NCT02341482

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

Completed Phase 1 Results posted Last updated 9 January 2020

What this trial tests

Phase 1 trial testing PF-04958242 in Healthy in 13 participants. Completed in 31 March 2015.

Timeline

5 February 2015

Primary endpoint
31 March 2015

31 March 2015

Quick facts

Lead sponsor	Biogen
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	13
Start date	5 February 2015
Primary completion	31 March 2015
Estimated completion	31 March 2015
Sites	1 location across United States

Drugs / interventions tested

• PF-04958242 — full drug profile →
• Itraconazole — full drug profile →

Conditions studied

• Healthy — all drugs for Healthy →

Sponsor

Biogen — full company profile →

Who can join

Adults 18 to 55, any sex, with Healthy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Group	Value	95% CI
PF-04958242 0.025 mg	4242	± 30
PF-04958242 0.025 mg + Itraconazole 200 mg	4073	± 25

Maximum Observed Plasma Concentration (Cmax) of PF-04958242 Primary · 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.

Group	Value	95% CI
PF-04958242 0.025 mg	553.4	± 27
PF-04958242 0.025 mg + Itraconazole 200 mg	541.6	± 20

Time for Cmax (Tmax) of PF-04958242 Secondary · 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.

Group	Value	95% CI
PF-04958242 0.025 mg	1.50	1.00 – 1.52
PF-04958242 0.025 mg + Itraconazole 200 mg	1.50	1.00 – 2.00

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

Group	Value	95% CI
PF-04958242 0.025 mg	256.5	± 35
PF-04958242 0.025 mg + Itraconazole 200 mg	238.2	± 30

Predose Concentration (Ctrough) of PF-04958242 Secondary · 0 hour at Day 1, Day 2, Day 3, Day 4, Day 7, Day 10, Day 13, Day 16, and Day 17 (pre-dose)

Group	Value	95% CI
PF-04958242 0.025 mg	289.3	± 37
PF-04958242 0.025 mg + Itraconazole 200 mg	255.0	± 29

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

Group	Value	95% CI
PF-04958242 0.025 mg	98.25	± 30
PF-04958242 0.025 mg + Itraconazole 200 mg	102.3	± 25

Number of Participants With Abnormal Clinical Laboratory Measurements Secondary · 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, a

Group	Value	95% CI
All Subjects	1

Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern Secondary · 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.

Supine SBP <90 mmHg

Group	Value	95% CI
All Subjects	0

Supine DBP <50 mmHg

Group	Value	95% CI
All Subjects	0

Supine Pulse Rate <40 BPM

Group	Value	95% CI
All Subjects	0

Supine Pulse Rate >120 BPM

Group	Value	95% CI
All Subjects	0

Supine SBP >=30 mmHg IFB

Group	Value	95% CI
All Subjects	2

Supine DBP >=20 mmHg IFB

Group	Value	95% CI
All Subjects	1

Supine SBP >=30 mmHg DFB

Group	Value	95% CI
All Subjects	0

Supine DBP >=20 mmHg DFB

Group	Value	95% CI
All Subjects	0

Number of Participants With Electrocardiogram Data Meeting Criteria of Potential Clinical Concern Secondary · 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 \>=

Group	Value	95% CI
All Subjects	0

Number of Participants With Significant Change in Neurological Examination From Previous Examination Secondary · 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 f

Group	Value	95% CI
All Subjects	0

Number of Participants With Significant Change in Physical Examination From Previous Examination Secondary · 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.

Group	Value	95% CI
All Subjects	0

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · 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.

AEs

Group	Value	95% CI
PF-04958242 0.025 mg	2
PF-04958242 0.025 mg + Itraconazole 200 mg	7
PF-04958242 0.1 mg	1

SAEs

Group	Value	95% CI
PF-04958242 0.025 mg	0
PF-04958242 0.025 mg + Itraconazole 200 mg	0
PF-04958242 0.1 mg	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to 28 days after last dose of study drug.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

PF-04958242 0.1 mg

Serious: 0/13 (0%)

Deaths: —

PF-04958242 0.025 mg

Serious: 0/13 (0%)

Deaths: —

PF-04958242 0.025 mg Combined With Itraconazole 200 mg

Serious: 0/13 (0%)

Deaths: —

Other adverse events (21 terms — click to expand)

Reaction	System	PF-04958242 0.1 mg	PF-04958242 0.025 mg	PF-04958242 0.025 mg Combi…
Diarrhoea	Gastrointestinal disorders	—	—	—
Thirst	General disorders	—	—	—
Somnolence	Nervous system disorders	—	—	—
Penile swelling	Reproductive system and breast disorders	—	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—	—
Change of bowel habit	Gastrointestinal disorders	—	—	—
Flatulence	Gastrointestinal disorders	—	—	—
Drug intolerance	General disorders	—	—	—
Fat tissue increased	General disorders	—	—	—
Oedema peripheral	General disorders	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—
Joint injury	Injury, poisoning and procedural complications	—	—	—
Urine output decreased	Investigations	—	—	—
Weight increased	Investigations	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Paraesthesia	Nervous system disorders	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—

Data from ClinicalTrials.gov NCT02341482 adverse events section.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. SLC transporters as therapeutic targets: emerging opportunities.
   Lin L, Yee SW, Kim RB, Giacomini KM. · · 2015 · cited 653× · PMID 26111766 · DOI 10.1038/nrd4626