequivalence Study of Individual Atazanavir and Cobicistat Compared With Atazanavir in Fixed-dose Combination With Cobicistat

Phase 1

Completed

• Conditions: Human Immunodeficiency Virus Type 1 (HIV-1)
• Interventions: Drug: Atazanavir/Cobicistat FDC; Drug: Atazanavir; Drug: Cobicistat

• Registration Number: NCT01837719
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

The purpose of the study is to compare the pharmacokinetics and bioequivalence of atazanavir in a fixed-dose combination with cobicistat with that of atazanavir coadministered with cobicistat as single agents.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-04
• Study First Submitted: 2013-04-18
• Study First Submitted QC: 2013-04-22
• Study First Posted: 2013-04-23
• Primary Completion: 2013-06
• Study Completion: 2013-06
• Results First Submitted: 2014-06-09
• Status Verified: 2014-08
• Results First Submitted QC: 2014-08-19
• Last Update Submitted: 2014-08-19
• Results First Posted: 2014-08-29
• Last Update Posted: 2014-08-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 64

Inclusion Criteria

• Healthy men and women, ages 18 to 49 years
• Body mass index 18 to 32 kg/m^2, inclusive
• Women of childbearing potential (WOCBP) who were not pregnant or breastfeeding
• WOCBP and men who are sexually active with WOCBP must use acceptable contraceptive methods

Key

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Exclusion Criteria

• Any significant acute or chronic medical illness

• Current or recent (within 3 months of study drug administration) gastrointestinal tract disease

• Any major surgery within 4 weeks of study drug administration

• Any gastrointestinal tract surgery (including cholecystectomy) that could have an impact on the absorption of study drug

• Donation of blood to a blood bank or in a clinical study (except a screening visit) within 4 weeks of study drug administration (within 2 weeks for plasma only)

• Blood transfusion within 4 weeks of study drug administration

• Inability to tolerate oral medication, to be venipunctured, or to tolerate venous access

• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination or electrocardiogram (ECG) findings, vital sign measurements, or results of clinical laboratory tests, beyond what is consistent with the target population

• Any of the following 12-lead ECG findings prior to study drug administration, confirmed by repeat testing

  • PR ≥210 msec
  • QRS ≥120 msec
  • QT ≥500 msec
  • QTcF ≥450 msec

• 2nd- or 3rd-degree A-V block or clinically relevant abnormalities in ECG findings

• Positive result on urine screening for drugs of abuse

• Positive result on blood screening for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 or -2 antibody

• Laboratory test results indicating levels outside of the ranges specified below:

  • Alanine aminotransferase >upper limit of normal (ULN)
  • Aspartate aminotransferase >ULN
  • Total bilirubin >ULN
  • Serum creatinine >ULN

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment B: Atazanavir/Cobicistat FDC	Atazanavir/Cobicistat FDC	Participants received a single fixed-dose combination (FDC) of atazanavir, 300 mg/cobicistat, 150 mg, following a light meal on Day 1 or 8
Treatment C: Atazanavir + Cobicistat coadministered	Atazanavir	Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Treatment A: Atazanavir + Cobicistat coadministered	Cobicistat	Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Treatment A: Atazanavir + Cobicistat coadministered	Atazanavir	Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, following a light meal on Day 1 or 8
Treatment C: Atazanavir + Cobicistat coadministered	Cobicistat	Participants received a single dose of atazanavir, 300 mg as capsule, coadministered with cobicistat,150 mg as tablet, in the fasted state on Day 15 or 22
Treatment D: Atazanavir/Cobicistat FDC	Atazanavir/Cobicistat FDC	Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, in the fasted state on Day 15 or 22
Treatment E: Atazanavir/Cobicistat FDC	Atazanavir/Cobicistat FDC	Participants received a single FDC dose of atazanavir, 300 mg/cobicistat, 150 mg, following a high-fat meal on Day 29

