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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Atazanavir + Ritonavir + Combivir

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 1

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936
    • Local Institution
• South Africa
  • Gauteng
    • Soweto, Gauteng, South Africa, 2001
      • Local Institution
    • Sunnyside, Gauteng, South Africa, 0002
      • Local Institution
    • Westdene, Gauteng, South Africa, 2092
      • Local Institution
• United States
  • Florida
    • West Palm Beach, Florida, United States, 33401
      • Triple O Medical Services, P.A.
  • Texas
    • Houston, Texas, United States, 77054
      • Women's Hospital of Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant Gestational Age at Delivery		At the time of delivery
Infant Gender		At the time of delivery
Infant Race		At the time of delivery
Mean ATV Maximum Plasma Concentration (Cmax) in One Dosing Interval	Cmax = maximum observed plasma concentration of atazanavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean RTV Maximum Plasma Concentration (Cmax) in One Dosing Interval	Cmax = maximum observed plasma concentration of ritonavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean ATV Area Under the Concentration Curve (AUC TAU)	AUC = area under the concentration curve (AUC [TAU]) of atazanavir in one dosing interval from time zero to 24 hours.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean RTV Area Under the Concentration Curve (AUC TAU)	AUC = area under the concentration curve (AUC [TAU]) of ritonavir in one dosing interval.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose	Cmin = plasma concentration 24 hours post dose of atazanavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose.
Mean RTV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose	Cmin = plasma concentration 24 hours post dose of ritonavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose.
Mean ATV Terminal Elimination Half Life (T 1/2)	T 1/2 = terminal elimination half life of atazanavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean RTV Terminal Elimination Half Life (T 1/2)	T 1/2 = terminal elimination half life of ritonavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean ATV Time of Maximum Observed Plasma Concentration (Tmax)	Tmax = time to reach maximum observed plasma concentration of atazanavir at specified time points.	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum
Mean RTV Time of Maximum Observed Plasma Concentration (Tmax)	Tmax = time to reach the maximum observed plasma concentration of ritonavir at specified time points.	Pregnancy Weeks 12 to 28, Weeks 28 to 36, and 4-6 Weeks Postpartum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal HIV Ribonucleic Acid (RNA) Level on Day of Delivery	The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.	Day of Delivery ± 2 Days
Median Change From Baseline to Day of Delivery in Maternal HIV RNA Level	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.	Baseline, Day of Delivery ± 2 Days
Mean HIV RNA Level at Baseline		Baseline
Median Change From Baseline to Day of Delivery in Maternal Cluster of Differentiation 4 (CD4) Cell Count	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.	Baseline, Day of Delivery ± 2 Days
Mean CD4 Cell Count at Baseline		Baseline
Infant HIV Status	The neonatal HIV-1 status are assessed by the Roche Amplicor HIV-1 DNA Assay Version 1.5 (Roche Molecular Systems).	Birth Through 6 Months on Study
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	During study period and 30 days post-study.
Number of Participants With Grade 2 to Grade 4 AEs and SAEs	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]).	During Study Period and 30 Days Post-Study.
SAEs in Enrolled Mothers	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.	During Study Period and 30 Days Post-Study.
SAEs in Enrolled Infants	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.	Birth Through Week 16 of Life
Mean Atazanavir Maternal Plasma Concentration and Neonatal Cord Blood Concentration	Mean atazanavir maternal plasma concentration and neonatal cord blood concentration as measured at the time of delivery.	At Time of Delivery
Median Infant Total Bilirubin Level	Median infant total bilirubin level as measured at specified time points.	Birth (Day 1), Day 3, Day 5, and Day 7 of Life
Mean Atazanavir Plasma Protein Binding	Atazanavir Plasma Protein Binding Percentage measured at specified time points.	Pregnancy Weeks 28 to Delivery at 3 Hours Postdose and 24 Hours Postdose, and Time of Delivery
Multicenter AIDS Cohort Study (MACS) Participant Adherence to Regimen and Drug Components for ATV 300 mg / RTV 100 mg Test Dose	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.	Study Week 2, Pregnancy Weeks 20 to Weeks 28, Pregnancy Weeks 28 to Delivery, Week 2 Postpartum, Week 4 Postpartum

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Xu XS, Rose A, Demers R, Eley T, Ryan J, Stouffer B, Cojocaru L, Arnold M. Quantitative determination of free/bound atazanavir via high-throughput equilibrium dialysis and LC-MS/MS, and the application in ex vivo samples. Bioanalysis. 2014;6(23):3169-82. doi: 10.4155/bio.14.251.
• Eley T, Huang SP, Conradie F, Zorrilla CD, Josipovic D, Botes M, Osiyemi O, Hardy H, Bertz R, McGrath D. Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy. AIDS Res Hum Retroviruses. 2013 Oct;29(10):1287-92. doi: 10.1089/AID.2013.0002. Epub 2013 Jul 19.
• Conradie F, Zorrilla C, Josipovic D, Botes M, Osiyemi O, Vandeloise E, Eley T, Child M, Bertz R, Hu W, Wirtz V, McGrath D. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med. 2011 Oct;12(9):570-9. doi: 10.1111/j.1468-1293.2011.00927.x. Epub 2011 May 16.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: May 15, 2006
• First Submitted That Met QC Criteria: May 16, 2006
• First Posted (Estimate): May 17, 2006

Study Record Updates

• Last Update Posted (Estimate): November 16, 2011
• Last Update Submitted That Met QC Criteria: November 4, 2011
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: HIV-1 infected pregnant women, either treatment naive or on ATV/RTV combined with ZDV/3TC
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Atazanavir Sulfate; Lamivudine, zidovudine drug combination
• Other Study ID Numbers: AI424-182