Pharmacokinetic And Pharmacodynamic Study Of A Single-Dose Of PF-04950615 (RN316) In Combination With Atorvastatin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01163851
First received: July 14, 2010
Last updated: April 20, 2015
Last verified: April 2015
  Purpose

The primary objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of a single dose of PF-04950615 (RN316) in volunteers on stable doses of atorvastatin. PF-04950615 (RN316) is an investigational drug that is currently being studies as a cholesterol lowering therapy.


Condition Intervention Phase
Hypercholesterolemia
Dyslipidemia
Biological: 4 mg/kg
Biological: 0.5 mg/kg
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study Evaluating The Pharmacokinetics And Pharmacodynamics Of Rn316 In Combination With Atorvastatin In Hypercholesterolemic Subjects

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hours (hrs) post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hrs post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
  • Maximum Observed Plasma Concentration (Cmax) of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hrs post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
  • Plasma Decay Half-Life (t1/2) of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hrs post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

  • Systemic Clearance (CL) of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hrs post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
    CL is a quantitative measure of the rate at which a drug substance is removed from the body.

  • Volume of Distribution at Steady State (Vss) of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hrs post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
    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 blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of PF-04950615 (RN316) [ Time Frame: 0 (pre-dose on Day 4), 1, 4, 8 and 12 hrs post intravenous PF-04950615 (RN316) dose, pre atorvastatin dose on Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 ] [ Designated as safety issue: No ]
    AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

  • Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 ] [ Designated as safety issue: No ]
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 ] [ Designated as safety issue: No ]
  • Maximum Observed Plasma Concentration (Cmax) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 ] [ Designated as safety issue: No ]
  • Plasma Decay Half-Life (t1/2) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 ] [ Designated as safety issue: No ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

  • Apparent Oral Clearance (CL/F) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 ] [ Designated as safety issue: No ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

  • Apparent Volume of Distribution (Vz/F) of Atorvastatin [ Time Frame: 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 12 hrs post-dose on Day 4, pre atorvastatin dose on Day 5, 6 and 7 ] [ Designated as safety issue: No ]
    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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.


Secondary Outcome Measures:
  • Change From Baseline in Fasting Low Density Lipoprotein-Cholesterol (LDL-C) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    LDL cholesterol is cholesterol in the bloodstream that is carried by low density lipoprotein. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting Total Cholesterol Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    Total cholesterol is the sum of all the cholesterol within the blood. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting Non-High-density Lipoprotein-Cholesterol (Non-HDL-C) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    Non-HDL-C calculated as total cholesterol minus HDL cholesterol. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting Triglycerides Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    Triglycerides are a type of fat circulating in the blood and account for the majority of the fats circulating in the blood. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting Apolipoprotein B (ApoB) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    ApoB is a major protein that makes up LDL cholesterol and is involved in transporting cholesterol and triglycerides to cells and tissues in the body. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    ApoA1 is a major protein that is a component of HDL cholesterol and helps in clearing cholesterol from the blood by removing cholesterol from organs and tissues to be destroyed by the liver. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Change From Baseline in Fasting High-Density Lipoprotein (HDL) Cholesterol Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    HDL cholesterol is cholesterol in the bloodstream that is carried by high density lipoprotein. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting Low Density Lipoprotein-Cholesterol (LDL-C) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    LDL cholesterol is cholesterol in the bloodstream that is carried by low density lipoprotein. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Total Cholesterol Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    Total cholesterol is the sum of all the cholesterol within the blood. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting Non-High-density Lipoprotein-cholesterol (Non-HDL-C) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    Non-HDL-C calculated as total cholesterol minus HDL cholesterol. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting Triglycerides Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    Triglycerides are a type of fat circulating in the blood and account for the majority of the fats circulating in the blood. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting Apolipoprotein B (ApoB) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    ApoB is a major protein that makes up LDL cholesterol and is involved in transporting cholesterol and triglycerides to cells and tissues in the body. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting High-Density Lipoprotein (HDL) Cholesterol Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    HDL cholesterol is cholesterol in the bloodstream that is carried by high density lipoprotein. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Percent Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64 [ Time Frame: Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: No ]
    ApoA1 is a major protein that is a component of HDL cholesterol and helps in clearing cholesterol from the blood by removing cholesterol from organs and tissues to be destroyed by the liver.. Fasting was required at least 10 hours before blood sample collection. Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

  • Durability of Additional Lipid Lowering Effects of PF-04950615 (RN316) in Combination With Atorvastatin on Days 4-64 [ Time Frame: Day 4 to Day 64 ] [ Designated as safety issue: No ]
    The median duration of the lipid-lowering effects (decrease in LDL-C levels by greater than or equal to 15 percent [%] compared to baseline) of PF-04950615 in combination with atorvastatin from Days 4 to 64 was reported.

