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

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.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

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.

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.

t1/2 is the time measured for the plasma concentration of drug to decrease by one half.

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.

Baseline was the average of observations collected on Days 7 and 1 prior to the study treatment administration.

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.

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).

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.

The injection site reaction included erythema, induration, ecchymosis, injection site pain, injection site pruritus.

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.

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.

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.

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.

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.

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).