A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of PF-04958242 in Healthy Subjects

A Phase 1, Open-label, Fixed-sequence Study To Estimate The Effects Of Multiple-dose Administration Of Itraconazole On The Pharmacokinetics Of Pf 04958242 In Healthy Adult Subjects

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02341482

Enrollment

Registered

2015-01-19

Start date

2015-02-05

Completion date

2015-03-31

Last updated

2020-01-09

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

Conditions

Healthy

Keywords

Itraconazole, Healthy Volunteers, Drug-drug interaction, PF-04958242

Brief summary

The purpose of the current study is to characterize the pharmacokinetic (PK) profile of PF 04958242 when co administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

Detailed description

This study was previously posted by Pfizer, Inc. Sponsorship of the trial was transferred to Biogen.

Interventions

DRUGPF-04958242

Administered as specified in the treatment arm

DRUGItraconazole

Administered as specified in the treatment arm

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

Inclusion criteria

Key Inclusion Criteria: -Healthy male subjects and female subjects of non childbearing with a Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>55 kg (121 lbs). Key

Exclusion criteria

* Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary: * Aspartate transaminase (AST)/serum glutamic oxaloacetic transminase (SGOT) or alanine transaminase (ALT)/serum glutamic pyruvic transminase (SGPT) \>=1 x upper limit of normal (ULN); * Total bilirubin \>=1.5 x ULN; subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is \<= ULN. * Subjects with epilepsy, or history of epilepsy, or conditions that lower seizure threshold, seizures of any etiology (including substance or drug withdrawal), or who have increased risk of seizures as evidenced by self reported history of electroencephalogram (EEG) with epileptiform activity. Subjects with a history of childhood seizures and history of head trauma with loss of consciousness requiring hospitalization overnight will be excluded as well. * Subjects who had a history of allergy or intolerance to azole antifungal drugs. NOTE: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21	AUCtau = area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau = 12 hours. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Maximum Observed Plasma Concentration (Cmax) of PF-04958242	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21	Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

Secondary

Measure	Time frame	Description
Predose Concentration (Ctrough) of PF-04958242	0 hour at Day 1, Day 2, Day 3, Day 4, Day 7, Day 10, Day 13, Day 16, and Day 17 (pre-dose)	—
Apparent Oral Clearance (CL/F) of PF-04958242	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21	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. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Number of Participants With Abnormal Clinical Laboratory Measurements	Baseline up to Day 21	The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell \[RBC\] count, mean corpuscular volume \[MCV\], mean corpuscular hemoglobin \[MCH\], mean corpuscular hemoglobin concentration \[MCHC\], platelet count, white blood cell \[WBC\] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen \[BUN\], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy \[if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase\]); others (follicle stimulating hormone \[FSH\], urine cotinine, and urine drug screening).
Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern	Baseline up to Day 21	Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate more than (\<)40 or less than (\>)120 beats per minute (bpm); systolic blood pressure (SBP) more than or equal to (\>=)30 millimeters of mercury (mm Hg) change from baseline in same posture or SBP \<90 mm Hg, diastolic blood pressure (DBP) \>=20 mm Hg change from baseline in same posture or DBP \<50 mm Hg. IFB = increase from baseline; DFB = decrease from baseline.
Time for Cmax (Tmax) of PF-04958242	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21	Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.
Number of Participants With Significant Change in Neurological Examination From Previous Examination	Baseline up to Day 21	The extended neurological examination, performed by a board certified neurologist, included observations for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger, nose, heel, shin, Romberg, tandem walking, positional and gaze evoked nystagmus, reflexes, muscle strength, cranial nerves, sensory function of upper and lower extremities. The brief neurological examination included an assessment of motor and sensory function, cranial nerves, reflexes, non-cerebellar tremor (eg, resting or positional) and cerebellar function. The assessment of cerebellar function were complemented by the Scale for Assessment and Rating of Ataxia (SARA).
Number of Participants With Significant Change in Physical Examination From Previous Examination	Baseline up to Day 21	A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The brief physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Baseline up to 28 days after last study drug administration	An AE was any untoward medical occurrence in a participant who received study drug. 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 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.
Number of Participants With Positive Response to Columbia-Suicide Severity Rating Scale (C-SSRS)	Baseline up to Day 21	The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment \[C-CASA\]) is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced the following: completed suicide (1), suicide attempt (2) (response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (3)(Yes on preparatory acts or behavior), suicidal ideation (4) (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 suicidal behavior or ideation, self-injurious behavior (7)(Yes on Has participant engaged in non-suicidal self-injurious behavior).
Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern	Baseline up to Day 21	Electrocardiogram (ECG) parameters included time from ECG Q wave to the end of the T wave corresponding to electrical systole (QT) interval, beginning of the P wave until the beginning of the QRS complex (PR) interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS) interval, QT interval corrected for heart rate (QTc) interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval \>=300 milliseconds (msec) or \>=25% increase when baseline is \>200 msec and \>=50% increase when baseline is less than or equal to (=\<)200 msec; QRS interval \>=140 msec or \>=50% increase from baseline; and QTcF \>=450 to \<480, 480 to \<500 and \>=500 msec or \>=30 to 60 msec increase and also \>=60 msec increase. The number of participants with potentially clinically significant ECG findings at any visit were reported.
Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242	Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
All Subjects PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.	13
Total	13