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and From Time 0 to Infinity (AUC[INF]) for Atazanavir	Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)	Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data.
Maximum Observed Plasma Concentration (Cmax) of Atazanavir	Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)	Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests	At Screening and on Days -1,4, 11, 18, and 31 (study discharge)	LLN=lower limit of normal; ULN=upper limit of normal; preRx=pretreatment; h=high; hpf=high power field. Abnormal criteria: Leukocytes, low (\*10\^3 c/uL): \<0.85\*preRx if preRx\<LLN; \<0.9\*LLN if LLN≤preRx≤ULN;\< 0.9\*LLN if preRx=missing;\<LLN if preRX\>ULN. Neutrophils, low (\*10\^3 c/uL): \<0.85\*preRx if preRx\<1.5; \<1.5 if preRx=missing; \<1.5 if preRx ≥1.5. Bilirubin, h (mg/dL): \>1.1\* ULN if preRx≤ULN; \>1.1\*ULN if preRx=missing; \>1.25\*preRx if preRx\>ULN. Bilirubin, h (mg/dL): \>1.1\* ULN if preRx≤ULN; \>1.1\*ULN if preRx=missing; \>1.25\*preRx if preRx\>ULN. Blood, urine, h: ≥2\*preRx if preRx≥1; ≥2 if preRx \<1; ≥2 if preRx=missing. RBCs/WBCs, h (hpf): ≥2 if preRx=missing ≥2 if preRx\<2 ≥4 if preRx ≥2. Creatine kinase, h (U/L): \>1.5\*preRx if preRx\>ULN; \>1.5\*ULN if preRx≤ULN; \>1.5\*ULN if preRx=missing; AST, h (U/L): \>1.25\* preRx if preRx\>ULN; \>1.25\*ULN if preRx≤ULN; \>1.25\*ULN if preRx=missing. Lactate dehydrogenase, h (U/L): \>1.25\*ULN if preRx≤ULN; \>1.25\*ULN if preRx=missing; \>1.5\*preRx if preRx\>ULN.
Observed Concentration at 24 Hours (C24) of Atazanavir	Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)	Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. C24 was derived from plasma concentration versus time data.
Number of Participants With Out-of-range Intervals on Electrocardiogram (ECG) Findings	At screening; on Day -1; predose and 4 hours postdose on Days 1, 18, 15, 22, and 29; and at study discharge (Day 31)	A 12-lead ECG was recorded at predose and 4 hours post dose at screening, Days -1, 1, 8 15, 22, 29 and study discharge. ECGs were recorded after the patient had been supine for at least 5 minutes. All ECG readings post dosing (including unscheduled) were included.
Time of Maximum Observed Concentration (Tmax) of Atazanavir	Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)	Blood samples for plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data.
Apparent Terminal Half-life (T-HALF) of Atazanavir	Days 1, 8, 15, 22, and 29 (predose and at 1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24, 30, and 36 hours postdose); Days 3, 10, 17, 24, and 31 (48 hours postdose)	Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data.
Time of Maximum Observed Concentration (Tmax) of Cobicistat	Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)	Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Tmax was derived from plasma concentration versus time data.
Area Under the Concentration Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-T]) and Area Under the Concentration Curve From Time 0 to Infinity (AUC[INF]) of Cobicistat	Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)	Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. AUC(0-T) and AUC(INF) were derived from plasma concentration versus time data.
Number of Participants Who Died and With Serious Adverse Events (SAEs)	On Day 24 or 31	An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant who receives an investigational product and that does not necessarily have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. An SAE is any untoward medical occurrence that at any dose results in death; is life-threatening; or requires or prolongs inpatient hospitalization.
Maximum Observed Plasma Concentration (Cmax) of Cobicistat	Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)	Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. Cmax was derived from plasma concentration versus time data.
T-HALF of Cobicistat	Days 1, 8, 15, 22, and 29 (1,2, 2.5, 3, 4, 5, 6, 8, 12, and 16 hours postdose); Days 2, 9, 16, 23, and 30 (24 hours postdose)	Blood samples for testing plasma concentrations were obtained at predose and at specific timepoints up to 48 hours after dosing on Days 1, 8, 15, 22, and 29. T-HALF was derived from plasma concentration versus time data.

Trial Locations

Locations (1)

Ppd Development, Inc.; 🇺🇸 Austin, Texas, United States