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

HIV Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00326716
• Other study ID #: AI424-182
• Status: Completed
• Phase: Phase 1
• First received: May 15, 2006
• Last updated: November 4, 2011
• Start date: June 2006
• Est. completion date: August 2009

Study information

• Verified date: November 2011
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationRepublic of South Africa: National Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 69
• Est. completion date: August 2009
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infection

Intervention

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

Locations

Country	Name	City	State
Puerto Rico	Local Institution	San Juan
South Africa	Local Institution	Soweto	Gauteng
South Africa	Local Institution	Sunnyside	Gauteng
South Africa	Local Institution	Westdene	Gauteng
United States	Women's Hospital Of Texas	Houston	Texas
United States	Triple O Medical Services, P.A.	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Puerto Rico,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Infant Gestational Age at Delivery		At the time of delivery	No
Primary	Infant Gender		At the time of delivery	No
Primary	Infant Race		At the time of delivery	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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.	No
Primary	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.	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Mean HIV RNA Level at Baseline		Baseline	No
Secondary	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	No
Secondary	Mean CD4 Cell Count at Baseline		Baseline	No
Secondary	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	No
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	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	Yes
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	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