Clinical Trial In Healthy Volunteers And Health Elderly Volunteers To Evaluate The Safety, Tolerability And Blood Concentration After Single And Multiple Escalating Oral Doses Of PF-06751979.

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 were events between first dose of study drug and up to the follow up visit (up to 36 days in Part A, 49 days in Part B and C), that were absent before treatment or that worsened relative to pretreatment state.

Full physical examination included head, ears, eyes, nose, mouth, skin, heart, lung, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Abnormality in physical examinations was based on investigator's discretion.

The neurological examination included the assessment of higher cortical function, the cranial nerves, motor function, deep tendon reflexes, sensory exam, and coordination and gait. Abnormality in neurological examinations was based on investigator's discretion.

C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at baseline were reported.

C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at Day 7 were reported.

C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at Day 14 were reported.

C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of "Yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("Yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome measure, number of participants with positive response (response of "yes") to suicidal behavior, ideation or any non-suicidal self-injurious behavior, at Day 19 were reported.

Criteria for abnormal values of ECG parameters: maximum pulse rate (PR) interval greater than or equal to (>=)300 milliseconds (msec); maximum PR interval increase from baseline (IFB): >=25 percent (%) when baseline was greater than (>)200 msec; or >=50 % when baseline was greater than (>)200 msec, maximum QRS interval >=140 msec and QRS interval IFB: >=50%. QT interval using Fridericia's correction (QTcF) ranges from 450 msec to maximum less than (<)480 msec, less than or equal to (<=) 480 msec to maximum <500 msec and maximum >=500 msec, maximum QTcF interval IFB range from <=30 to <60 msec and maximum >=60 msec. Only categories which included at least 1 participant with abnormality are reported in this outcome measure.

In all Periods of Part A, continuous cardiac monitoring was maintained for 8 hours (or longer if considered clinically necessary by the investigator) following dose administration on Day 1. All abnormal cardiac rhythms were recorded and reviewed by the study physician for the presence of rhythms of potential clinical concern.

Criteria for vital signs abnormalities: systolic blood pressure (SBP) <90 millimeter of mercury (mmHg), diastolic blood pressure (DBP) <50 mmHg, supine pulse rate <40 beats per minute (bpm). Maximum IFB in Supine SBP >=30 mmHg, Maximum decrease from baseline (DFB) in Supine SBP >=30 mmHg, maximum DFB in Supine DBP >=20 mmHg.

Abnormalities criteria:hematology(hemoglobin; hematocrit; RBC<0.8*lower limit of normal [LLN]; platelets<0.5*LLN,>1.75*upper limit of normal [ULN]; WBC<0.6*LLN,>1.5*ULN; lymphocytes; neutrophils; basophils; eosinophils; monocytes<0.8*LLN,>1.2*ULN; coagulation(prothrombin ratio>1.1*ULN), liver(bilirubin>1.5*ULN; aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase; gamma GT>0.3*ULN; protein; albumin<0.8*LLN,>1.2*ULN); renal(blood urea nitrogen, creatinine>1.3*ULN; uric acid>1.2*ULN); electrolytes(sodium<0.95*LLN,>1.05*ULN; potassium; chloride; calcium; bicarbonate<0.9*LLN,>1.1*ULN), chemistry(glucose<0.6*LLN,>1.5* ULN); urinalysis(pH <4.5,>8; glucose, ketones, protein, blood, urobilinogen, nitrite, bilirubin, leukocyte, esterase>1; WBC; bacteria>=20, epithelial cells>=6; granular casts, hyaline casts, red cell casts, white cell casts>1; lipids(cholesterol[C], LDL-C>1.3*ULN; HDL-C<0.8*LLN, triglycerides>1.3*ULN); hormones(T4, T3, T4, TSH<0.8*LLN,>1.2*ULN).

Area under the plasma concentration-time profile from time zero to the time of last measured concentration (AUClast).

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).

Cmax(dn) was obtained calculated by dividing Cmax by the exact dose of PF-06751979 (in milligram) administered to a participant.

AUClast(dn) was calculated by dividing AUClast by the exact dose of PF-06751979 (in mg) administered to a participant. AUClast was area under the plasma concentration-time profile from time zero to the time of last measured concentration.

AUCinf (dn) was calculated by dividing AUCinf by the exact dose of PF-06751979 (in mg) administered to a participant. AUCinf was area under the plasma concentration-time profile from time zero extrapolated to infinite time (0-inf).

Plasma decay half-life is the time duration for the plasma concentration of PF-06751979 to decrease by one-half of its original concentration.

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 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 volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours.

Cmax(dn) was obtained calculated by dividing Cmax by the exact dose of PF-06751979 (in mg) administered to a participant.

Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours. AUCtau (dn) was calculated by dividing AUCtau by the exact dose of PF-06751979 (in mg) administered to a participant.

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

Peak-to-trough ratio was calculated by dividing Cmax with Cmin of PF-06751979. Cmax was maximum plasma concentration during the dosing interval and Cmin was minimum observed plasma concentration during the dosing interval.

Rac for AUCtau for Day 7 was calculated as: AUCtau on Day 7 divided by AUCtau on Day 1. Rac for AUCtau for Day 14 was calculated as: AUCtau on Day 14 divided by AUCtau on Day 1.

Rac for Cmax on Day 7 was calculated as: Cmax on Day 7 divided by Cmax on Day 1 and Rac for Cmax on Day 14 was calculated as: Cmax on Day 14 divided by Cmax on Day 1, where Cmax was the maximum observed plasma concentration.

Plasma decay half-life is the time duration for the plasma concentration of PF-06751979 to decrease by one-half of its original concentration.

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 volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours.

Cmax(dn) was obtained calculated by dividing Cmax by the exact dose of PF-06751979 (in mg) administered to a participant.

Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours. AUCtau (dn) was calculated by dividing AUCtau by the exact dose of PF-06751979 (in mg) administered to a participant.

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

Minimum observed concentration during the dosing interval.

Peak-to-trough ratio was calculated by dividing Cmax with Cmin of PF-06751979. Cmax was maximum plasma concentration during the dosing interval and Cmin was minimum observed plasma concentration during the dosing interval.

Rac for AUCtau at Day 14 was calculated as: AUCtau on Day 14 divided by AUCtau on Day 1.

Rac for Cmax on Day 14 was calculated as: Cmax on Day 14 divided by Cmax on Day 1, where Cmax was the maximum observed plasma concentration.

Plasma decay half-life was the time duration for the plasma concentration to decrease by one-half of its original concentration.

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 volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Aetau was the amount of drug excreted unchanged in urine during the dosing interval tau, where tau was 24 hours.

Aetau% was calculated as: 100*Aetau/dose. Aetau was the amount of drug excreted unchanged in urine during the dosing interval tau, where tau was 24 hours.

Renal clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated in urine. It was calculated as amount of drug excreted unchanged in urine during the dosing interval tau (Aetau) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours.

ABeta is the peptide fragment of the amyloid precursor protein. Percent change from baseline in CSF concentration of ABeta fragments (ABeta 1-38, ABeta 1-40, ABeta 1-42, ABeta total, ABeta x-38, ABeta x-40, ABeta x-42, soluble amyloid precursor protein alpha (sAPP-alpha), soluble amyloid precursor protein beta (sAPP-beta) at Day 14 was reported in this outcome measure.