HIV Infections
Conditions
Keywords
Treatment Naive
Brief summary
This 2 arm study will assess the effect of moderate liver impairment on the pharmacokinetics of saquinavir and ritonavir at steady state following administration of saquinavir/ritonavir 1000mg/100mg po bid in HIV patients. Saquinavir/ritonavir will be administered concomitantly with 2 to 3 active nucleoside reverse transcriptase inhibitors. The study will compare a group of HIV patients without known liver disease and a group with moderate liver disease. The anticipated time on study treatment is \<3 months, and the target sample size is \<100 individuals.
Interventions
DRUGRitonavir
100mg po bid
1000mg po bid
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* adult patients, 18-65 years of age; * HIV infection; * normal liver function, or moderate liver disease (Child-Pugh grade B); * antiretroviral therapy naive and eligible to take antiretroviral treatment as per treatment guidelines, or treatment experienced for at least 4 weeks prior to first dosing.
Exclusion criteria
* severe ascites at screening, or Child-Pugh grade C; * acute infection or current malignancy requiring treatment; * taking any inhibitor of CYP3A4 (with the exception of anti-HIV drugs) within 14 days prior to first dosing; * taking any inducer of CYP3A4 (with the exception of anti-HIV drugs) within 4 weeks prior to pharmacokinetic evaluation (day 14 or 28); * evidence of resistance to saquinavir.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours After Dosing (AUC 0-12h) of Saquinavir (SQV) and Ritonavir (RTV) | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14 | Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. The pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the area under the plasma concentration-time curve from 0 to 12 hours after dosing (AUC (0-12h) of SQV and RTV The AUC (0-12hours) was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
| Maximum Observed Plasma Concentration (Cmax) of SQV and RTV | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14 | The plasma concentration (Cmax) is defined as maximum observed analyte concentration. The pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the maximum observed plasma concentration (C max) of SQV and Ritonavir RTV The Cmax was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Observed Plasma Concentration (Cmin) of SQV and RTV | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post dose on Day 14 | Cmin is the minimum blood plasma concentration that a drug achieves. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the minimum observed plasma concentration (C min) of SQV and RTV The Cmin was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
| Plasma Clearance After Oral Administration (CL/F) of SQV and RTV | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post dose on Day 14 | The CL/F is the oral clearance; that is clearance based on oral bioavailability. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the plasma clearance after oral administration (CL/F)of SQV and RTV The CL/F was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
| Volume of Distribution (Vd) of SQV and RTV | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post dose on Day 14 | Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. The pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the Vd of SQV and RTV The Vd was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
| Time of Maximum Plasma Concentration (Tmax) of SQV and RTV | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14 | The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the time of maximum plasma concentration of SQV and RTV. The Tmax was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
| Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Up to Day 35 | Laboratory parameters specified in Clinical Operating Guidelines (COG) were summarized. AIDS Clinical Trial Group (ACTG) and American Heart Association (AHA) criteria were used to grade COG laboratory test values. Laboratory parameters for which an increase to Grade 3 (G3) or Grade 4 (G4) occurred are presented in the table below. |
| Number Participants With Abnormal Vital Signs | Up to Day 35 | Abnormal Vital signs included are high and low Pulse rate (PR), high and how Temperature (Temp), high and low Systolic Blood Pressure (SBP) and high and low Diastolic Blood Pressure (DBP). Vital signs (SBP, DBP, PR,Temp) were measured after participants were in a semi-supine position for at least 5 minutes. |
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Up to Day 35 | Abnormal ECG findings included are high and low Heart Rate (HRT), high and low PQ/PR interval (PQ/PR), high and low QRS interval (QRS), high and low QT interval (QT), high and low QTCB interval (QTcB), high and low QTcF interval (QTcF), high and low RR interval (RR), high and low T Wave, high and low U Wave, high and low ECG. The 12 Lead ECG was recorded after participants were in a semi-supine position for at least 5 minutes. Only participants with abnormal ECG findings are presented in the table below. |
| Cluster of Differentiation 4 (CD4 ) Count | Screening (Day -35 to -1), pre-dose on Day 8, Day 14 and at follow up (Day 28-Day 35) | The pharmacodynamic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the cluster of differentiation 4 (CD4) count in participants in each group. |
| Terminal Half-life (T1/2) of SQV and RTV | Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14 | Terminal half-life is the time measured for the plasma concentration to decrease by one half. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the terminal half-life (T1/2) of SQV and RTV. The T1/2 was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin. |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
The study was conducted from 12 September 2006 to 09 April 2009 at 3 sites in US and 2 in Canada.
