A Pharmacokinetic and Pharmacodynamic Study of PF-04950615 (RN316) in Subjects With Hypercholesterolemia

Study Overview
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Brief Summary
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This Phase 1 study has been designed to evaluate the absolute bioavailability of PF-04950615 (RN316) in subjects with hypercholesterolemia who are not currently on lipid-lowering therapy.

Official Title
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A Phase 1, Open-label, Randomized, Single Dose, Parallel Group Study To Assess The Pharmacokinetics And Pharmacodynamics Of Pf-04950615 Following Subcutaneous And Intravenous Doses In Adult Subjects With Hypercholesterolemia

Conditions
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Hypercholesterolemia, Dyslipidemias, Hyperlipidemias, Lipid Metabolism Disorders, Metabolic Diseases

Intervention / Treatment
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* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)
* Biological: PF-04950615 (RN316)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fasting LDL-C greater than or equal to 130 mg/dL at two qualifying screening visits. Total body weight greater than or equal to 50 kg (110 lbs) and less than or equal to 150 kg (330 lbs) Exclusion Criteria: Lipid-lowering prescription medications, homeopaths, herbal medicines, or nutritional supplements. Poorly controlled type 1 or type 2 diabetes. History of a cardiovascular or cerebrovascular event or related procedure during the past year. Poorly controlled hypertension.

Ages Eligible for Study
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Minimum Age: 18 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br> | Biological: PF-04950615 (RN316)<br>* Dose A - single-dose intravenous infusion<br>|
| Experimental: Group B<br> | Biological: PF-04950615 (RN316)<br>* Dose B - single-dose subcutaneous injection<br>|
| Experimental: Group C<br> | Biological: PF-04950615 (RN316)<br>* Dose C - single-dose subcutaneous injection<br>|
| Experimental: Group D<br> | Biological: PF-04950615 (RN316)<br>* Dose D - single-dose subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of PF-04950615 |  | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615 |  | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of PF-04950615 |  | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero To Infinity (AUCinf) of PF-04950615 |  | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Apparent Clearance (CL/F) of PF-04950615 Subcutaneous Groups | Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance (CL/F) is influenced by the fraction of the dose absorbed from plasma after SC administration of drug. | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Clearance (CL) of PF-04950615 Intravenous Group | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Apparent Volume of Distribution (Vz/F) of PF-04950615 Subcutaneous Groups | Volume of distribution (Vz) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction of the dose absorbed from plasma after SC administration of drug. | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Volume of Distribution at Steady State (Vss) of PF-04950615 Intravenous Group | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is determined when overall intake of drug is in dynamic equilibrium with its elimination. | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Terminal Elimination Half-life (t1/2) of PF-04950615 | t1/2 is the time measured for the plasma concentration of drug to decrease by one half. | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 
| Absolute Bioavailability of PF-04950615 Subcutaneous Groups | Bioavailability is defined as the rate and extent to which the active moiety administered drug reaches the systemic circulation. Absolute bioavailability of the subcutaneous doses was estimated by comparing log-transformed dose-normalized AUClast for subcutaneous to intravenous dose. | Pre-dose, 30 minutes, 1, 8, 24, 48, 72, 96, 120, 168, 336, 504, 672, 840, 1008, 1176, 1344, 1512, 1680, 2016 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Value of Fasting Low-density Lipoprotein Cholesterol (LDL-C) |  | Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85 | 
| Percent Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) at Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 85 | Baseline was the average of observations collected on Days 7 and 1 prior to the study treatment administration. | Baseline, Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85 | 
| Duration of Fasting LDL-C Suppressed Below 70 mg/dL and 100 mg/dL |  | Day 1 up to Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RN316, PF-04950615