A Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Study Of PF-06700841, With Bioavailability/Food Effect Investigation

Pfizer96 enrolled

Overview

The main purpose of the study is to determine if PF-06700841 is safe and well tolerated when administered to humans. A secondary purpose is to assess what the body does to PF-06700841 and to assess what PF-06700841 does to the body when given as single and multiple doses. The pharmacokinetic properties of different forms of PF-06700841 may be studied (tablet and solution/suspension forms).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Masking

TRIPLE

Enrollment

Conditions

Plaque Psoriasis

Interventions

PF-06700841 oral solution/suspensionDRUG

Oral solution or suspension of study drug PF-06700841 (once daily or twice daily during multiple dosing periods)

PlaceboOTHER

Matching placebo given during the single ascending and multiple dose periods

PF-06700841 tabletDRUG

PF-06700841 tablet formulation administered during the bioavailability / food effect investigation

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: Key Inclusion Criteria for Healthy Subject Cohorts: * Healthy male subjects and/or female subjects of non-childbearing potential between the ages of 18 and 55 years, inclusive * No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) Key Inclusion Criteria for Psoriasis Subject Cohorts: * Male subjects and/or female subjects of non-childbearing potential with a diagnosis of plaque psoriasis who are between the ages of 18 and 65 years, inclusive * Have a diagnosis of plaque psoriasis for at least 6 months prior to first study dose Exclusion Criteria: Key Exclusion Criteria for Healthy Subject Cohorts: * Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) * Males of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product Key Exclusion Criteria for Psoriasis Subject Cohorts: * Currently have non plaque forms of psoriasis, (eg, erythrodermic, guttate, or pustular psoriasis). * Have current drug induced psoriasis, eg, a new onset of psoriasis or an exacerbation of psoriasis from beta blockers, calcium channel blockers, antimalarial drugs or lithium * Males of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product

Locations (1)

Anaheim Clinical Trials, LLC

Anaheim, California, United States

Outcomes

Primary Outcomes

Single Ascending Dose (SAD) Cohort: Change From Baseline in Blood Pressure at Day 1

Time frame: Baseline, 24 hours post-dose on Day 1

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Blood Pressure at Day 10

Time frame: Baseline, 16 hours post-dose on Day 10

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Blood Pressure at Day 28

Time frame: Baseline, 16 hours post-dose on Day 28

Single Ascending Dose (SAD) Cohort: Change From Baseline in Pulse Rate at Day 1

Time frame: Baseline, 24 hours post-dose on Day 1

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Pulse Rate at Day 10

Time frame: Baseline, 16 hours post-dose on Day 10

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Pulse Rate at Day 28

Time frame: Baseline, 16 hours post-dose on Day 28

Single Ascending Dose (SAD) Cohort: Change From Baseline in Oral Temperature at Day 1

Time frame: Baseline, 24 hours post-dose on Day 1

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Oral Temperature at Day 10

Time frame: Baseline, 16 hours post-dose on Day 10

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Oral Temperature at Day 28

Time frame: Baseline, 16 hours post-dose on Day 28

Number of Participants With Change From Baseline in Physical Examinations

Data from ClinicalTrials.gov

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Physical examinations included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems.

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 28, MAD Psoriasis Cohort: Baseline up to Day 56, Food Effect Cohort: Baseline up to Day 37

Single Ascending Dose (SAD) Cohort: Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters (PR Interval, QRS Complex, QT Interval, QTC Interval) at Day 1

Time frame: Baseline, 24 hours post-dose on Day 1

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters (PR Interval, QRS Complex, QT Interval, QTC Interval) at Day 10

Time frame: Baseline, 16 hours post-dose on Day 10

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters (PR Interval, QRS Complex, QT Interval, QTC Interval) at Day 28

Time frame: Baseline, 16 hours post-dose on Day 28

Single Ascending Dose (SAD) Cohort: Change From Baseline in Heart Rate at Day 1

Time frame: Baseline, 24 hours post-dose on Day 1

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Heart Rate at Day 10

Time frame: Baseline, 16 hours post-dose on Day 10

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Heart Rate at Day 28

Time frame: Baseline, 16 hours post-dose on Day 28

Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Discontinuation Due to AEs

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is 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 up to the end of study (up to Day 8 in SAD cohort, Day 28 in MAD cohort, Day 56 in MAD Psoriasis cohort, Day 37 in Food effect cohort), that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAE and non-SAE.

