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

An Open-Label, Parallel Group, Single And Multiple Dose Study To Evaluate The Pharmacokinetics, Safety And Toleration Of Maraviroc Administered To Subjects With Various Degrees Of Renal Impaired And Normal Renal Function

The purpose of this study is to assess whether a dosing adjustment is needed in patients with renal impairment.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus (HIV) Infection
• Intervention / Treatment: Drug: Maraviroc; Drug: Maraviroc; Drug: Ritonavir; Drug: Saquinavir; Drug: Maraviroc; Drug: Maraviroc; Drug: Maraviroc; Drug: Maraviroc

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Pfizer Investigational Site
  • Muenchen, Germany, 81241
    • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Stable Renal Function defined as ≤20% (25% for normal renal function) difference between 2 measurements of serum creatinine obtained on 2 occasions separated by at least 2 weeks.
• Body Mass Index (BMI) of approximately 18 to 40 kg/m2 inclusive.
• Total body weight >50 kg (110 lbs).
• Male or female subjects between the ages of 18 and 85 years.

Exclusion Criteria:

• Subjects with acute renal disease and/or history of renal transplant.
• Supine BP at Screening ≥160 mm Hg systolic or ≥95 mm Hg diastolic.
• Supine BP at Screening ≤80 mm Hg systolic or ≤40 mm Hg diastolic.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Subjects; Subjects with Normal Renal Function (Creatinine Clearance > 80mL/min) (I) Maraviroc single dose, followed by (II) Maraviroc + Saquinavir/Ritonavir	Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose; Drug: Maraviroc; Maraviroc 150 mg tablet twice daily x 7 days; Drug: Ritonavir; Ritonavir 100 mg capsule twice daily x 7 days; Drug: Saquinavir; Saquinavir 1000 mg (500 mg x 2 tablets) twice daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once every 48 hours x 7 days; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose one hour following completion of hemodialysis; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose three hours prior to start of hemodialysis
Experimental: Mild Renal Impairment; Subjects with Mild Renal Impairment (Creatinine Clearance >50 and ≤80 mL/min)	Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose; Drug: Maraviroc; Maraviroc 150 mg tablet twice daily x 7 days; Drug: Ritonavir; Ritonavir 100 mg capsule twice daily x 7 days; Drug: Saquinavir; Saquinavir 1000 mg (500 mg x 2 tablets) twice daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once every 48 hours x 7 days; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose one hour following completion of hemodialysis; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose three hours prior to start of hemodialysis
Experimental: Moderate Renal Impairment; Subjects with Moderate Renal Impairment (Creatinine Clearance ≥30 and ≤50 mL/min)	Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose; Drug: Maraviroc; Maraviroc 150 mg tablet twice daily x 7 days; Drug: Ritonavir; Ritonavir 100 mg capsule twice daily x 7 days; Drug: Saquinavir; Saquinavir 1000 mg (500 mg x 2 tablets) twice daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once every 48 hours x 7 days; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose one hour following completion of hemodialysis; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose three hours prior to start of hemodialysis
Experimental: Severe Renal Impairment; Subjects with Severe Renal Impairment (Creatinine Clearance <30 mL/min)	Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose; Drug: Maraviroc; Maraviroc 150 mg tablet twice daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once every 48 hours x 7 days; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose one hour following completion of hemodialysis; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose three hours prior to start of hemodialysis
Experimental: ESRD on Hemodialysis; Subjects with End Stage Renal Impairment receiving Hemodialysis(Creatinine Clearance <30 mL/min) (I) Maraviroc single dose one hour following completion of hemodialysis, followed by (II) Maraviroc single dose three hours prior to start of hemodialysis	Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose; Drug: Maraviroc; Maraviroc 150 mg tablet twice daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once daily x 7 days; Drug: Maraviroc; Maraviroc 150 mg tablet once every 48 hours x 7 days; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose one hour following completion of hemodialysis; Drug: Maraviroc; Maraviroc 300 mg (150 mg x 2 tablets) x single dose three hours prior to start of hemodialysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Time-curve From Zero to the Last Measured Concentration (AUClast)	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) measured in nanograms * hour divided by milliliters (ng*hr/mL).	Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72.
AUCtau	AUCtau: area under the plasma concentration-time profile from time zero to the end of the dosing interval (tau); measured in nanograms * hours divided by milliliters (ng.hr/mL).	Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72.
Maximum Observed Plasma Concentration (Cmax)	Maximum observed plasma concentration (Cmax) within the dosing interval; measured in nanograms per milliliter (ng/mL).	Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Protein Binding	Percent protein binding (protein unbound maraviroc (MVC) fraction [percent free]) was determined by rapid equilibrium dialysis. Percent free = 100 - percent bound.	2 hours post-dose; normal Day -3 and Day 7; mild moderate: Day 7; severe and ESRD: Day 1
Area Under the Time Curve From 0 to Infinity (AUCinf)	Area under the plasma concentration-time profile from time zero to the time infinate in subjects who received single dose treatment; measured in nanograms * hour divided by millilters (ng*hr/mL).	Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72
Time of First Occurrence (Tmax)	Time (hours) of first occurrence (Tmax); time after dosing when Cmax (maximum plasma concentration) occured.	Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72.
Half-life (t1/2)	Elimination half-life (t1/2) measured in hours: time required for half the quantity of maraviroc to be metabolized or eliminated by normal biological processes.	Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72.
Renal Clearance (CLR) in Subjects With Normal, Mild, Moderate and Severe Renal Function	Renal clearance (CLR) measured in milliliters per minute (mL/min).	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.
Derivation of Renal Clearance in Subjects With Normal, Mild, Moderate and Severe Renal Function: Ae	Ae: amount of drug excreted unchanged in the urine; measured in milligrams (mg).	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.
Hemodialysis Clearance of Maraviroc (MVC) in Subjects With End Stage Renal Disease (ESRD) Undergoing Hemodialysis: CLdD	CLdD: dialysate clearance before dialysis; measured in milliliters per minute.	Before dialysis
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	Number of subjects with absolute values of supine systolic blood pressure (BP) measured in millimeters of mercury (mm/Hg), range: <90 mmHg; and supine diastolic blood pressure, range: <50 mmHg. Number of subjects with a maximum increase and decrease from Baseline in supine systolic BP ≥ 30 mmHg. Number of subjects with a maximum increase and decrease from Baseline in supine diastolic BP ≥ 20 mmHg.	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
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	Number of subjects with pulse rate < 40 beats per minute (BPM), number of subjects with pulse rate > 120 BPM.	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
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	Single 12-lead ECG: number of subjects with maximum QTC interval, maximum QTCB interval (Bazett's correction), and maximum QTCF interval (Friderica's correction) measured in milliseconds (msec); range: 450 to <480 msec, 480 to <500 msec, and >500 msec. Maximum QTC interval increase from Baseline; citeria: change = ≥ 30 msec to < 60 msec, and change = ≥ 60 msec.	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

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): November 1, 2008
• Study Completion (Actual): November 1, 2008

Study Registration Dates

• First Submitted: July 15, 2008
• First Submitted That Met QC Criteria: July 15, 2008
• First Posted (Estimate): July 16, 2008

Study Record Updates

• Last Update Posted (Estimate): November 19, 2010
• Last Update Submitted That Met QC Criteria: November 10, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Keywords: maraviroc, pharmacokinetics, renal impairment
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Ritonavir; Maraviroc; Saquinavir
• Other Study ID Numbers: A4001075