  • Number of Participants With Toxicity or Intolerable Dose Criteria [ Time Frame: Baseline, Days 1, 2, 3, 4, 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64 ] [ Designated as safety issue: Yes ]
    Toxicity criteria included any of the following : serious adverse event (SAE), increased liver transaminases (alanine aminotransferase [ALT]/aspartate aminotransferase (AST) , increased bilirubin (in absence of ALT/AST elevations), pancreatitis, creatine kinase (CK) , hyper or hypoglycemia, decreased platelet count, increased serum creatinine, diarrhea, enteritis or nausea, prolongation of QTcF interval [Fridericia's Correction] and other considered appropriate by investigator.

  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Day 64 ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 64 days after last dose that were absent before treatment or that worsened relative to pretreatment state. TEAEs (all causalities), treatment related TEAEs and common terminology criteria for adverse events (CTCAE) severity grades for AEs were reported. Same participant may be reported in more than 1 CTCAE severity grade.

  • Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Identified by Physical Examination [ Time Frame: Baseline up to Day 64 ] [ Designated as safety issue: Yes ]
    Complete physical examination was conducted to assess skin, ears, throat, cardiac, respiratory, gastrointestinal, and musculoskeletal systems for systemic TEAEs.

  • Number of Participants With Anti-Drug-Antibodies (ADA) [ Time Frame: Baseline up to Day 64 ] [ Designated as safety issue: Yes ]
    Participants with positive antibody titer greater than 0 International Units/milliliter (IU/mL) was considered as antibody positive.

  • Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Identified by Vital Signs [ Time Frame: Baseline up to Day 64 ] [ Designated as safety issue: Yes ]
    Vital sign parameters body temperature, blood pressure and heart rate were assessed to identify systemic TEAEs. TEAEs (all causalities), treatment related TEAEs and CTCAE severity grades for AEs were reported. Same participant may be reported in more than 1 CTCAE severity grade.

  • Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Identified by Electrocardiogram (ECG) Parameters [ Time Frame: Baseline up to Day 64 ] [ Designated as safety issue: Yes ]
    ECG is used to measure the rate and regularity of heartbeats, as well as the size and position of the chambers, the presence of any damage to the heart, and the effects of drugs or devices used to regulate the heart. ECG parameters RR interval, PR interval, QRS complex, QT interval, [Bazett's Correction], QTcF interval [Fridericia's Correction] were assessed to identify systemic TEAEs. TEAEs (all causalities), treatment related TEAEs and CTCAE severity grades for AEs were reported.

  • Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Identified by Laboratory Parameters [ Time Frame: Baseline up to Day 64 ] [ Designated as safety issue: Yes ]
    Laboratory parameters alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, albumin, hemoglobin, protein, amylase, creatine kinase, lipase, basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets, white blood cells, bicarbonate, chloride, potassium, sodium, bilirubin, blood urea nitrogen, c-reactive protein , calcium, creatinine, direct bilirubin, glucose, magnesium, phosphate, uric acid, hematocrit, partial thromboplastin time , prothrombin time, red blood cells , urine pH, urine specific gravity were assessed to identify systemic TEAEs. TEAEs (all causalities), treatment related TEAEs and CTCAE severity grades for AEs were reported. Same participant may be reported in more than 1 CTCAE severity grade.


Enrollment: 25
Study Start Date: July 2010
Study Completion Date: April 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PF-04950615 (RN316) Biological: 4 mg/kg
RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.
Other Name: PF-04950615 (RN316)
Biological: 0.5 mg/kg
RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.
Other Name: PF-04950615 (RN316)

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • On stable doses of atorvastatin (40 mg daily) for 45 days prior to Day 1.
  • BMI 18.5 to 40 kg/m2 inclusive, and body weight equal or lower than 150 kg.

Exclusion Criteria:

  • History of a cardiovascular event (e.g., MI ) during the past year.
  • Poorly controlled Type 1 or Type 2 Diabetes mellitus (definition: uncontrolled diabetes is defined as HBIAc >9%).
  • Poorly controlled hypertension (uncontrolled hypertension is defined as a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg, even with treatment). Subjects who have hypertension and are controlled on stable dosages of anti-hypertensive medications can be included.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01163851

Locations
United States, Arizona
Premier Research Group, Limited
Peoria, Arizona, United States, 85381
Dedicated Phase 1, Inc.
Phoenix, Arizona, United States, 85013
Premier Research Group Limited
Phoenix, Arizona, United States, 85027
United States, Kansas
Vince and Associates Clinical Research
Overland Park, Kansas, United States, 66211
Vince and Associates Clinical Research
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01163851     History of Changes
Other Study ID Numbers: B1481003
Study First Received: July 14, 2010
Results First Received: April 20, 2015
Last Updated: April 20, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Hypercholesterolemia
Dyslipidemia
LDL
Cholesterol
High Cholesterol
PF-04950615
RN316

Additional relevant MeSH terms:
Dyslipidemias
Hypercholesterolemia
Hyperlipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Atorvastatin
Anticholesteremic Agents
Antimetabolites
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on June 29, 2015