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

Study Overview
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Brief Summary
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The purpose of the study was to assess the steady-state pharmacokinetics (PK) of efavirenz (EFV) in human immunodeficiency virus type 1 (HIV-1) infected subjects on stable antiretroviral regimens containing EFV, and having selected degrees of hepatic impairment or normal hepatic function.

Official Title
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Pharmacokinetics of Efavirenz During Treatment of HIV-1 Infected Subjects With Hepatic Impairment.

Conditions
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HIV Infections, Hepatic Impairment

Intervention / Treatment
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* Drug: efavirenz containing antiretroviral regimen
* Drug: efavirenz containing antiretroviral regimen
* Drug: efavirenz containing antiretroviral regimen
* Drug: efavirenz containing antiretroviral regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection with or without Hepatitis B or C infection Stable antiretroviral regimen containing efavirenz and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) for at least 1 month Mild, moderate or severe hepatic impairment with hepatic cirrhosis Exclusion Criteria: Acute flare of hepatitis Positive pregnancy test for a female Significant acute medical illness in past 2 months Use of agents known to significantly affect liver metabolism Change in medications to treat a chronic disease in the past 2 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EFV600mg Participants With Mild Hepatic Impairment<br> | Drug: efavirenz containing antiretroviral regimen<br>* Capsule or Tablet, Oral, once daily for 2 days<br>* Other names: BMS-561525;|
| Experimental: EFV600mg Participants With Moderate Hepatic Impairment<br> | Drug: efavirenz containing antiretroviral regimen<br>* Capsule or Tablet, Oral, once daily for 2 days<br>* Other names: BMS-561525;|
| Experimental: EFV600mg Participants With Severe Hepatic Impairment<br> | Drug: efavirenz containing antiretroviral regimen<br>* Capsule or Tablet, Oral, once daily for 2 days<br>* Other names: BMS-561525;|
| Active Comparator: EFV600mg Participants With Normal Hepatic Function<br> | Drug: efavirenz containing antiretroviral regimen<br>* Capsule or Tablet, Oral, once daily for 2 days<br>* Other names: BMS-561525;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) | Cmax was obtained directly from the concentration-time data. | 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. | 
| Minimum Plasma Concentration (Cmin) | Cmin was obtained directly from the concentration-time data. | 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. | 
| Area Under the Plasma Concentration-time Curve Over the Dosing Interval of 24 Hours (AUC[TAU]) | The AUC(TAU), from time 0 to the time of the last measurable concentration (t), was calculated by the linear trapezoidal rule. | 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. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax was obtained directly from the concentration-time data. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died or Experienced Other Serious Adverse Events (SAEs) | An SAE was defined as any adverse event (AE) occurring at any dose that; resulted in death; was life threatening; resulted in a persistent or significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was a cancer; or was an overdose. | 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. | 
| Number of Participants Who Experienced AEs | AEs were defined as any new untoward medical occurrences or worsening of a pre-existing medical condition in a participant administered a medicinal product, whether or not considered related to the medicinal product. | 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). | 
| Number of Participants Who Experienced AEs Leading to Study Drug Discontinuation | AEs were defined as any new untoward medical occurrences or worsening of a pre-existing medical condition in a participant administered a medicinal product, whether or not considered related to the medicinal product. Participants who discontinued the study due to an AE were recorded. | 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). | 
| Number of Participants With Marked Abnormalities (MAs) in Hematology Measurements | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Low platelet count: <0.85 x lower limit of normal (LLN) (or if pre-treatment value <LLN, then <0.85 x pre-treatment value). Low leukocytes: <0.9 x LLN (or if pre-treatment value <LLN, then <0.85 x pre-treatment value. If pre-treatment value >upper limit of normal [ULN], then <LLN). Low neutrophils+bands (absolute): <=1.500 10^3 cells/microliter (uL). Low lymphocytes (absolute): <0.750 10^3 cells/uL. | Throughout study, from screening (within 21 days of Day 1 dosing) through Day 3. | 
| Number of Participants With Serum Chemistry MAs | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify the criteria for MAs in the data presented. High bilirubin (total): >1.1 x ULN (or if pre-treatment value >ULN, then >1.25 x pre-treatment value). High creatinine: >1.33 x pre-treatment value. Low albumin: <0.9 x LLN (or if pre-treatment value <LLN, then <0.9 x pre-treatment value). High amylase (total): >2 x pre-treatment value. | Throughout study, from screening (within 21 days of Day 1 dosing) through Day 3. | 
| Number of Participants With Urinalysis MAs | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following urinalysis MA definitions specify the criteria for MAs in the data presented. The presence of white blood cells (WBCs) and red blood cells (RBCs) in the urine was graded on a scale: 0 = no cells present (negative); trace =a small number of cells present; then 1+, 2+, 3+ and 4+, denoting increasingly positive urine results (ie, WBCs/RBCs present in the urine). The MA for both WBCs and RBCs was >= 2+ (or, if pre-treatment value >=2+, then >= 4+). | Throughout study, from screening (within 21 days of Day 1 dosing) through Day 3. | 
| Number of Participants With Identified Electrocardiogram (ECG) Abnormalities | ECG abnormalities are findings that are clinically meaningful by the judgment of the investigator. A 12-lead ECG was performed and all ECG recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed. | 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) | 
| Number of Participants With Clinically Meaningful Vital Signs Measures | Vital signs were recorded throughout the study and included investigations related to body temperature, respiratory rate, seated blood pressure (systolic and diastolic), and heart rate. The investigator used his/her clinical judgement to decide whether or not abnormalities in vital signs were clinically meaningful. | 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) | 
| Number of Participants With Abnormal Physical Examination Findings at Baseline (Screening and/or Day 1) | The physical examination included an evaluation of the participant's height and body mass index (BMI) (at screening only), and weight. Abnormal physical examination are findings that are clinically meaningful by the judgment of the investigator | 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) |