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Pharmacokinetics, Safety And Toleration Of Maraviroc Administered To Subjects With Various Degrees Of Renal Impaired And Normal Renal Function

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by:
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT00717067
First received: July 15, 2008
Last updated: November 10, 2010
Last verified: November 2010
Results First Received: November 16, 2009  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Human Immunodeficiency Virus (HIV) Infection
Interventions: Drug: Maraviroc
Drug: Ritonavir
Drug: Saquinavir

  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
Two centers took part in this study between 15 July 2008 and 21 November 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were enrolled into treatment groups (healthy subjects, mild, moderate, severe renal impairment, or end stage renal impairment on hemodialysis) based on creatinine clearance results obtained closest to the dosing date at screening as determined by the Cockcroft-Gault equation (with the exception of subjects undergoing hemodialysis).

Reporting Groups
  Description
Healthy Subjects (I) Maraviroc single 300 mg dose, followed 4 days later by (II) Maraviroc 150 mg twice a day (BID) co-administered with saquinavir 1,000 mg/ritonavir 100 mg twice a day (BID) for 6 days, and a single dose of both agents on Day 7.
Mild Renal Impairment Maraviroc 150 mg once a day (QD) co-administered with saquinavir 1,000 mg/ritonavir 100 mg twice a day (BID) for 7 days.
Moderate Renal Impairment Maraviroc 150 mg every 48 hours co-administered with saquinavir 1,000 mg/ritonavir 100 mg twice a day (BID) for 7 days.
Severe Renal Impairment Maraviroc 300 mg single dose.
ESRD: Single Dose (I) Maraviroc single dose one hour following completion of morning hemodialysis, followed at least 1 week later by (II) Maraviroc single dose three hours prior to start of hemodialysis.

Participant Flow for 3 periods

Period 1:   Part 1a: Normal/Mild/Moderate Group
    Healthy Subjects     Mild Renal Impairment     Moderate Renal Impairment     Severe Renal Impairment     ESRD: Single Dose  
STARTED     6     6     6     0     0  
COMPLETED     6     6     5     0     0  
NOT COMPLETED     0     0     1     0     0  
Adverse Event                 0                 0                 1                 0                 0  

Period 2:   Part 1b: Severe Renal Impairment
    Healthy Subjects     Mild Renal Impairment     Moderate Renal Impairment     Severe Renal Impairment     ESRD: Single Dose  
STARTED     0     0     0     6     0  
COMPLETED     0     0     0     6     0  
NOT COMPLETED     0     0     0     0     0  

Period 3:   Part 2: End Stage Renal Disease
    Healthy Subjects     Mild Renal Impairment     Moderate Renal Impairment     Severe Renal Impairment     ESRD: Single Dose  
STARTED     0     0     0     0     6  
COMPLETED     0     0     0     0     6  
NOT COMPLETED     0     0     0     0     0  



  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
Healthy Subjects Subjects with Normal Renal Function (Creatinine Clearance > 80mL/min)
Mild Renal Impairment Subjects with Mild Renal Impairment (Creatinine Clearance >50 and ≤80 mL/min)
Moderate Renal Impairment Subjects with Moderate Renal Impairment (Creatinine Clearance ≥30 and ≤50 mL/min)
Severe Renal Impairment Subjects with Severe Renal Impairment (Creatinine Clearance <30 mL/min)
ESRD on Hemodialysis Subjects with End Stage Renal Disease Requiring Regular Hemodialysis 3 Times a Week for at Least 6 Weeks Prior to Screening (Creatinine Clearance <30 mL/min)
Total Total of all reporting groups

Baseline Measures
    Healthy Subjects     Mild Renal Impairment     Moderate Renal Impairment     Severe Renal Impairment     ESRD on Hemodialysis     Total  
Number of Participants  
[units: participants]
  6     6     6     6     6     30  
Age, Customized  
[units: years]
           
18 - 44 years     0     0     1     1     1     3  
45 - 64 years     5     4     0     2     4     15  
>= 65 years     1     2     5     3     1     12  
Gender  
[units: participants]
           
Female     2     2     2     2     0     8  
Male     4     4     4     4     6     22  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Area Under the Plasma Concentration Time-curve From Zero to the Last Measured Concentration (AUClast)   [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

2.  Primary:   AUCtau   [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

3.  Primary:   Maximum Observed Plasma Concentration (Cmax)   [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

4.  Secondary:   Plasma Protein Binding   [ Time Frame: 2 hours post-dose; normal Day -3 and Day 7; mild moderate: Day 7; severe and ESRD: Day 1 ]

5.  Secondary:   Area Under the Time Curve From 0 to Infinity (AUCinf)   [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 ]

6.  Secondary:   Time of First Occurrence (Tmax)   [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

7.  Secondary:   Half-life (t1/2)   [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

8.  Secondary:   Renal Clearance (CLR) in Subjects With Normal, Mild, Moderate and Severe Renal Function   [ Time Frame: Hour 0 (prior to MVC dosing [single dose] or prior to last MVC dose [multiple dose]) to 72 hours post-dose ; hours 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

9.  Secondary:   Derivation of Renal Clearance in Subjects With Normal, Mild, Moderate and Severe Renal Function: Ae   [ Time Frame: Hour 0 (prior to MVC dosing [single dose] or prior to last MVC dose [multiple dose]) to 72 hours post-dose ; hours 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ]

