Pharmacokinetics of Atazanavir/Ritonavir in HIV-1 Infected Pregnant Women

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00326716
First received: May 15, 2006
Last updated: November 4, 2011
Last verified: November 2011
  Purpose

To determine what dosing regimen of atazanavir (ATV) / ritonavir (RTV) produces adequate drug exposure during pregnancy compared to drug exposure in historical data in human immunodeficiency virus (HIV) infected participants.


Condition Intervention Phase
HIV Infection
Drug: Atazanavir + Ritonavir + Combivir
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Study of the Pharmacokinetics of Atazanavir (ATV)/Ritonavir(RTV) Administered as Part of Highly Active Antiretroviral Therapy (HAART) in HIV-1 Infected Pregnant Women

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Infant Gestational Age at Delivery [ Time Frame: At the time of delivery ] [ Designated as safety issue: No ]
  • Infant Gender [ Time Frame: At the time of delivery ] [ Designated as safety issue: No ]
  • Infant Race [ Time Frame: At the time of delivery ] [ Designated as safety issue: No ]
  • Mean ATV Maximum Plasma Concentration (Cmax) in One Dosing Interval [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    Cmax = maximum observed plasma concentration of atazanavir at specified time points.

  • Mean RTV Maximum Plasma Concentration (Cmax) in One Dosing Interval [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    Cmax = maximum observed plasma concentration of ritonavir at specified time points.

  • Mean ATV Area Under the Concentration Curve (AUC TAU) [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    AUC = area under the concentration curve (AUC [TAU]) of atazanavir in one dosing interval from time zero to 24 hours.

  • Mean RTV Area Under the Concentration Curve (AUC TAU) [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    AUC = area under the concentration curve (AUC [TAU]) of ritonavir in one dosing interval.

  • Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose. ] [ Designated as safety issue: No ]
    Cmin = plasma concentration 24 hours post dose of atazanavir at specified time points.

  • Mean RTV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose. ] [ Designated as safety issue: No ]
    Cmin = plasma concentration 24 hours post dose of ritonavir at specified time points.

  • Mean ATV Terminal Elimination Half Life (T 1/2) [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    T 1/2 = terminal elimination half life of atazanavir at specified time points.

  • Mean RTV Terminal Elimination Half Life (T 1/2) [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    T 1/2 = terminal elimination half life of ritonavir at specified time points.

  • Mean ATV Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    Tmax = time to reach maximum observed plasma concentration of atazanavir at specified time points.

  • Mean RTV Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Pregnancy Weeks 12 to 28, Weeks 28 to 36, and 4-6 Weeks Postpartum ] [ Designated as safety issue: No ]
    Tmax = time to reach the maximum observed plasma concentration of ritonavir at specified time points.


Secondary Outcome Measures:
  • Maternal HIV Ribonucleic Acid (RNA) Level on Day of Delivery [ Time Frame: Day of Delivery ± 2 Days ] [ Designated as safety issue: No ]
    The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.

  • Median Change From Baseline to Day of Delivery in Maternal HIV RNA Level [ Time Frame: Baseline, Day of Delivery ± 2 Days ] [ Designated as safety issue: No ]
    The maternal HIV RNA level was determined at baseline and the day of delivery ± 2 days using VR-OC. The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.

  • Mean HIV RNA Level at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Median Change From Baseline to Day of Delivery in Maternal Cluster of Differentiation 4 (CD4) Cell Count [ Time Frame: Baseline, Day of Delivery ± 2 Days ] [ Designated as safety issue: No ]
    The median CD4 cell count change from baseline was calculated for all treated mothers at the time of delivery ± 2 days. Maternal CD4 cell counts were assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.

  • Mean CD4 Cell Count at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Infant HIV Status [ Time Frame: Birth Through 6 Months on Study ] [ Designated as safety issue: No ]
    The neonatal HIV-1 status are assessed by the Roche Amplicor HIV-1 DNA Assay Version 1.5 (Roche Molecular Systems).

  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: During study period and 30 days post-study. ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE =any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

  • Number of Participants With Grade 2 to Grade 4 AEs and SAEs [ Time Frame: During Study Period and 30 Days Post-Study. ] [ Designated as safety issue: Yes ]
    AEs and SAEs considered possibly, probably, or certainly related to study treatment, were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). Hyperbilirubinemia (Grade 1=1.1 to 1.5 upper limit of normal [ULN] [mild], Grade 2=1.6 to 2.5 ULN [moderate], Grade 3=2.6 to 5.0 ULN [severe], Grade 4= > 5.0 ULN [potentially life threatening]).