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 28, MAD Psoriasis Cohort: Baseline up to Day 56, Food Effect Cohort: Baseline up to Day 37

Number of Adverse Events (AEs) According to Severity

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs were classified according to the severity in 3 categories a) mild - AEs does not interfere with participant's usual function b) moderate - AEs interferes to some extent with participant's usual function c) severe - AEs interferes significantly with participant's usual function.

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 28, MAD Psoriasis Cohort: Baseline up to Day 56, Food Effect Cohort: Baseline up to Day 37

Number of Participants With Laboratory Abnormalities

Criteria for abnormality:hematology: hemoglobin, hematocrit, red blood cell count: less than(\<) 0.8\*lower limit of normal (LLN); mean corpuscular volume; mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration: \<0.9\*LLN,\>1.1\*upper limit of normal (ULN); platelets: \<0.5\*LLN,\>1.75\*ULN, white blood cell count: \<0.6\*LLN, \>1.5\*ULN; lymphocytes, total neutrophils: \<0.8\*LLN, \>1.2\*ULN; eosinophils, basophils, monocytes: \>1.2\*ULN; coagulation: activated partial thromboplastin time, prothrombin, prothrombin international ratio: \>1.1\*ULN; liver function: bilirubin: \>1.5\*ULN; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase: \>3.0\*ULN; protein, albumin: \<0.8\*LLN\>\</0\>1.2\*ULN; renal function:blood urea nitrogen,creatinine: \>1.3\*ULN; uric acid: \>1.2\*ULN; electrolytes: sodium, potassium, chloride, calcium, bicarbonate: \<0.9\*LLN,\>1.1\*ULN; urinalysis: pH\<4.5, \>8; glucose, protein, blood, ketones, urobilinogen, bilirubin, nitrite; Other(glucose: \<0.6\*LLN,\>1.5\*ULN)

Time frame: SAD Cohort: Baseline up to Day 8, MAD Cohort: Baseline up to Day 28, MAD Psoriasis Cohort: Baseline up to Day 56, Food Effect Cohort: Baseline up to Day 37

Single Ascending Dose (SAD) Cohort: Change From Baseline in Creatinine Clearance at Day 1

Creatinine clearance is a measure of kidney function. Creatinine clearance is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time.

Time frame: Baseline, 24 hours post-dose on Day 1

Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Change From Baseline in Creatinine Clearance at Day 10

Creatinine clearance is a measure of kidney function. Creatinine clearance is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time.

Time frame: Baseline, 16 hours post-dose on Day 10

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Creatinine Clearance at Day 28

Creatinine clearance is a measure of kidney function. Creatinine clearance is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time.

Time frame: Baseline, 16 hours post-dose on Day 28

Food Effect Cohort: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06700841

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

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post dose on Day 1

Food Effect Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-06700841

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

Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post dose on Day 1

Food Effect Cohort: Maximum Observed Plasma Concentration (Cmax) of PF-06700841

Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post dose on Day 1

Secondary Outcomes

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Maximum Observed Plasma Concentration (Cmax) of PF-06700841

Time frame: SAD: pre-dose, 0.5,1,2,4,6,8,12,16,24,36,48,72,96 hour post dose on Day 1; MAD: pre-dose 0.5,1,2,4,6,8,12,24 hour post-dose on Day 10; MAD Psoriasis: pre-dose, 0.5,1,2,4,6,8,12,16,24 hours post dose on Day 28

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06700841

Food Effect Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF--06700841

Time frame: Pre--dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post dose on Day 1

Single Ascending Dose (SAD) Cohort: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06700841

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

Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post dose on Day 1

Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06700841

Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 24 hours for MAD once daily cohorts, 12 hours for MAD twice daily cohort and 24 hours for MAD Psoriasis cohort.

