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

Kokeellinen: PF-04950615 (RN316)

Biologinen: 4 mg/kg

RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.

Muut nimet:

• PF-04950615 (RN316)

Biologinen: 0.5 mg/kg

RN316 10 mg/ml vial sd. Infusion based on weight Infusion duration = 60 minutes.

Muut nimet:

• PF-04950615 (RN316)

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-04950615

Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04950615

Maximum Observed Plasma Concentration (Cmax) of PF-04950615

Plasma Decay Half-Life (t1/2) of PF-04950615

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

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

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.

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of PF-04950615

Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Atorvastatin

AUCtau was the AUC from time 0 to the end of the dosing interval, where the dosing interval was 12 hours.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Atorvastatin

Maximum Observed Plasma Concentration (Cmax) of Atorvastatin

Plasma Decay Half-Life (t1/2) of Atorvastatin

Plasma decay half-life is the time measured for the plasma concentration of atorvastatin to decrease by one half.

Apparent Oral Clearance (CL/F) of Atorvastatin

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.

Apparent Volume of Distribution (Vz/F) of Atorvastatin

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.

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 value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

Change From Baseline in Fasting Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

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 value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

Change From Baseline in Fasting Triglycerides at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

Change From Baseline in Fasting Apolipoprotein B (ApoB) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

Change From Baseline in Fasting Apolipoprotein A1 (ApoA1) at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

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 at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

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 value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

Percent Change From Baseline in Total Cholesterol at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

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 value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 administration.

Percent Change From Baseline in Fasting Triglycerides Values at Day 5, 6, 7, 15, 22, 29, 36, 43, 50, 57 and 64

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

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

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 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

Baseline value calculated as average of Day 2 and Day 4 measurements prior to PF-04950615 (RN316) administration.

Duration of Low Density Lipoprotein (LDL) Lowering Effects

In this outcome measure duration of the lipid-lowering effects was reported. Lipid lowering was defined as decrease in LDL-C levels by greater than or equal to 15 percent.

Number of Participants With Toxicity or Intolerable Dose Criteria

Toxicity criteria included any of the following: serious adverse event; increased liver transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]: increased to greater than [>] 5*upper limit of normal reference range [ULN]); increased bilirubin (in absence of ALT or AST elevations, common terminology criteria for adverse events [CTCAE] greater than or equal to [>=] Grade 2); pancreatitis, increased serum creatinine (CTCAE >= Grade 2); creatine kinase, hyperglycemia or hypoglycemia, diarrhea or enteritis or nausea (CTCAE >= Grade 3); decreased platelet count (less than [<] 100000 per microliter); prolongation of QT interval with Fridericia's Correction (QTcF) (QTcF >500 millisecond [msec] [CTCAE >= Grade 3] or increase from baseline of >=60 msec) and other considered appropriate by investigator. CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event.

Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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 that were absent before treatment or that worsened relative to pretreatment state. Adverse events included both serious and non-serious adverse events.

Number of Participants With Treatment-Emergent Adverse Events by Severity

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. AEs were assessed for severity by CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. Categories with at least 1 participant were reported

Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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 Participants With Systemic Treatment Emergent Adverse Events Identified by Physical Examination

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. Complete physical examination was conducted to assess skin, ears, throat, cardiac, respiratory, gastrointestinal, and musculoskeletal systems for systemic AEs.

Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Vital Signs

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. Vital sign parameters body temperature, blood pressure and heart rate were assessed to identify systemic adverse events. AEs (all causalities), treatment related AEs and CTCAE severity grades for AEs were reported. CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. Categories with at least 1 participant were reported

Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Electrocardiogram (ECG) Parameters

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 64 days that were absent before treatment or that worsened relative to pretreatment state. ECG parameters RR interval, PR interval, QRS complex, QT interval, [Bazett's Correction], QTcF interval [Fridericia's Correction] were assessed to identify systemic AEs. AEs (all causalities), treatment related AEs and CTCAE severity grades for AEs were reported. CTCAE Grade 4.0: Grade 1= mild; Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences and Grade 5= death related to adverse event. Categories with at least 1 participant were reported.

Number of Participants With Systemic Treatment Emergent Adverse Events Identified by Laboratory Parameters

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 AEs. AEs (all causalities), treatment related AEs and CTCAE severity grades for AEs were reported. Same participant may be reported in more than 1 CTCAE severity grade. Categories with at least 1 participant were reported.

Number of Participants With Positive Anti-drug Antibodies (ADA)

Human serum ADA samples of participants who received PF-04950615 (RN316) were analyzed for the presence of anti-PF-04950615 (RN316) antibodies. Results with titer value >=4.32 nanogram per milliliter of anti-PF-04950615 antibodies were counted as positive. Number of participants with presence of anti-PF-04950615 antibodies were reported in this outcome measure.