This first in human study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06826647 in healthy subjects and subjects with plaque psoriasis.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
109
PF-06826647 tablet for oral administration
PF-06826647 suspension for oral administration (oral suspension to be administered to the 3mg starting dose cohort only)
placebo oral solution for the single ascending dose, first cohort only
Anaheim Clinical Trials, LLC
Anaheim, California, United States
Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Single Ascending Dose [SAD] Period)
Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure \[BP\] and supine pulse rate \[PR\]) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Time frame: Baseline up to Day 8
Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Multiple Ascending Dose [MAD] Period)
Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure and supine pulse rate) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.
Time frame: Baseline up to Day 28
Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Psoriasis Cohorts)
Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure and supine pulse rate) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.
Time frame: Baseline up to Day 56
Number of Participants With Physical Examination Data Meeting Pre-Specified Criteria (SAD Period)
Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
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Matching placebo tablet
Time frame: Baseline up to Day 8
Number of Participants With Physical Examination Data Meeting Pre-Specified Criteria (MAD Period)
Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
Time frame: Baseline up to Day 28
Number of Participants With Physical Examination Data Meeting Pre-Specified Criteria (Psoriasis Cohorts)
Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
Time frame: Baseline up to Day 56
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-Specified Criteria (SAD Period)
ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and \<480 millisecond (msec), ≥480 and \<500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and \<60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline \>200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Time frame: Baseline up to Day 8
Number of Participants With ECG Data Meeting Pre-Specified Criteria (MAD Period)
ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and \<480 millisecond (msec), ≥480 and \<500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and \<60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline \>200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.
Time frame: Baseline up to Day 28
Number of Participants With ECG Data Meeting Pre-Specified Criteria (Psoriasis Cohorts)
ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and \<480 millisecond (msec), ≥480 and \<500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and \<60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline \>200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.
Time frame: Baseline up to Day 56
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Who Withdrew Due to Adverse Events (AEs) (SAD Period)
An AE was any untoward medical occurrence in a participant who received study treatment 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; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE. PBO SAD cohorts = \[PBO SAD (3mg, 10mg)\] cohorts + \[PBO SAD -\> PBO QD MAD\] cohorts.
Time frame: Baseline up to Day 8
Number of Participants With TEAEs, SAEs, and Who Withdrew Due to AEs (MAD Period)
An AE was any untoward medical occurrence in a participant who received study treatment 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; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.
Time frame: Baseline up to Day 28
Number of Participants With TEAEs, SAEs, and Who Withdrew Due to AEs (Psoriasis Cohorts)
An AE was any untoward medical occurrence in a participant who received study treatment 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; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.
Time frame: Baseline up to Day 84
Number of Participants With Laboratory Abnormalities (SAD Period)
Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters for laboratory abnormalities evaluation included: erythrocyte mean corpuscular volume (Ery. MCV), erythrocyte mean corpuscular hemoglobin (Ery. MCH), reticulocytes/erythrocytes (%), limphocytes, eosinophils, bilirubin, aspartate aminotransferase (AST), urate, high-density lipoproteins (HDL) cholesterol, low-density lipoproteins (LDL) cholesterol, triglycerides, cholesterol, ketones, nitrite, leukocyte esterase, epithelial cells, urinalysis-bacteria. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Time frame: Baseline up to Day 8
Number of Participants With Laboratory Abnormalities (MAD Period)
Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters and corresponding primary criteria for laboratory abnormalities evaluation included: Ery. MCV \<0.9 × LLN, Ery. Mean corpuscular hemoglobin (Ery. MCH) \<0.9 × LLN or \>1.1 ULN, reticulocytes/erythrocytes (%) \>1.5 × ULN, lymphocytes \<0.8 × LLN or \>1.2 × ULN, neutrophils \<0.8 × LLN, eosinophils \>1.2 × ULN, bilirubin \>1.5 × ULN, urate \>1.2 × ULN, HDL cholesterol \<0.8 × LLN, LDL cholesterol \>1.2 × ULN, triglycerides \>1.3 × ULN, bicarbonate \>1.1 × ULN, cholesterol \>1.3 × ULN, urine glucose ≥1, urine hemoglobin ≥1, nitrite ≥1, leukocyte esterase ≥1, epithelial cells ≥6/LPF, urinalysis-casts \>1/LPF, urinalysis-bacteria \>20/HPF, urine 24 hours creatinine \>1.1 × ULN.