Pre-assignment details
Total 19 participants were screened. A total 9 participants with HIV infection with moderate liver disease (Group 2) and 7 participants with HIV infection with normal liver function (Group 1) were enrolled in the study. Participants in Group 1 were matched with those in Group 2 on the basis of age, gender, weight, and tobacco use.
Participants by arm
| Arm | Count |
|---|---|
| Normal Liver Function Participants with human immunodeficiency virus (HIV) infection and with normal liver function receiving saquinavir (SQV)/ritonavir (RTV) 1000/100 mg orally twice a day (BID) for 14 days. | 7 |
| Moderate Hepatic Impairment Participants with HIV infection and with moderate hepatic impairment receiving SQV/RTV 1000/100 mg orally BID for 14 days. | 9 |
| Total | 16 |
Baseline characteristics
| Characteristic | Normal Liver Function | Moderate Hepatic Impairment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 7 | 5 / 9 |
| serious Total, serious adverse events | 0 / 7 | 1 / 9 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours After Dosing (AUC 0-12h) of Saquinavir (SQV) and Ritonavir (RTV)
Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time. It is used to characterize drug absorption. The pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the area under the plasma concentration-time curve from 0 to 12 hours after dosing (AUC (0-12h) of SQV and RTV The AUC (0-12hours) was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours After Dosing (AUC 0-12h) of Saquinavir (SQV) and Ritonavir (RTV) | AUC for SQV | 28518 ng*hr/mL | Standard Deviation 20157 |
| Normal Liver Function | Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours After Dosing (AUC 0-12h) of Saquinavir (SQV) and Ritonavir (RTV) | AUC for RTV | 10985 ng*hr/mL | Standard Deviation 1723 |
| Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours After Dosing (AUC 0-12h) of Saquinavir (SQV) and Ritonavir (RTV) | AUC for SQV | 24332 ng*hr/mL | Standard Deviation 24700 |
| Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours After Dosing (AUC 0-12h) of Saquinavir (SQV) and Ritonavir (RTV) | AUC for RTV | 9930 ng*hr/mL | Standard Deviation 5243 |
Comparison: Comparison between normal liver function and moderate hepatic impairment for SQV90% CI: [0.268, 1.603]
Comparison: Comparison between normal liver function and moderate hepatic impairment for RTV.90% CI: [0.505, 1.156]
Primary
Maximum Observed Plasma Concentration (Cmax) of SQV and RTV
The plasma concentration (Cmax) is defined as maximum observed analyte concentration. The pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the maximum observed plasma concentration (C max) of SQV and Ritonavir RTV The Cmax was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Maximum Observed Plasma Concentration (Cmax) of SQV and RTV | Cmax of SQV | 4300 ng/mL | Standard Deviation 2940 |
| Normal Liver Function | Maximum Observed Plasma Concentration (Cmax) of SQV and RTV | Cmax of RTV | 1500 ng/mL | Standard Deviation 294 |
| Moderate Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of SQV and RTV | Cmax of SQV | 3610 ng/mL | Standard Deviation 3000 |
| Moderate Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) of SQV and RTV | Cmax of RTV | 1460 ng/mL | Standard Deviation 690 |
Comparison: Comparison between normal liver function and moderate hepatic impairment for SQV.90% CI: [0.311, 1.644]
Comparison: Comparison between normal liver function and moderate hepatic impairment for RTV.90% CI: [0.551, 1.292]
Secondary
Cluster of Differentiation 4 (CD4 ) Count
The pharmacodynamic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the cluster of differentiation 4 (CD4) count in participants in each group.
