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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01435382

Enrollment

Registered

2011-09-16

Start date

2011-10-31

Completion date

2012-04-30

Last updated

2018-07-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Keywords

PF-04950615, RN316

Brief summary

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.

Interventions

BIOLOGICALPF-04950615 (RN316)

Dose A - single-dose intravenous infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Absolute Bioavailability of PF-04950615 Subcutaneous Groups	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	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.
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	—
Terminal Elimination Half-life (t1/2) 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	t1/2 is the time measured for the plasma concentration of drug to decrease by one half.
Volume of Distribution at Steady State (Vss) of PF-04950615 Intravenous Group	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 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.
Apparent Volume of Distribution (Vz/F) of PF-04950615 Subcutaneous Groups	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 (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.
Clearance (CL) of PF-04950615 Intravenous Group	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 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) of PF-04950615 Subcutaneous Groups	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 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.
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	—
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	—
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	—

Secondary

Measure	Time frame	Description
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, Day 2, 3, 4, 5, 6, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85	Baseline was the average of observations collected on Days 7 and 1 prior to the study treatment administration.
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	—
Duration of Fasting LDL-C Suppressed Below 70 mg/dL and 100 mg/dL	Day 1 up to Day 85	—

Other

Measure	Time frame	Description
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Day 1 up to Day 85	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. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state.
Percentage of Participants With Positive Anti-drug (Anti-PF 04950615) Antibodies	Day 1 up to Day 85	Human serum samples of participants who received PF-04950615 were analyzed for the presence of anti-PF-04950615 antibodies by using the semi quantitative enzyme-linked immunosorbent assay (ELISA).
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)	Day 1 up to Day 85	ECG abnormalities included 1) PR interval: maximum \>=300 maximum millisecond (msec), increase of \>=25 percent (%) for baseline value of \>200 msec and maximum increase of \>=50% for baseline value of less than or equal to (\<=) 200 msec; 2) QRS interval: maximum \>=200 msec, maximum increase of \>=25 % for baseline value of \>100 msec and maximum increase of \>=50% for baseline value of \<=100 msec; 3) QT interval corrected using the Fridericia's formula (QTCF): 450 msec to \<= 480 msec, 480 msec to \<=500 msec, \> 500 msec, maximum increase from baseline of \>30 to \<=60 msec and maximum increase from baseline of \>60 msec. Clinical significance of ECG were judged by investigator.
Number of Participants With Clinically Significant Changes in Vital Signs	Day 1 up to Day 85	Vital signs abnormalities included: maximum increase or decrease from baseline in supine systolic blood pressure (BP) greater than or equal to (\>=) 30 millimeter of mercury (mmHg); maximum increase or decrease from baseline in supine diastolic BP of \>=20 mmHg; supine pulse rate less than (\<) 40 beats per minute (bpm) and greater than (\>) 120 bpm; standing pulse rate less than (\<) 40 beats per minute (bpm) and greater than (\>) 140 bpm. Clinical significance of vital signs were judged by investigator.
Number of Participants With Clinically Significant Laboratory Abnormalities	Day 1 up to Day 85	Laboratory parameters evaluated for abnormalities were: hematology (hemoglobin \[Hgb\], hematocrit, red blood cell \[RBC\] count, platelets, white blood cell count \[WBC\], lymphocytes, total neutrophils, basophils, eosinophils, monocytes); coagulation (partial thromboplastin time, prothrombin time \[PT\], PT international ratio); clinical chemistry (glucose, creatine kinase, amylase, lipase); liver function (total, direct and indirect bilirubin, aspartate aminotransferase \[AT\], alanine AT, gamma-glutamyl transferase, alkaline phosphatase, total protein, albumin, lactate dehydrogenase); renal function (blood urea nitrogen, creatinine, uric acid); urinalysis (urine- specific gravity, pH, glucose, ketones, blood/Hgb, nitrite, leukocyte, esterase, RBC, WBC, epithelial cells, hyaline cast and bacteria); lipid (cholesterol); electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate, bicarbonate). Clinical significance of laboratory abnormalities were judged by investigator.
Visual Analogue Scale (VAS)	Day 1: Immediately post-dose, 0.5, 1.0, 2.0, 8.0 hours post-dose; Day 2, 3	Participants indicated the amount of pain experienced due to study drug injection, on a VAS of 0 (no pain) to 100 (very severe pain), where higher scores indicate higher intensity of pain.
Number of Injection Site Reactions Reported as Adverse Events	Day 1 up to Day 3	The injection site reactions included erythema, induration, ecchymosis, injection site pain and injection site pruritus. An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Number of Participants With Injection Site Reactions	Day 1 up to Day 3	The injection site reaction included erythema, induration, ecchymosis, injection site pain, injection site pruritus.
Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	Day 1 up to Day 85	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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.
Number of Adverse Events (AEs) by Severity	Day 1 up to Day 85	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was assessed according to severity; mild (not causing any significant problem, dose adjustment not required), moderate (caused problem that does not interfere significantly with usual activities or the clinical status, dose adjustment needed due to adverse event) and severe (caused problem that interferes significantly with usual activities or the clinical status, study drug stopped due to adverse event).

Countries

United States

Participant flow

Participants by arm

Arm	Count
PF-04950615 IV 200 mg Participants received single intravenous (IV) infusion dose of PF-04950615 200 milligram (mg) on Day 1. Participants were followed up to Day 85.	12
PF-04950615 SC 200 mg (2 Injections of 1 mL) Participants received subcutaneous (SC) dose of PF-04950615 200 mg on Day 1; 2 injections (100 milligram per milliliter \[mg/mL\]) of 1 milliliter (mL) each at two different quadrants of the abdomen; 1 injection per quadrant. Participants were followed up to Day 85.	13
PF-04950615 SC 200 mg (1 Injection of 2 mL) Participants received single SC dose of PF-04950615 200 mg on Day 1; 1 injection (100 mg/mL) of 2 mL. Participants were followed up to Day 85.	13
PF-04950615 SC 100 mg (1 Injection of 1 mL) Participants received single SC dose of PF-04950615 100 mg on Day 1; 1 injection (100 mg/mL) of 1 mL. Participants were followed up to Day 85.	11
Total	49

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Lost to Follow-up	1	0	1	0
Overall Study	Withdrawal by Subject	0	2	0	1

Baseline characteristics

Characteristic	PF-04950615 IV 200 mg	PF-04950615 SC 200 mg (2 Injections of 1 mL)	PF-04950615 SC 200 mg (1 Injection of 2 mL)	PF-04950615 SC 100 mg (1 Injection of 1 mL)	Total
Age, Continuous	50.8 years STANDARD_DEVIATION 9.9	55.6 years STANDARD_DEVIATION 9.8	52.1 years STANDARD_DEVIATION 6.9	53.2 years STANDARD_DEVIATION 12.3	52.9 years STANDARD_DEVIATION 9.7
Sex: Female, Male Female	4 Participants	4 Participants	7 Participants	6 Participants	21 Participants
Sex: Female, Male Male	8 Participants	9 Participants	6 Participants	5 Participants	28 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	7 / 12	7 / 13	8 / 13	6 / 11
serious Total, serious adverse events	0 / 12	0 / 13	0 / 13	0 / 11

Outcome results

Primary

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.