  • SAEs in Enrolled Mothers [ Time Frame: During Study Period and 30 Days Post-Study. ] [ Designated as safety issue: Yes ]
    SAEs were evaluated for all treated and untreated participants. An SAE was defined as an untoward medical occurrence that results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event); might have caused death if it were more severe, required inpatient hospitalization or prolongation of existing hospitalization, in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, an important medical event that required intervention to prevent serious outcomes.

  • SAEs in Enrolled Infants [ Time Frame: Birth Through Week 16 of Life ] [ Designated as safety issue: Yes ]
    SAEs were evaluated for all treated and untreated participants. An SAE was defined as an untoward medical occurrence that results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event); might have caused death if it were more severe, required inpatient hospitalization or prolongation of existing hospitalization, in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, an important medical event that required intervention to prevent serious outcomes.

  • Mean Atazanavir Maternal Plasma Concentration and Neonatal Cord Blood Concentration [ Time Frame: At Time of Delivery ] [ Designated as safety issue: No ]
    Mean atazanavir maternal plasma concentration and neonatal cord blood concentration as measured at the time of delivery.

  • Median Infant Total Bilirubin Level [ Time Frame: Birth (Day 1), Day 3, Day 5, and Day 7 of Life ] [ Designated as safety issue: Yes ]
    Median infant total bilirubin level as measured at specified time points.

  • Mean Atazanavir Plasma Protein Binding [ Time Frame: Pregnancy Weeks 28 to Delivery at 3 Hours Postdose and 24 Hours Postdose, and Time of Delivery ] [ Designated as safety issue: No ]
    Atazanavir Plasma Protein Binding Percentage measured at specified time points.

  • Multicenter AIDS Cohort Study (MACS) Participant Adherence to Regimen and Drug Components for ATV 300 mg / RTV 100 mg Test Dose [ Time Frame: Study Week 2, Pregnancy Weeks 20 to Weeks 28, Pregnancy Weeks 28 to Delivery, Week 2 Postpartum, Week 4 Postpartum ] [ Designated as safety issue: No ]
    The MACS was administered to evaluate participant adherence to each drug and the adherence to the regimen. The MACS adherence questionnaire asks patients how many medication doses they missed during the previous day, 2 days, 3 days and 4 days. Drug-specific questions included adherence with dose and frequency. Adherence was defined as taking all doses and numbers of pills as prescribed for each medication. This strict adherence cut-off was based on the guidelines stating that anything less than excellent adherence may result in a virus breakthrough and development of resistance.


Enrollment: 69
Study Start Date: June 2006
Study Completion Date: August 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment Drug: Atazanavir + Ritonavir + Combivir
Capsules, tablets, Oral, initially ATV 300 mg + RTV 100 mg + ZDV/3TC 300/150 mg, dose escalated to ATV 400 mg + RTV 100 mg + ZDV/3TC 300/150 mg, ATV and RTV once daily, lamivudine (ZDV) / zidovudine (3TC) twice daily (BID), up to 36 weeks
Other Names:
  • Reyataz
  • BMS-232632

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-infected pregnant women
  • > 18 years of age
  • Between week 12 and 32 gestation
  • CD4 > 200 cells/mm³
  • Treatment-naive with HIV RNA > 400 c/mL, on HAART with HIV RNA <50 c/mL, or previously treated with ATV (< 3 weeks) with HIV RNA>400 c/mL
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00326716

Locations
United States, Florida
Triple O Medical Services, P.A.
West Palm Beach, Florida, United States, 33401
United States, Texas
Women's Hospital Of Texas
Houston, Texas, United States, 77054
Puerto Rico
Local Institution
San Juan, Puerto Rico, 00936
South Africa
Local Institution
Soweto, Gauteng, South Africa, 2001
Local Institution
Sunnyside, Gauteng, South Africa, 0002
Local Institution
Westdene, Gauteng, South Africa, 2092
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00326716     History of Changes
Other Study ID Numbers: AI424-182
Study First Received: May 15, 2006
Results First Received: January 5, 2011
Last Updated: November 4, 2011
Health Authority: United States: Food and Drug Administration
Republic of South Africa: National Ministry of Health

Keywords provided by Bristol-Myers Squibb:
HIV-1 infected pregnant women, either treatment naive or on ATV/RTV combined with ZDV/3TC

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Ritonavir
Atazanavir
Lamivudine, zidovudine drug combination
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014