Time frame: Screening (Day -35 to -1), pre-dose on Day 8, Day 14 and at follow up (Day 28-Day 35)
Population: PD analysis population: All participants who received at least 1 dose of the study medication and had at least 1 pharmacodynamic (PD) measure were included in the PD analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Cluster of Differentiation 4 (CD4 ) Count | Screening; n=7, 9 | 540.000 cells/cubic millimeter | Standard Deviation 218.187 |
| Normal Liver Function | Cluster of Differentiation 4 (CD4 ) Count | Day 8;n=6, 9 | 638.500 cells/cubic millimeter | Standard Deviation 254.358 |
| Normal Liver Function | Cluster of Differentiation 4 (CD4 ) Count | Day 14;n=7, 9 | 683.571 cells/cubic millimeter | Standard Deviation 250.16 |
| Normal Liver Function | Cluster of Differentiation 4 (CD4 ) Count | Follow up; n=6, 8 | 692.500 cells/cubic millimeter | Standard Deviation 150.045 |
| Moderate Hepatic Impairment | Cluster of Differentiation 4 (CD4 ) Count | Follow up; n=6, 8 | 567.625 cells/cubic millimeter | Standard Deviation 261.947 |
| Moderate Hepatic Impairment | Cluster of Differentiation 4 (CD4 ) Count | Screening; n=7, 9 | 451.444 cells/cubic millimeter | Standard Deviation 249.011 |
| Moderate Hepatic Impairment | Cluster of Differentiation 4 (CD4 ) Count | Day 14;n=7, 9 | 566.333 cells/cubic millimeter | Standard Deviation 257.484 |
| Moderate Hepatic Impairment | Cluster of Differentiation 4 (CD4 ) Count | Day 8;n=6, 9 | 558.000 cells/cubic millimeter | Standard Deviation 243.994 |
Secondary
Minimum Observed Plasma Concentration (Cmin) of SQV and RTV
Cmin is the minimum blood plasma concentration that a drug achieves. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the minimum observed plasma concentration (C min) of SQV and RTV The Cmin was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Minimum Observed Plasma Concentration (Cmin) of SQV and RTV | Cmin of SQV | 965 ng/mL | Standard Deviation 920 |
| Normal Liver Function | Minimum Observed Plasma Concentration (Cmin) of SQV and RTV | Cmin of RTV | 399 ng/mL | Standard Deviation 172 |
| Moderate Hepatic Impairment | Minimum Observed Plasma Concentration (Cmin) of SQV and RTV | Cmin of SQV | 834 ng/mL | Standard Deviation 870 |
| Moderate Hepatic Impairment | Minimum Observed Plasma Concentration (Cmin) of SQV and RTV | Cmin of RTV | 418 ng/mL | Standard Deviation 300 |
Secondary
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Abnormal ECG findings included are high and low Heart Rate (HRT), high and low PQ/PR interval (PQ/PR), high and low QRS interval (QRS), high and low QT interval (QT), high and low QTCB interval (QTcB), high and low QTcF interval (QTcF), high and low RR interval (RR), high and low T Wave, high and low U Wave, high and low ECG. The 12 Lead ECG was recorded after participants were in a semi-supine position for at least 5 minutes. Only participants with abnormal ECG findings are presented in the table below.
Time frame: Up to Day 35
Population: Safety population: All participants who received at least 1 dose of study medication (whether or not they were withdrawn prematurely) and had safety follow-up data were included in safety analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- PQ (PR); n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QTcF; n=5, 8 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- RR; n=5, 8 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- RR; n=5, 8 | 1 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- T WAVE; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- T WAVE; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- HRT ECG ; n=7, 9 | 1 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- HRT ECG; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- U WAVE; n=1, 0 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- PQ (PR); n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- U WAVE; n=1, 0 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- ECG; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- ECG; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QRS; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QRS; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QT; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QT; n=7, 9 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QTcB; n=5, 8 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QTcB; n=5, 8 | 0 participants |
| Normal Liver Function | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QTcF; n=5, 8 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QTcB; n=5, 8 | 2 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- RR; n=5, 8 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- U WAVE; n=1, 0 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QTcF; n=5, 8 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QT; n=7, 9 | 2 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- ECG; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- RR; n=5, 8 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QTcF; n=5, 8 | 2 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- T WAVE; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- ECG; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QT; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- HRT ECG ; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- QRS; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- T WAVE; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- HRT ECG; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QTcB; n=5, 8 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- PQ (PR); n=7, 9 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- QRS; n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | LOW- PQ (PR); n=7, 9 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Abnormal Electrocardiogram (ECG) Findings | HIGH- U WAVE; n=1, 0 | 0 participants |
Secondary
Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters
Laboratory parameters specified in Clinical Operating Guidelines (COG) were summarized. AIDS Clinical Trial Group (ACTG) and American Heart Association (AHA) criteria were used to grade COG laboratory test values. Laboratory parameters for which an increase to Grade 3 (G3) or Grade 4 (G4) occurred are presented in the table below.
