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

• 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. ] [ Designated as safety issue: No ]
  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).
• AUCtau [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ] [ Designated as safety issue: No ]
  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).
• 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. ] [ Designated as safety issue: No ]
  Maximum observed plasma concentration (Cmax) within the dosing interval; measured in nanograms per milliliter (ng/mL).

• Calculate the hemodialysis clearance of MVC in subjects with end stage renal disease (ESRD) undergoing hemodialysis. [ Time Frame: 3 days ] [ Designated as safety issue: No ]
• Characterize the pharmacokinetics of MVC (300 mg) in healthy subjects, subjects with severe renal impairment and those receiving chronic hemodialysis. [ Time Frame: 3 days ] [ Designated as safety issue: No ]
• Characterize the pharmacokinetics of MVC (150 mg) in the presence of SQV/r (a potent CYP3A4 inhibitor) in both healthy subjects and subjects with mild and moderate renal impairment. [ Time Frame: 10 days ] [ Designated as safety issue: No ]

• Plasma Protein Binding [ Time Frame: 2 hours post-dose; normal Day -3 and Day 7; mild moderate: Day 7; severe and ESRD: Day 1 ] [ Designated as safety issue: No ]
  Percent protein binding (protein unbound maraviroc (MVC) fraction [percent free]) was determined by rapid equilibrium dialysis. Percent free = 100 - percent bound.
• 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 ] [ Designated as safety issue: No ]
  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).
• 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. ] [ Designated as safety issue: No ]
  Time (hours) of first occurrence (Tmax); time after dosing when Cmax (maximum plasma concentration) occured.
• Half-life (t1/2) [ Time Frame: Pre-dose, post-dose hours 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72. ] [ Designated as safety issue: No ]
  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.
• 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. ] [ Designated as safety issue: No ]
  Renal clearance (CLR) measured in milliliters per minute (mL/min).
• 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. ] [ Designated as safety issue: No ]
  Ae: amount of drug excreted unchanged in the urine; measured in milligrams (mg).
• Hemodialysis Clearance of Maraviroc (MVC) in Subjects With End Stage Renal Disease (ESRD) Undergoing Hemodialysis: CLdD [ Time Frame: Before dialysis ] [ Designated as safety issue: No ]
  CLdD: dialysate clearance before dialysis; measured in milliliters per minute.
• 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 ] [ Designated as safety issue: No ]
  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.
• 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 ] [ Designated as safety issue: No ]
  Number of subjects with pulse rate < 40 beats per minute (BPM), number of subjects with pulse rate > 120 BPM.
• 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 ] [ Designated as safety issue: No ]
  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.

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

• 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: Healthy Subjects
  Subjects with Normal Renal Function (Creatinine Clearance > 80mL/min) (I) Maraviroc single dose, followed by (II) Maraviroc + Saquinavir/Ritonavir
  Interventions:

  • Drug: Maraviroc
  • Drug: Maraviroc
  • Drug: Ritonavir
  • Drug: Saquinavir
• Experimental: Mild Renal Impairment
  Subjects with Mild Renal Impairment (Creatinine Clearance >50 and ≤80 mL/min)
  Interventions:

  • Drug: Maraviroc
  • Drug: Ritonavir
  • Drug: Saquinavir
• Experimental: Moderate Renal Impairment
  Subjects with Moderate Renal Impairment (Creatinine Clearance ≥30 and ≤50 mL/min)
  Interventions:

  • Drug: Maraviroc
  • Drug: Ritonavir
  • Drug: Saquinavir
• Experimental: Severe Renal Impairment
  Subjects with Severe Renal Impairment (Creatinine Clearance <30 mL/min)
  Intervention: Drug: Maraviroc
• 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
  Interventions:

  • Drug: Maraviroc
  • Drug: Maraviroc

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.