10.  Secondary:   Hemodialysis Clearance of Maraviroc (MVC) in Subjects With End Stage Renal Disease (ESRD) Undergoing Hemodialysis: CLdD   [ Time Frame: Before dialysis ]

11.  Secondary:   Safety and Tolerability of Maraviroc in the Absence and Presence of a Potent CYP3A4 Inhibitor in Subjects With Various Degrees of Renal Impairment or Undergoing Hemodialysis: Number of Subjects With Maximum Increase and Decrease in Supine Blood Pressure   [ Time Frame: Normal renal function: screening, Day -3 to Day -1; normal, mild and moderate RI: Day 7 to Day 10 and follow-up; severe RI: Day 1 to Day 4 and follow-up; ESRD: Day 1, Day 4, and follow-up ]

12.  Secondary:   Safety and Tolerability of Maraviroc in the Absence and Presence of a Potent CYP3A4 Inhibitor in Subjects With Various Degrees of Renal Impairment or Undergoing Hemodialysis: Number of Subjects With Pulse Rate < 40 and > 120 Beats Per Minute   [ Time Frame: Normal renal function: screening, Day -3 to Day -1; normal, mild and moderate RI: Day 7 to Day 10 and follow-up; severe RI: Day 1 to Day 4 and follow-up; ESRD: Day 1, Day 4, and follow-up ]

13.  Secondary:   Safety and Tolerability of Maraviroc in the Absence and Presence of a Potent CYP3A4 Inhibitor in Subjects With Various Degrees of Renal Impairment or Undergoing Hemodialysis: Number of Subjects With Maximum EGC QTC, QTCB and QTCF Intervals   [ Time Frame: Normal renal function: screening, Day -3 and Day -1; normal renal function, mild and moderate RI: Day 7 to Day 9 and follow-up; severe RI: screening, Day 1, Day 3, Day 4, and follow-up; ESRD: screening, Day 1, Day 3, Day 4, and follow-up ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame No text entered.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   0%  

Reporting Groups
  Description
Healthy Subjects Maraviroc 150 mg twice a day (BID) co-administered with saquinavir 1,000 mg/ritonavir 100 mg twice a day (BID) for 7 days.
Mild Renal Impairment Maraviroc 150 mg once a day (QD) co-administered with saquinavir 1,000 mg/ritonavir 100 mg twice a day (BID) for 7 days.
Moderate Renal Impairment Maraviroc 150 milligrams (mg) every 48 hours co-administered with saquinavir 1,000 mg/ritonavir 100 mg twice a day (BID) for 7 days.
Healthy Subjects: Single Dose Maraviroc 300 mg single dose.
Severe Renal Impairment: Maraviroc 300 mg single dose.
ESRD: Dosing After Dialysis Maraviroc 300 mg single dose one hour following completion of morning hemodialysis.
ESRD: Dosing Before Dialysis Maraviroc 300 mg single dose three hours prior to start of hemodialysis.

Other Adverse Events
    Healthy Subjects     Mild Renal Impairment     Moderate Renal Impairment     Healthy Subjects: Single Dose     Severe Renal Impairment:     ESRD: Dosing After Dialysis     ESRD: Dosing Before Dialysis  
Total, other (not including serious) adverse events                
# participants affected / at risk     2/6     6/6     6/6     1/6     3/6     2/6     1/6  
Eye disorders                
conjunctival hyperaemia † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
# events     0                          
visual impairment † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Gastrointestinal disorders                
abdominal distension † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
abdominal pain upper † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
constipation † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
diarrhea † 1              
# participants affected / at risk     1/6 (16.67%)     1/6 (16.67%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
dry mouth † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)  
dyspepsia † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
flatulence † 1              
# participants affected / at risk     2/6 (33.33%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
nausea † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     1/6 (16.67%)  
vomiting † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)  
General disorders                
fatigue † 1              
# participants affected / at risk     0/6 (0.00%)     2/6 (33.33%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
pain † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
sensation of foreign body † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Infections and infestations                
rhinitis † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Injury, poisoning and procedural complications                
wound † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)  
Investigations                
blood bilirubin increased † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
blood creatinine increased † 1              
# participants affected / at risk     0/6 (0.00%)     4/6 (66.67%)     4/6 (66.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
blood urea increased † 1              
# participants affected / at risk     0/6 (0.00%)     3/6 (50.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
renal function test abnormal † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Metabolism and nutrition disorders                
dehydration † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
hyperuricaemia † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
hypokalaemia † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Musculoskeletal and connective tissue disorders                
muscle spasms † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Nervous system disorders                
dizziness † 1              
# participants affected / at risk     1/6 (16.67%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
headache † 1              
# participants affected / at risk     2/6 (33.33%)     3/6 (50.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
paraesthesia † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Renal and urinary disorders                
nocturia † 1              
# participants affected / at risk     0/6 (0.00%)     3/6 (50.00%)     3/6 (50.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
renal pain † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)  
Respiratory, thoracic and mediastinal disorders                
cough † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
throat irritation † 1              
# participants affected / at risk     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
Skin and subcutaneous tissue disorders                
hyperhidrosis † 1              
# participants affected / at risk     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)  
pruritus † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)  
Vascular disorders                
orthostatic hypotension † 1              
# participants affected / at risk     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     0/6 (0.00%)     1/6 (16.67%)     0/6 (0.00%)     0/6 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 11.1



  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
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