Time frame: Baseline up to Day 28
Number of Participants With Laboratory Abnormalities (Psoriasis Cohorts)
Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters and corresponding primary criteria for laboratory abnormalities evaluation included: reticulocytes/erythrocytes (%) \>1.5 × ULN, lymphocytes \<0.8 × LLN, neutrophils \<0.8 × LLN or \>1.2 × ULN, eosinophils \>1.2 × ULN, bilirubin \>1.5 × ULN, alanine aminotransferase (ALT) \>3.0 × ULN, creatinine \>1.3 × ULN, urate \>1.2 × ULN, HDL cholesterol \<0.8 × LLN, LDL cholesterol \>1.2 × ULN, triglycerides \>1.3 × ULN, potassium \>1.1 × ULN, bicarbonate \>1.1 × ULN, glucose \<0.6 × LLN or \>1.5 × ULN, Creatine Kinase (CK) \>2.0 × ULN, cholesterol \>1.3 × ULN, urine glucose ≥1, ketones ≥1, urine hemoglobin ≥1, urine bilirubin ≥1, leukocyte esterase ≥1, epithelial cells ≥6/LPF, urinalysis-bacteria/HPF.
Time frame: Baseline up to Day 56
Change in 24 Hour Creatinine Clearance From Day -1 on Day 10 (MAD Period)
Change in 24-hour creatinine clearance at Day 10 from Day -1 (baseline) during the MAD was presented by treatment group.
Time frame: Day -1 and Day 10
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) (SAD Period)
AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Secondary: Dose Normalized AUCinf (AUCinf[dn]) (SAD Period)
AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). AUCinf(dn) = AUCinf / dose. Dose normalized AUC values of PF-06826647 was plotted against dose and included individual participant values and the geometric means for each dose. These plots were used to help understand the relationship between the plasma PK parameters and dose.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Area Under the Concentration-Time Profile From Time 0 to 24 Hours (AUC24) (SAD Period)
AUC24 was summarized by dosing regimen and period. It was determined by linear/log trapezoidal method.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) (SAD Period)
AUClast was summarized by dosing regimen and period. It was determined by linear/log trapezoidal method.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Dose Normalized AUClast (AUClast[dn]) (SAD Period)
AUClast(dn) = AUClast / dose. Dose normalized AUC values of PF-06826647 were plotted against dose and included individual participant values and the geometric means for each dose. These plots was used to help understand the relationship between the plasma PK parameters and dose.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Maximum Plasma Concentration (Cmax) (SAD Period)
Cmax was summarized by dosing regimen and period. It was observed directly from data.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Dose Normalized Cmax (Cmax[dn]) (SAD Period)
Cmax(dn) = Cmax / dose. To assess the relationship between Cmax and dose, dose normalized Cmax was plotted against dose, and included individual participant values and the geometric means for each dose.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Time for Cmax (Tmax) (SAD Period)
Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Terminal Elimination Half-Life ((t½) (SAD Period)
t1/2 was summarized by dosing regimen and period. It was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Mean Residence Time (MRT) (SAD Period)
MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from time 0 to infinity.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Apparent Volume of Distribution (Vz/F) (SAD Period)
Vz/F 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: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Apparent Clearance (CL/F) (SAD Period)
CL/F 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 pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose
Area Under the Plasma Concentration-Time Profile Over the Dosing Interval τ (AUCτ) (MAD Period Day 1)
AUCτ was summarized by dosing regimen and period. Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval was 24 hours for QD dosing and 12 hours for BID dosing. It was determined by linear/log trapezoidal method.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Dose Normalized AUCτ (AUCτ[dn]) (MAD Period Day 1)
Area Under the Plasma Concentration-Time Profile over the Dosing interval τ (AUCτ). Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. AUCτ(dn) = AUCτ / Dose. To assess the relationship between the PK parameters and the dose, dose normalized AUCτ was plotted against dose, and included individual participant values and the geometric means for each dose.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Cmax (MAD Period Day 1)
Cmax was summarized by dosing regimen and period. It was observed directly from data.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Cmax(dn) (MAD Period Day 1)
Cmax(dn) = Cmax / dose. To assess the relationship between Cmax and dose, dose normalized Cmax was plotted against dose, and included individual participant values and the geometric means for each dose.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Tmax (MAD Period Day 1)
Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.
