Pharmacokinetics of Efavirenz in HIV-1 Infected Subjects With Hepatic Impairment

This study has been completed.
Sponsor:
Information provided by:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00162097
First received: September 9, 2005
Last updated: September 7, 2010
Last verified: September 2010
Results First Received: July 28, 2010  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: HIV Infections
Hepatic Impairment
Intervention: Drug: efavirenz containing antiretroviral regimen

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
21 participants were enrolled in the study; 5 discontinued prior to study drug administration (1 adverse event, 1 enrollment completed, 1 screen failure, 1 no longer met study criteria and 1 withdrew consent).

Reporting Groups
  Description
EFV600mg Participants With Mild Hepatic Impairment Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz, either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM), on an empty stomach. The duration of efavirenz administration was 2 days and participants were admitted to the clinical facility for this period. Mild hepatic impairment (grade A) is defined as a Child-Pugh (CP) total score of 5-6. The CP classification assesses 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy) on a scale of 1 (mild or none) to 3 (most severe). Total score range is 5 (mild) to 15 (severe).
EFV600mg Participants With Moderate Hepatic Impairment Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz, either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM), on an empty stomach. The duration of efavirenz administration was 2 days and participants were admitted to the clinical facility for this period. Moderate hepatic impairment (grade B) is defined as a CP total score of 7-9.
EFV600mg Participants With Severe Hepatic Impairment Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz, either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM), on an empty stomach. The duration of efavirenz administration was 2 days and participants were admitted to the clinical facility for this period. Participants who were on an off-label reduced dose of efavirenz (eg, 400 mg) continued on the reduced dose. Severe hepatic impairment (grade C) is defined as a CP total score of 10-15.
EFV600mg Participants With Normal Hepatic Function Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM) on an empty stomach. The duration of efavirenz administration was 2 days when participants were admitted to the clinical facility. Participants were enrolled after at least 6 participants with hepatic impairment had completed. One participant enrolled twice in the study and is hence counted twice in this group

Participant Flow:   Overall Study
    EFV600mg Participants With Mild Hepatic Impairment     EFV600mg Participants With Moderate Hepatic Impairment     EFV600mg Participants With Severe Hepatic Impairment     EFV600mg Participants With Normal Hepatic Function  
STARTED     6 [1]   2 [1]   1 [1]   7 [2]
COMPLETED     6     2     1     6  
NOT COMPLETED     0     0     0     1  
Participant no longer met study criteria                 0                 0                 0                 1  
[1] Treated on Day 1
[2] Treated on Day 1. One participant enrolled twice in the study and is hence counted twice



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
EFV600mg Participants With Mild Hepatic Impairment Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz, either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM), on an empty stomach. The duration of efavirenz administration was 2 days and participants were admitted to the clinical facility for this period. Mild hepatic impairment (grade A) is defined as a Child-Pugh (CP) total score of 5-6. The CP classification assesses 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy) on a scale of 1 (mild or none) to 3 (most severe). Total score range is 5 (mild) to 15 (severe).
EFV600mg Participants With Moderate Hepatic Impairment Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz, either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM), on an empty stomach. The duration of efavirenz administration was 2 days and participants were admitted to the clinical facility for this period. Moderate hepatic impairment (grade B) is defined as a CP total score of 7-9.
EFV600mg Participants With Severe Hepatic Impairment Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz, either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM), on an empty stomach. The duration of efavirenz administration was 2 days and participants were admitted to the clinical facility for this period. Participants who were on an off-label reduced dose of efavirenz (eg, 400 mg) continued on the reduced dose. Severe hepatic impairment (grade C) is defined as a CP total score of 10-15.
EFV600mg Participants With Normal Hepatic Function Participants were administered a dose of 600 mg once daily (capsules or tablets) of efavirenz either in the morning (at approximately 9:00 AM) or before bed time (at approximately 9:00 PM) on an empty stomach. The duration of efavirenz administration was 2 days when participants were admitted to the clinical facility. Participants were enrolled after at least 6 participants with hepatic impairment had completed. One participant enrolled twice in the study and is hence counted twice in this group
Total Total of all reporting groups

Baseline Measures
    EFV600mg Participants With Mild Hepatic Impairment     EFV600mg Participants With Moderate Hepatic Impairment     EFV600mg Participants With Severe Hepatic Impairment     EFV600mg Participants With Normal Hepatic Function     Total  
Number of Participants  
[units: participants]
  6     2     1     7     16  
Age  
[units: years]
Mean ± Standard Deviation
  50  ± 11     51  ± 1     47     49  ± 4     49  ± 7  
Age, Customized  
[units: participants]
         