Time frame: Up to Day 35
Population: Safety population: All participants who received at least 1 dose of study medication (whether or not they were withdrawn prematurely) and had safety follow-up data were included in safety analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Sodium, (Hypo) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Cholesterol, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ALAT (SGPT), (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Cholesterol, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Platelets, (Hypo) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Triglycerides, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Direct Bilirubin, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Calcium, (Hypo) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatinine, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Calcium, (Hypo) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Direct Bilirubin, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Potassium, (Hypo) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Proteinuria 0 to 4+, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Potassium, (Hypo) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatinine, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Sodium, (Hypo) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ASAT (SGOT), (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Albumin, (Hypo) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Platelets, (Hypo) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ASAT (SGOT), (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Neutrophils, (Hypo) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Albumin, (Hypo) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Neutrophils, (Hypo) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Alkaline Phosphatase, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Fasting Glucose, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Prothrombin Time seconds(Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Fasting Glucose, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Alkaline Phosphatase, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Amylase, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Prothrombin Time seconds (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Amylase, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Triglycerides, (Hyper) G3 | 2 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Uric Acid, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatine Kinase, (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Uric Acid, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ALAT (SGPT), (Hyper) G3 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Proteinuria 0 to 4+, (Hyper) G4 | 0 participants |
| Normal Liver Function | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatine Kinase, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Proteinuria 0 to 4+, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Alkaline Phosphatase, (Hyper) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatinine, (Hyper) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Cholesterol, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Platelets, (Hypo) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Proteinuria 0 to 4+, (Hyper) G3 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ASAT (SGOT), (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Alkaline Phosphatase, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ALAT (SGPT), (Hyper) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ALAT (SGPT), (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Direct Bilirubin, (Hyper) G3 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Direct Bilirubin, (Hyper) G4 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatinine, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Albumin, (Hypo) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Albumin, (Hypo) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Prothrombin Time seconds(Hyper) G3 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Prothrombin Time seconds (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatine Kinase, (Hyper) G3 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Creatine Kinase, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Cholesterol, (Hyper) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Triglycerides, (Hyper) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Triglycerides, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Calcium, (Hypo) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Calcium, (Hypo) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Potassium, (Hypo) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Potassium, (Hypo) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Sodium, (Hypo) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Sodium, (Hypo) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Platelets, (Hypo) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Neutrophils, (Hypo) G3 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Neutrophils, (Hypo) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Fasting Glucose, (Hyper) G3 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Fasting Glucose, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Amylase, (Hyper) G3 | 1 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Amylase, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Uric Acid, (Hyper) G3 | 2 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | Uric Acid, (Hyper) G4 | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With the Indicated Grade 3 and Grade 4 Laboratory Parameters | ASAT (SGOT), (Hyper) G3 | 1 participants |
Secondary
Number Participants With Abnormal Vital Signs
Abnormal Vital signs included are high and low Pulse rate (PR), high and how Temperature (Temp), high and low Systolic Blood Pressure (SBP) and high and low Diastolic Blood Pressure (DBP). Vital signs (SBP, DBP, PR,Temp) were measured after participants were in a semi-supine position for at least 5 minutes.
