Healthy
Conditions
Brief summary
This is a phase 1, open label, two-arm study to assess target occupancy and functional inhibition of JAK3 and TEC kinases by Ritlecitinib in healthy adult participants
Interventions
50 mg single dose
DRUGRitlecitinib 200 mg
200 mg single dose
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Participants are eligible to be included in the study only if all the following criteria apply: * Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. * Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination including BP and pulse rate measurement, 12-lead ECG, or clinical and laboratory tests. * BMI of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb).
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply: * Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). * Infection with HIV, hepatitis B or hepatitis C viruses * Have evidence of untreated or inadequately treated active or latent Mycobacterium TB infection * Known active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections. * Have received only one of the 2 required doses of COVID-19 vaccine. * Participants have a known present or a history of malignancy other than a successfully treated or excised non metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Target Occupancy for JAK3 | -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Target occupancy for janus kinase 3 (JAK3) in peripheral blood mononuclear cells (PBMCs) by ritlecitinib was investigated in human blood by chemical probe-based enrichment and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0. |
| Percent Target Occupancy for BTK | -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Target occupancy for Bruton's tyrosine kinase (BTK) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0. |
| Percent Target Occupancy for ITK | -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Target occupancy forIL 2 inducible T-cell kinase (ITK) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0. |
| Percent Target Occupancy for TXK | -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Target occupancy for tyrosine kinase expressed in T cells (TXK) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0. |
| Percent Target Occupancy for TEC | -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Target occupancy for tyrosine kinase expressed carcinoma (TEC) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0. |
| Percent Target Occupancy for BMX | -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Target occupancy for bone marrow tyrosine kinase gene in chromosome X (BMX) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point) \*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days) | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness to study treatment was assessed by the investigator. A serious adverse event (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 were events between first dose of study treatment and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Treatment-Emergent Adverse Events by Severity | From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days) | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness to study treatment was assessed by the investigator. Treatment-emergent are events between first dose of study treatment and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs are 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. |
| Maximum Observed Plasma Concentration (Cmax) of Ritlecitinib | 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Cmax is maximum observed plasma concentration. Cmax for ritlecitinib was observed directly from data. |
| Number of Participants With Pre-defined Criteria for Vital Signs | From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days) | Pre-defined criteria included: 1) Diastolic blood pressure (DBP), a) supine DBP: less than (\<) 50 mmHg, b) supine DBP: change of \>= 20mmHg increase, c) supine DBP: change of \>= 20mmHg decrease; 2) Systolic blood pressure (SBP), a) supine SBP: \<90 mmHg, b) supine SBP: change of \>=30mmHg increase, c) supine SBP: change of \>=30mmHg decrease; 3) Supine pulse rate, a) \<40 bpm, b) \>120 bpm. mmHg=millimeters of mercury, bpm=beats per minute. |
| Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days) | Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocyte, platelet, neutrophils, eosinophils, monocytes, basophils, lymphocytes, etc), chemistry (glucose, calcium, sodium, potassium, chloride, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, etc), and urinalysis (glucose, protein, hemoglobin, ketones, nitrite, leukocytes, urine bacteria, etc). Baseline = the pre-dose measurement on Day -1. Laboratory abnormalities meeting pre-defined criteria are reported for this outcome measure. Only those categories in which at least 1 participant had data were reported. ULN=upper limit of normal. LPF=low power field. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ritlecitinib | 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Tmax is time for Cmax. Tmax for ritlecitinib was observed directly from data as time of first occurrence. |
| Last Quantifiable Plasma Concentration (Clast) of Ritlecitinib | 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | Clast is last quantifiable plasma concentration. Clast for ritlecitinib was observed directly from data. |
| Average Plasma Concentration From Time 0 to 24 Hours (Cav) of Ritlecitinib | 0 (pre-dose), 1, 2, 4, 8, 24 hours post-dose | Cav is average plasma concentration from time 0 to 24 hours over the 24 hours period. Cav for ritlecitinib was calculated as area under the plasma concentration-time curve from 0 to 24 hours (AUC24) divided by 24. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Ritlecitinib | 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose | AUClast is area under the plasma concentration-time profile from time 0 to the time of the Clast. AUClast for ritlecitinib was determined using linear/log trapezoidal method. |
| Area Under the Curve From Time 0 to 24 Hours (AUC24) of Ritlecitinib | 0 (pre-dose), 1, 2, 4, 8, 24 hours post-dose | AUC24 is area under the plasma concentration-time curve from time 0 to 24 hours. AUC24 for ritlecitinib was determined using linear/log trapezoidal method. |
Countries
United States
Participant flow
Pre-assignment details
A total of 16 participants were assigned to study treatment; 8 in the ritlecitinib 50 mg group and 8 in the ritlecitinib 200 mg group. All the participants were treated in this study.