Arm

Count

All Subjects

PF-04958242 0.10 mg loading dose was administered orally BID on Day 1. Each participant was given 2 daily doses of PF-04958242 (0.025 mg) orally for 16 subsequent days (Day 2 to Day 17), with the last dose occurring in the morning of Day 17. On Day 4, a 200 mg dose of itraconazole was administered orally approximately 1 hour before PF-04958242 morning administration and for 13 additional days (Day 4 to Day 17), QD.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1

Baseline characteristics

Characteristic	All Subjects
Age, Continuous	42.5 years STANDARD_DEVIATION 8.5
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	1 / 13	2 / 13	7 / 13
serious Total, serious adverse events	0 / 13	0 / 13	0 / 13

Outcome results

Primary

Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242

AUCtau = area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau = 12 hours. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

Time frame: Day 1 (0,1.5,12,13.5 hours post-dose), Day 2 (0,1.5,12,13.5 hours post-dose), Day 3 (0,0.5,1,1.5,2,3,4,6,8,12 hours post-dose), Day 4, Day 7, Day 10, Day 13, Day 16, Day 17 (0,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose) Day 18, Day 19, Day 20, Day 21

Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-04958242 0.025 mg	Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242	4242 picogramhours per milliliter pgh/mL	Geometric Coefficient of Variation 30
PF-04958242 0.025 mg + Itraconazole 200 mg	Area Under the Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval, Where Tau = 12 Hours (AUCtau) of PF-04958242	4073 picogramhours per milliliter pgh/mL	Geometric Coefficient of Variation 25

Primary

Maximum Observed Plasma Concentration (Cmax) of PF-04958242

Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

Population: All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-04958242 0.025 mg	Maximum Observed Plasma Concentration (Cmax) of PF-04958242	553.4 pg/mL	Geometric Coefficient of Variation 27
PF-04958242 0.025 mg + Itraconazole 200 mg	Maximum Observed Plasma Concentration (Cmax) of PF-04958242	541.6 pg/mL	Geometric Coefficient of Variation 20

Secondary

Apparent Oral Clearance (CL/F) of PF-04958242

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. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Collected at Day 3 for PF-04958242 0.025 mg Arm and Day 17 for PF-04958242 0.025 mg + itraconazole 200 mg Arm.

Population: The PK analysis population included all participants enrolled and treated who had at least 1 of the PK parameters of interest measured.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-04958242 0.025 mg	Apparent Oral Clearance (CL/F) of PF-04958242	98.25 milliliters per minute (mL/min)	Geometric Coefficient of Variation 30
PF-04958242 0.025 mg + Itraconazole 200 mg	Apparent Oral Clearance (CL/F) of PF-04958242	102.3 milliliters per minute (mL/min)	Geometric Coefficient of Variation 25

Secondary

Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242

Population: All enrolled participants treated who received at least 1 dose of PF-04958242 and had at least 1 measureable concentration.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-04958242 0.025 mg	Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242	256.5 pg/mL	Geometric Coefficient of Variation 35
PF-04958242 0.025 mg + Itraconazole 200 mg	Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-04958242	238.2 pg/mL	Geometric Coefficient of Variation 30

Secondary

Number of Participants With Abnormal Clinical Laboratory Measurements

The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell \[RBC\] count, mean corpuscular volume \[MCV\], mean corpuscular hemoglobin \[MCH\], mean corpuscular hemoglobin concentration \[MCHC\], platelet count, white blood cell \[WBC\] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen \[BUN\], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy \[if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase\]); others (follicle stimulating hormone \[FSH\], urine cotinine, and urine drug screening).

Time frame: Baseline up to Day 21