Time frame: Up to Day 35
Population: Safety population: All participants who received at least 1 dose of study medication (whether or not they were withdrawn prematurely) and had safety follow-up data were included in safety analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Liver Function | Number Participants With Abnormal Vital Signs | High PR | 0 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | High-DBP | 0 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | Low PR | 0 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | High Temp | 0 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | Low Temp | 0 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | High-SBP | 1 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | Low-SBP | 0 participants |
| Normal Liver Function | Number Participants With Abnormal Vital Signs | Low-DBP | 1 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | Low-DBP | 2 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | High PR | 0 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | Low-SBP | 0 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | Low Temp | 0 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | High-DBP | 0 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | Low PR | 0 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | High-SBP | 1 participants |
| Moderate Hepatic Impairment | Number Participants With Abnormal Vital Signs | High Temp | 0 participants |
Secondary
Plasma Clearance After Oral Administration (CL/F) of SQV and RTV
The CL/F is the oral clearance; that is clearance based on oral bioavailability. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the plasma clearance after oral administration (CL/F)of SQV and RTV The CL/F was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Plasma Clearance After Oral Administration (CL/F) of SQV and RTV | CL/F of SQV | 47.052 L/hr | Standard Deviation 20.254 |
| Normal Liver Function | Plasma Clearance After Oral Administration (CL/F) of SQV and RTV | CL/F of RTV | 9.289 L/hr | Standard Deviation 1.392 |
| Moderate Hepatic Impairment | Plasma Clearance After Oral Administration (CL/F) of SQV and RTV | CL/F of SQV | 84.416 L/hr | Standard Deviation 68.645 |
| Moderate Hepatic Impairment | Plasma Clearance After Oral Administration (CL/F) of SQV and RTV | CL/F of RTV | 12.568 L/hr | Standard Deviation 5.885 |
Secondary
Terminal Half-life (T1/2) of SQV and RTV
Terminal half-life is the time measured for the plasma concentration to decrease by one half. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the terminal half-life (T1/2) of SQV and RTV. The T1/2 was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Terminal Half-life (T1/2) of SQV and RTV | T1/2 of RTV | 3.80 hour | Standard Deviation 0.908 |
| Normal Liver Function | Terminal Half-life (T1/2) of SQV and RTV | T1/2 of SQV | 3.31 hour | Standard Deviation 0.823 |
| Moderate Hepatic Impairment | Terminal Half-life (T1/2) of SQV and RTV | T1/2 of RTV | 4.82 hour | Standard Deviation 2.82 |
| Moderate Hepatic Impairment | Terminal Half-life (T1/2) of SQV and RTV | T1/2 of SQV | 4.10 hour | Standard Deviation 1.9 |
Secondary
Time of Maximum Plasma Concentration (Tmax) of SQV and RTV
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. The Pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the time of maximum plasma concentration of SQV and RTV. The Tmax was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post-dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Time of Maximum Plasma Concentration (Tmax) of SQV and RTV | Tmax of SQV | 5.00 hour | Standard Deviation 1.83 |
| Normal Liver Function | Time of Maximum Plasma Concentration (Tmax) of SQV and RTV | Tmax of RTV | 4.29 hour | Standard Deviation 1.5 |
| Moderate Hepatic Impairment | Time of Maximum Plasma Concentration (Tmax) of SQV and RTV | Tmax of SQV | 5.00 hour | Standard Deviation 2.38 |
| Moderate Hepatic Impairment | Time of Maximum Plasma Concentration (Tmax) of SQV and RTV | Tmax of RTV | 4.07 hour | Standard Deviation 1.75 |
Secondary
Volume of Distribution (Vd) of SQV and RTV
Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. The pharmacokinetic profile for following 14 days of administration with SQV/RTV 1000/100 mg BID included determining the Vd of SQV and RTV The Vd was analyzed for SQV and RTV by non-compartmental methods, using WinNonlin.
Time frame: Pre-dose and at 0.5 hr, 1hr, 2hrs, 3hrs, 4hrs, 5hrs, 6hrs, 8hrs, 10hrs, and 12 hrs post dose on Day 14
Population: Pharmacokinetic (PK) analysis population: All participants who adhered to the study protocol and had evaluable concentration data and PK parameters on Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Liver Function | Volume of Distribution (Vd) of SQV and RTV | Vd of SQV | 213.294 Litres | Standard Deviation 95.048 |
| Normal Liver Function | Volume of Distribution (Vd) of SQV and RTV | Vd of RTV | 50.232 Litres | Standard Deviation 11.888 |
| Moderate Hepatic Impairment | Volume of Distribution (Vd) of SQV and RTV | Vd of SQV | 464.049 Litres | Standard Deviation 334.46 |
| Moderate Hepatic Impairment | Volume of Distribution (Vd) of SQV and RTV | Vd of RTV | 102.585 Litres | Standard Deviation 112.579 |