< 65 years     5     2     1     7     15  
>= 65 years     1     0     0     0     1  
Gender  
[units: participants]
         
Female     4     0     1     0     5  
Male     2     2     0     7     11  
Ethnicity (NIH/OMB)  
[units: participants]
         
Hispanic or Latino     1     0     1     0     2  
Not Hispanic or Latino     5     2     0     6     13  
Unknown or Not Reported     0     0     0     1     1  
Race/Ethnicity, Customized  
[units: participants]
         
American Indian     1     0     0     0     1  
Black     3     1     0     5     9  
White     2     1     0     2     5  
Hispanic/Latino     0     0     1     0     1  
Body mass index (BMI) Continuous [1]
[units: kg/m^2]
Mean ± Standard Deviation
  26.3  ± 3.7     24.6  ± 0.1     24.0     22.8  ± 2.2     24.4  ± 3.0  
Height Continuous  
[units: cm]
Mean ± Standard Deviation
  165.5  ± 11.9     173.4  ± 3.7     160.0     175.6  ± 7.2     170.6  ± 10.0  
Weight, Continuous  
[units: kilogram]
Mean ± Standard Deviation
  71.5  ± 7.2     73.9  ± 2.9     61.5     70.4  ± 9.6     70.7  ± 7.9  
[1] BMI is defined as the individual's body weight divided by the square of his or her height.



  Outcome Measures
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1.  Primary:   Maximum Plasma Concentration (Cmax)   [ Time Frame: Blood samples were collected at time 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose, relative to administration of PM or AM dose. ]

2.  Primary:   Minimum Plasma Concentration (Cmin)   [ Time Frame: Blood samples were collected at time 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose, relative to administration of PM or AM dose. ]

3.  Primary:   Area Under the Plasma Concentration-time Curve Over the Dosing Interval of 24 Hours (AUC[TAU])   [ Time Frame: Blood samples were collected at time 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose, relative to administration of PM or AM dose. ]

4.  Primary:   Time to Reach Maximum Observed Plasma Concentration (Tmax)   [ Time Frame: Blood samples were collected at time 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose, relative to administration of PM or AM dose. ]

5.  Secondary:   Number of Participants Who Died or Experienced Other Serious Adverse Events (SAEs)   [ Time Frame: From screening (within 21 days of Day 1 dosing) to the study discharge day (Day 2 for AM dosing or Day 3 for PM dosing). Participants were monitored for SAEs up to 30 days after study discharge. ]

6.  Secondary:   Number of Participants Who Experienced AEs   [ Time Frame: From screening (within 21 days of Day 1 dosing) to the study discharge day (Day 2 for AM dosing or Day 3 for PM dosing). ]

7.  Secondary:   Number of Participants Who Experienced AEs Leading to Study Drug Discontinuation   [ Time Frame: From screening (within 21 days of Day 1 dosing) to the study discharge day (Day 2 for AM dosing or Day 3 for PM dosing). ]

8.  Secondary:   Number of Participants With Marked Abnormalities (MAs) in Hematology Measurements   [ Time Frame: Throughout study, from screening (within 21 days of Day 1 dosing) through Day 3. ]

9.  Secondary:   Number of Participants With Serum Chemistry MAs   [ Time Frame: Throughout study, from screening (within 21 days of Day 1 dosing) through Day 3. ]

10.  Secondary:   Number of Participants With Urinalysis MAs   [ Time Frame: Throughout study, from screening (within 21 days of Day 1 dosing) through Day 3. ]

11.  Secondary:   Number of Participants With Identified Electrocardiogram (ECG) Abnormalities   [ Time Frame: From screening (within 21 days of Day 1 dosing) to the study discharge day (Day 2 for AM dosing or Day 3 for PM dosing) ]

12.  Secondary:   Number of Participants With Clinically Meaningful Vital Signs Measures   [ Time Frame: From screening (within 21 days of Day 1 dosing) to the study discharge day (Day 2 for AM dosing or Day 3 for PM dosing) ]

13.  Secondary:   Number of Participants With Abnormal Physical Examination Findings at Baseline (Screening and/or Day 1)   [ Time Frame: From screening (within 21 days of Day 1 dosing) to the study discharge day (Day 2 for AM dosing or Day 3 for PM dosing) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The study was terminated early leading to a small number of participants treated and analyzed. Due to the small sample size, no conclusion could be made for participants with Child-Pugh scores B and C (moderate and severe hepatic impairment).


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00162097     History of Changes
Other Study ID Numbers: AI266-917
Study First Received: September 9, 2005
Results First Received: July 28, 2010
Last Updated: September 7, 2010
Health Authority: United States: Food and Drug Administration