Multiple Dose Study Of BIIB118 (PF-05251749) In Healthy Volunteers

The Bond and Lader Visual Analogue Scales (VAS) monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three affective dimensions/subscales a) alertness (average of 9 items [total range 0 to 100, where each item is ordered so that higher scores indicated more alertness]), b) mood (average of 2 items [total range 0 to 100, where higher scores indicated elevated mood]), and c) calmness (average of 5 items [total range 0 to 100, where higher scores indicated more calmness]). Baseline is defined as the last available recording prior to dosing on Day 1.

The Bond and Lader Visual Analogue Scales (VAS) monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three affective dimensions/subscales a) alertness (average of 9 items [total range 0 to 100, where each item is ordered so that higher scores indicated more alertness]), b) mood (average of 2 items [total range 0 to 100, where higher scores indicated elevated mood]), and c) calmness (average of 5 items [total range 0 to 100, where higher scores indicated more calmness]). Baseline is defined as the last available recording prior to dosing on Day 1.

The Bond and Lader Visual Analogue Scales (VAS) monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 mm about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three affective dimensions/subscales a) alertness (average of 9 items [total range 0 to 100, where each item is ordered so that higher scores indicated more alertness]), b) mood (average of 2 items [total range 0 to 100, where higher scores indicated elevated mood]), and c) calmness (average of 5 items [total range 0 to 100, where higher scores indicated more calmness]). Baseline is defined as the last available recording prior to dosing on Day 1.

The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced any of the following 1: completed suicide, 2: suicide attempt (response of "yes" on "actual attempt"), 3: preparatory acts toward imminent suicidal behavior ("yes" on "aborted attempt", "interrupted attempt", "preparatory acts or behavior"), 4: any suicidal behavior or ideation, 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"), 7: self-injurious behavior, no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). The new onset and worsening of post-baseline suicidality for C-SSRS was reported.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; The event has a causal relationship with the treatment or usage.

The laboratory test included: hematology (hemoglobin, hematocrit, red blood cell count, MCV, MCH, MCHC, platelets, white blood cell count, absolute lymphocytes, absolute total neutrophils, absolute basophils, absolute eosinophils and absolute monocytes), coagulation (PPT, prothrombin, PT international, ratio and fibrinogen, liver function(total bilirubin, direct bilirubin, aspartate, AST, Alanine, ALT, gamma GT, alkaline phosphatase, total protein and albumin), renal function (blood urea nitrogen, creatinine, HDL cholesterol, LDL cholesterol, triglycerides), Electrolytes (sodium, potassium, chloride, calcium, phosphate, venous bicarbonate), clinical chemistry (glucose, creatinine kinase), urinalysis dipstick (urine PH, urine glucose, urine ketones, urine protein, urine blood, urine urobilinogen, urine nitrite, urine leukocyte, esterase), urinalysis microscopy (urine RBC, urine WBC, urine casts, urine bacteria), miscellaneous (absolute lymphocyte marker CD4, CD8, CD19)

Number of participants with vital signs data of absolute values meeting categorical criteria was reported as following: (1) Supine systolic BP < 90 mmHg; (2) Supine Diastolic BP < 50 mmHg; (3) Supine Pulse Rate < 40 BPM ; (4) Supine Pulse Rate > 120 BPM.

Number of participants with vital signs data of increase from baseline meeting the following criteria was reported: Criterion A: maximum increase from baseline in supine systolic BP >= 30 mmHg; Criterion B: maximum increase from baseline in supine diastolic BP >= 20 mmHg. Baseline was defined as the last available recording prior to dosing.

Number of participants with vital signs data of increase from baseline meeting the following criteria was reported: Criterion A: maximum decrease from baseline in supine systolic BP >= 30 mmHg; Criterion B: maximum decrease from baseline in supine diastolic BP >= 20 mmHg. Baseline was defined as the last available recording prior to dosing.

Number of participants with ECG data of absolute values meeting categorical criteria was reported as following: Criterion A: maximum PR interval (time from the beginning of P wave to the start of QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization) >= 300 msec; Criterion B: maximum QRS complex (time from Q wave to the end of S wave, corresponding to ventricle depolarization)>= 140 msec; Criterion C: Maximum QT interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole)>= 500 msec; Criterion D: maximum QTC interval (QT interval corrected for heart rate) 450-<480 msec; Criterion E: maximum QTC interval 480-<500 msec; Criterion F: maximum QTC interval >=500 msec; Criterion G: maximum QTCF interval (QT interval corrected for heart rate using Fridericia's formula) 450 -< 480 msec; Criterion H: maximum QTCF interval 480 -< 500 msec; Criterion I: maximum QTCF interval >=500 msec.

Number of participants with ECG Data of increase from baseline meeting the following criteria was reported: Criterion A: maximum PR interval increase from baseline percentage change (PctChg)>=25/50%; Criterion B: maximum QRS complex increase from baseline PctChg >=50%; Criterion C: maximum QTC interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole, corrected for heart rate) increase from baseline 30<=change<60 msec; Criterion D: maximum QTC interval increase from baseline change >=60 msec; Criterion E: maximum QTCF (Fridericia's correction) interval increase from baseline 30<=change<60; Criterion F: maximum QTCF interval increase from baseline change >=60 msec. Baseline was defined as the average of the triplicate measurements prior to dosing on Day 1.

Physical examination included examination of ears, eyes, gastrointestinal, head, heart, lungs, lymph nodes, mouth, musculoskeletal, nose, skin. The number of participants with new-intensified physical examination findings were reported.

The number of participants with new-intensified neurological examination findings were reported.

Maximum plasma concentration (Cmax) of PF-05251749 was observed directly from data on Days 1, 7 and 14.

AUCtau referred to the area under the curve from time 0 to time tau, the dosing interval, where tau equaled to 24 hours on Days 1, 7 and 14.

Tmax of PF-05251749 was observed directly from data on Days 1, 7 and 14, as time of first occurrence.

Apparent clearance was influenced by the fraction of the dose absorbed, which was measured by Dose/AUCtau.

Minimum concentration observed (Cmin) of PF-05251749 was observed directly from data on Days 7 and 14.

Peak-to-through ratio (PTR) was the ratio of Cmax to Cmin, which was measured on Days 7 and 14.

Observed accumulation ratio (Rac) was calculated as AUCtau (Days 7 or 14) divided by AUCtau (Day 1).

Observed accumulation ratio for Cmax (Rac,Cmax) was calculated as: Cmax on Day 7 or 14 divided by Cmax on Day 1.

Terminal half-life (t1/2) was calculated as Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.

Apparent volume of distribution (Vz/F) was calculated by Dose/(AUCtau × kel) on Day 14.

Aetau was the cumulative amount of drug recovered unchanged in urine from time 0 to end of the dosing interval, which was calculated by sum of (urine concentration × volume of urine).

Aetau% was the percentage of dose recovered unchanged into urine from 0 to end of the dosing interval, which was calculated by 100 × Aetau/Dose.

Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), Aetau/AUCtau.

Dim Light Melatonin Onset (DLMO) was defined as point in time when the smooth melatonin curve exceeds the threshold. The threshold for each melatonin profile was calculated as the mean of three low consecutive daytime values (raw data points) plus twice the standard deviation of these points.

DLMO was defined as point in time when the smooth melatonin curve exceeds the threshold. The threshold for each melatonin profile was calculated as the mean of three low consecutive daytime values (raw data points) plus twice the standard deviation of these points.