Time frame: MAD: pre-dose 0.5, 1, 2, 4, 6, 8, 12, 24 hour post-dose on Day 10; MAD Psoriasis: pre-dose, 0.5,1,2,4,6,8,12,16,24 hours post dose on Day 28

Single Ascending Dose (SAD) Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-06700841

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

Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post dose on Day 1

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Dose Normalized Maximum Observed Plasma Concentration (Cmax[dn]) of PF-06700841

Dose normalized (dn) Cmax was calculated by dividing Cmax by the exact dose of PF 06700841 (in mg) administered to a participant.

Single Ascending Dose (SAD) Cohort: Dose Normalized Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf[dn]) of PF-06700841

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUCinf(dn) was calculated by dividing AUCinf by the exact dose of PF-06700841 (in mg) administered to a participant.

Time frame: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post dose on Day 1

Single Ascending Dose (SAD) Cohort: Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn]) of PF-06700841

Area under the plasma concentration time-curve from time zero to the time of last measured concentration (AUClast). AUClast(dn) was calculated by dividing AUClast by the exact dose of of PF-06700841 (in mg) administered to a participant.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post dose on Day 1

Multiple Ascending Dose (MAD) Cohort: Dose Normalized Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau[dn]) of PF-06700841

Area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 24 hours for MAD once daily cohorts, 12 hours for MAD twice daily cohort. AUCtau(dn) was calculated by dividing AUCtau by the exact dose of of PF-06700841 (in mg) administered to a participant.

Time frame: pre-dose 0.5,1,2,4,6,8,12,24 hour post-dose on Day 10

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Plasma Decay Half-Life (t1/2) of PF-06700841

Plasma decay half-life is the time measured for the plasma concentration of PF-06700841 to decrease by one half.

Time frame: SAD: pre--dose, 0.5,1,2,4,6,8,12,16,24,36,48,72,96 hour post-dose on Day 1; MAD: pre--dose 0.5,1,2,4,6,8,12,24 hour post-dose on Day 10; MAD Psoriasis: pre--dose, 0.5,1,2,4,6,8,12,16,24 hours post-dose on Day 28

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Mean Residence Time (MRT) of PF-06700841

MRT= AUMCinf/AUCinf, where AUMCinf is the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method.

Time frame: SAD: pre--dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post-dose on Day 1; MAD: pre--dose 0.5, 1, 2, 4, 6, 8, 12, 24 hour post--dose on Day 10; MAD Psoriasis: pre--dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24 hours post-dose on Day 28

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Apparent Volume of Distribution (Vz/F) of PF-06700841

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.

Time frame: SAD: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post-dose on Day 1; MAD: pre-dose 0.5, 1, 2, 4, 6, 8, 12, 24 hour post-dose on Day 10; MAD Psoriasis: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24 hours post-dose on Day 28

Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Apparent Clearance (CL/F) of PF-06700841

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Clearance obtained after oral dose is influenced by the fraction of the dose absorbed. CL/F =Dose of PF-06700841/AUCinf.

Time frame: SAD: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96 hour post-dose on Day 1; MAD: pre-dose 0.5, 1, 2, 4, 6, 8, 12, 16, 24 hour post-dose on Day 10; MAD Psoriasis: pre-dose, 0.5, 1, 2, 4, 6, 8, 12, 16, 24 hours post-dose on Day 28

Multiple Ascending Dose (MAD) and MAD Psoriasis Cohort: Peak-Trough Fluctuation (PTF) of PF-06700841

PTF was calculated as: Cmax-Cmin/Cavg. Cmax is the maximum observed plasma concentration of PF-06700841. Cmin is the minimum observed plasma concentration of PF-06700841. Cavg is the average observed plasma concentration of PF-06700841 calculated as area under the plasma concentration-time curve during a dosing Interval (AUC\[tau\]) divided by the dosing interval (tau), where dosing interval was 24 hours for MAD once daily cohorts, 12 hours for MAD twice daily cohort and 24 hours for MAD Psoriasis cohort.

Time frame: MAD: pre--dose 0.5, 1, 2, 4, 6, 8, 12, 24 hour post--dose on Day 10; MAD Psoriasis: pre--dose, 0.5,1,2,4,6,8,12,16,24 hours post-dose on Day 28

Multiple Ascending Dose (MAD) Cohort: Amount of PF-06700841 Recovered Unchanged in the Urine Over the Time Interval Tau (Aetau)

Aetau is the amount of drug recovered unchanged in urine during the dosing interval (tau), where dosing interval was 24 hours for MAD once daily cohorts, 12 hours for MAD twice daily cohort.

