A Phase 1 Study Evaluating The Pharmacokinetics And Pharmacodynamics Of Rn316 In Combination With Atorvastatin In Hypercholesterolemic Subjects
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Hypercholesterolemia
- Sponsor
- Pfizer
- Enrollment
- 25
- Locations
- 4
- Primary Endpoint
- Plasma Decay Half-Life (t1/2) of PF-04950615
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •On stable doses of atorvastatin (40 mg daily) for 45 days prior to Day
- •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.
Outcomes
Primary Outcomes
Plasma Decay Half-Life (t1/2) of PF-04950615
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
Plasma decay half-life is the time measured for the plasma concentration of PF-04950615 to decrease by one half.
Systemic Clearance (CL) of PF-04950615
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
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
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
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.
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
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.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615
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
Maximum Observed Plasma Concentration (Cmax) of PF-04950615
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
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of PF-04950615
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
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
AUCtau was the AUC from time 0 to the end of the dosing interval, where the dosing interval was 12 hours.
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
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-04950615
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
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
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
Plasma decay half-life is the time measured for the plasma concentration of atorvastatin to decrease by one half.
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
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 Outcomes
- Change From Baseline in Fasting Low Density Lipoprotein-Cholesterol (LDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Change From Baseline in Fasting Non High-density Lipoprotein-Cholesterol (Non-HDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Percent Change From Baseline in Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Percent Change From Baseline in Fasting Non-High-density Lipoprotein-cholesterol (Non-HDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Change From Baseline in Fasting Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Change From Baseline in Fasting Triglycerides at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Change From Baseline in Fasting Apolipoprotein B (ApoB) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Percent Change From Baseline in Fasting Low Density Lipoprotein-Cholesterol (LDL-C) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Percent Change From Baseline in Fasting Triglycerides Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Number of Participants With Toxicity or Intolerable Dose Criteria(Day 1 up to Day 64)
- Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Physical Examination(Day 1 up to Day 64)
- Change From Baseline in Fasting High-Density Lipoprotein (HDL) Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Duration of Low Density Lipoprotein (LDL) Lowering Effects(Day 4 to Day 64)
- Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Laboratory Parameters(Day 1 up to Day 64)
- 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(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Percent Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)(Day 1 up to Day 64)
- Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Electrocardiogram (ECG) Parameters(Day 1 up to Day 64)
- Number of Participants With Positive Anti-drug Antibodies (ADA)(Day 1 up to Day 64)
- Percent Change From Baseline in Fasting Apolipoprotein B (ApoB) Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64(Baseline, Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57, 64)
- Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Vital Signs(Day 1 up to Day 64)
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(Day 1 up to Day 64)
- Number of Participants With Treatment-Emergent Adverse Events by Severity(Day 1 up to Day 64)