Time frame: Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
AUCτ (MAD Period Day 10)
AUCτ was summarized by dosing regimen and period. Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval was 24 hours for QD dosing and 12 hours for BID dosing. It was determined by linear/log trapezoidal method.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
AUCτ(dn) (MAD Period Day 10)
Area Under the Plasma Concentration-Time Profile over the Dosing interval τ (AUCτ). Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. AUCτ(dn) = AUCτ / Dose. To assess the relationship between the PK parameters and the dose, dose normalized AUCτ was plotted against dose, and included individual participant values and the geometric means for each dose.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Cmax (MAD Period Day 10)
Cmax was summarized by dosing regimen and period. It was observed directly from data.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Cmax(dn) (MAD Period Day 10)
Cmax(dn) = Cmax / dose. To assess the relationship between Cmax and dose, dose normalized Cmax was plotted against dose, and included individual participant values and the geometric means for each dose.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Tmax (MAD Period Day 10)
Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Average Concentration at Steady State (Cav) (MAD Period Day 10)
Cav = AUCτ,ss / τ, where ss means 'at steady state', and where the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. Cav was summarized by dosing regimen and period.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Lowest Concentration Observed During the Dosing Interval τ (Cmin) (MAD Period Day 10)
Cmin was observed directly from data. It was summarized by dosing regimen and period. Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Terminal Elimination Half-Life ((t½) (MAD Period Day 10)
t1/2 was summarized by dosing regimen and period. It was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24,48,72,96,168 hours post-dose
MRT (MAD Period Day 10)
MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from time 0 to infinity.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24,48,72,96,168 hours post-dose
Peak Trough Ratio (PTR) (MAD Period Day 10)
PTR = Cmax,ss / Cmin,ss, where ss means 'at steady state'. It was summarized by dosing regimen and period.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Observed Accumulation Ratio Based on AUC (Rac) (MAD Period Day 10)
Rac = AUCτ,ss / AUCτ,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac = AUCτ(Day 10) / AUCτ(Day 1). Rac was summarized by dosing regimen and period.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Observed Accumulation Ratio Based on Cmax (Rac,Cmax) (MAD Period Day 10)
Rac,Cmax = Cmax,ss / Cmax,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac,Cmax = Cmax(Day10) / Cmax(Day 1). Rac,Cmax was summarized by dosing regimen and period.
Time frame: Days 1 and 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Vz/F (MAD Period Day 10)
Vz/F 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: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
CL/F (MAD Period Day 10)
CL/F 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 pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Cumulative Amount of Drug Recovered Unchanged in Urine From Time 0 to the Dosing Interval τ Hours Post-Dose (Aeτ) (MAD Period Day 10)
Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. Aeτ = Sum of \[urine concentration \* sample volume\] for each collection interval. Aer was summarized by dosing regimen and period.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Percentage of Dose Recovered Unchanged in Urine From Time 0 to the Dosing Interval τ Hours Post-Dose (Aeτ%) (MAD Period Day 10)
Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. Aeτ% = Aeτ / Dose \* 100. Aeτ%was summarized by dosing regimen and period.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
Renal Clearance (Clr) (MAD Period Day 10)
Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Aeτ) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCτ), where dosing interval is 24 hours for QD dosing and 12 hours for BID dosing.
Time frame: Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose
AUCτ (Psoriasis Cohorts)
AUCτ was summarized by dosing regimen and period. It was determined by linear/log trapezoidal method.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
AUCτ(dn) (Psoriasis Cohorts)
AUCτ(dn) = AUCτ / Dose. To assess the relationship between the PK parameters and the dose, dose normalized AUCτ was plotted against dose, and included individual participant values and the geometric means for each dose.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Cmax (Psoriasis Cohorts)
Cmax was summarized by dosing regimen and period. It was observed directly from data.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Cmax(dn) (Psoriasis Cohorts)
Cmax was summarized by dosing regimen and period. It was observed directly from data.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Tmax (Psoriasis Cohorts)
Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Cav (Psoriasis Cohorts)
Cav = AUCτ,ss / τ, where ss means 'at steady state'. Cav was summarized by dosing regimen and period.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Cmin (Psoriasis Cohorts)
Cmin was observed directly from data. It was summarized by dosing regimen and period.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Terminal Elimination Half-Life ((t½) (Psoriasis Cohorts)
t1/2 was summarized by dosing regimen and period. It was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24,168 hours post-dose
MRT (Psoriasis Cohorts)
MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from time 0 to infinity.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24,168 hours post-dose
PTR (Psoriasis Cohorts)
PTR = Cmax,ss / Cmin,ss, it was summarized by dosing regimen and period.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Vz/F (Psoriasis Cohorts)
Vz/F 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: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
CL/F (Psoriasis Cohorts)
CL/F 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 pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose
Change From Baseline in Psoriasis Area and Severity Index (PASI) Score at Day 28
Combined assessment of lesion severity and area affected into single score. Body was divided into 4 sections: head, arms, trunk, legs. For each section, percent area of skin involved was estimated: 0= 0% to 6= 90-100%. Severity was estimated by clinical signs: erythema, induration, desquamation; scale: 0= none to 4= maximum. Final PASI = sum of severity parameters for each section\*area score\*weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4); total possible score range: 0= no disease to 72= maximal disease.
Time frame: Baseline and Day 28