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

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

Official Title
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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

Conditions
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Human Immunodeficiency Virus (HIV) Infection

Intervention / Treatment
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* Drug: Maraviroc
* Drug: Maraviroc
* Drug: Ritonavir
* Drug: Saquinavir
* Drug: Maraviroc
* Drug: Ritonavir
* Drug: Saquinavir
* Drug: Maraviroc
* Drug: Ritonavir
* Drug: Saquinavir
* Drug: Maraviroc
* Drug: Maraviroc
* Drug: Maraviroc


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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maraviroc, pharmacokinetics, renal impairment