Time frame: 0-24 hour on Day 10

Multiple Ascending Dose (MAD) Cohort: Percentage of Dose of PF-06700841 Recovered Unchanged in the Urine Over the Time Interval Tau (Aetau%)

Aetau% was calculated as: 100\*Aetau/dose. Aetau is the amount of drug recovered unchanged in urine during the dosing interval (tau), where dosing interval was 24 hours for MAD once daily cohorts, 12 hours for MAD twice daily cohort.

Time frame: 0-24 hours on Day 10

Multiple Ascending Dose (MAD) Cohort: Renal Clearance

Renal clearance was calculated as amount of drug recovered 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 for MAD once daily cohorts, 12 hours for MAD twice daily cohort.

Time frame: 0-24 hours on Day 10

Single Ascending Dose (SAD) Cohort: Interferon Gamma-induced Protein 10 (IP-10) Concentration in Serum at Baseline

Serum samples for IP-10 were analyzed using a validated analytical assay. Lower limit of quantification (LLOQ) for IP-10 was 10 pg/mL.

Time frame: Baseline

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Interferon Gamma-induced Protein 10 (IP-10) Concentration in Serum at Day 2, 5, 10, 11, 28

Serum samples for IP-10 were analyzed using a validated analytical assay. LLOQ for IP-10 was 10 pg/mL.

Time frame: Baseline, Day 2, 5, 10, 11, 28

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Interferon Gamma-Induced Protein 10 (IP-10) Concentration in Serum at Day 2, 5, 7, 14, 21, 28, 29, 35, 56

Serum samples for IP-10 were analyzed using a validated analytical assay. Lower limit of quantification (LLOQ) for IP-10 was 10 pg/mL.

Time frame: Baseline, Day 2, 5, 7, 14, 21, 28, 29, 35, 56

Single Ascending Dose (SAD) Cohort: High Sensitivity C-reactive Protein (hsCRP) Concentration in Serum at Baseline

Serum samples for hsCRP were analyzed using a validated analytical assay. Reference range for measurement of CRP was 0.015 to 2.0 mg/dL. LLOQ for hsCRP was 0.03 mg/dL and limit of detection was 0.015 mg/dL.

Time frame: Baseline

Multiple Ascending Dose (MAD) Cohort: Change From Baseline In High Sensitivity C-reactive Protein (hsCRP) at Day 2, 5, 10, 11, 28

Time frame: Baseline, Day 2, 5, 10, 11, 28

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline In High Sensitivity C-reactive Protein (hsCRP) at Day 2, 5, 7, 14, 21, 28, 29, 35 and 56

Time frame: Baseline, Day 2, 5 ,7,14, 21, 28, 29, 35, 56

Single Ascending Dose (SAD) Cohort: Change From Baseline in Neutrophil Counts at Day 2, 5 and 8

Time frame: Baseline, Day 2, 5, 8

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Neutrophil Counts at Day 4, 8, 10, 11, 14, 28

Time frame: Baseline, Day 4, 8, 10, 11, 14, 28

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Neutrophil Counts at Day 4, 6, 8, 10, 13, 14, 21, 28, 35, 42 and 56

Time frame: Baseline, Day 4, 6 ,8,10, 13, 14, 21, 28, 35, 42, 56

Single Ascending Dose (SAD) Cohort: Change From Baseline in Reticulocyte Counts at Day 2, 5, 8

Time frame: Baseline, Day 2, 5, 8

Multiple Ascending Dose (MAD) Cohort: Change From Baseline in Reticulocyte Counts at Day 4, 8, 10, 11, 14 and 28

Time frame: Baseline, Day 4, 8, 10, 11, 14, 28

Multiple Ascending Dose (MAD) Psoriasis Cohort: Change From Baseline in Reticulocyte Counts at Day 4, 6, 8, 10, 13, 14, 21, 28, 35, 42 and 56

Time frame: Baseline, Day 4, 6 ,8,10, 13, 14, 21, 28, 35, 42, 56