Participants by arm
| Arm | Count |
|---|---|
| RITLECITINIB 50 MG CAPSULE Healthy participants enrolled to receive 50 mg single dose of ritlecitinib capsule on Day 1. | 8 |
| RITLECITINIB 200 MG CAPSULE Healthy participants enrolled to receive 200 mg single dose of 4 ritlecitinib 50 mg capsules on Day 1. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | RITLECITINIB 50 MG CAPSULE | RITLECITINIB 200 MG CAPSULE | Total |
|---|---|---|---|
| Age, Continuous | 43.9 Years STANDARD_DEVIATION 10.95 | 37.9 Years STANDARD_DEVIATION 12.97 | 40.9 Years STANDARD_DEVIATION 12 |
| Age, Customized <18 | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 18-44 | 3 Participants | 4 Participants | 7 Participants |
| Age, Customized 45-64 | 5 Participants | 4 Participants | 9 Participants |
| Age, Customized >=65 | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 3 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Percent Target Occupancy for BMX
Target occupancy for bone marrow tyrosine kinase gene in chromosome X (BMX) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point) \*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0.
Time frame: -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with non-misssing value at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | 2H | 85.26 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | 8H | 87.08 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | 1H | 67.51 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | 24H | 68.13 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | 4H | 84.93 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | 48H | 26.50 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BMX | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | 48H | 62.34 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | 1H | 99.13 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | 2H | 92.53 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | 4H | 92.26 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | 8H | 92.48 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BMX | 24H | 91.32 percentage of occupancy |
Primary
Percent Target Occupancy for BTK
Target occupancy for Bruton's tyrosine kinase (BTK) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0.
Time frame: -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with non-misssing value at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | 2H | 96.83 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | 8H | 93.52 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | 1H | 98.45 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | 24H | 83.21 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | 4H | 96.43 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | 48H | 69.86 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for BTK | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | 48H | 82.66 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | 1H | 99.57 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | 2H | 99.37 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | 4H | 99.35 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | 8H | 99.21 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for BTK | 24H | 92.13 percentage of occupancy |
Primary
Percent Target Occupancy for ITK
Target occupancy forIL 2 inducible T-cell kinase (ITK) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0.
Time frame: -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with non-misssing value at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | 2H | 67.77 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | 8H | 28.76 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | 1H | 94.40 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | 24H | -16.77 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | 4H | 57.54 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | 48H | -9.87 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for ITK | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | 48H | 20.62 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | 1H | 97.03 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | 2H | 97.06 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | 4H | 92.27 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | 8H | 76.59 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for ITK | 24H | 32.33 percentage of occupancy |
Primary
Percent Target Occupancy for JAK3
Target occupancy for janus kinase 3 (JAK3) in peripheral blood mononuclear cells (PBMCs) by ritlecitinib was investigated in human blood by chemical probe-based enrichment and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0.
Time frame: -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with non-misssing value at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | 2H | 12.28 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | 8H | -23.34 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | 1H | 72.41 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | 24H | -24.72 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | 4H | -1.39 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | 48H | -25.34 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for JAK3 | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | 48H | 33.44 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | 1H | 28.74 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | 2H | 64.14 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | 4H | 62.06 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | 8H | 58.76 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for JAK3 | 24H | 37.08 percentage of occupancy |
Primary
Percent Target Occupancy for TEC
Target occupancy for tyrosine kinase expressed carcinoma (TEC) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0.
Time frame: -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with non-misssing value at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | 2H | 94.60 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | 8H | 93.12 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | 1H | 96.50 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | 24H | 90.64 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | 4H | 94.23 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | 48H | 82.48 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TEC | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | 48H | 92.32 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | 1H | 100.0 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | 2H | 99.42 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | 4H | 98.78 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | 8H | 99.57 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TEC | 24H | 96.85 percentage of occupancy |
Primary
Percent Target Occupancy for TXK
Target occupancy for tyrosine kinase expressed in T cells (TXK) in PBMCs by ritlecitinib was investigated in human blood by chemical probe-based enrichment and LC-MS/MS analysis. % TO is calculated as \[(baseline value - value at specified time point)\*100/baseline value\], where baseline value in this formula is defined as the mean of the two pre-dose measurements at Hour -1 and Hour 0 on Day 1. Since (baseline value - value at specified time point)=0 at baseline, % TO at baseline is 0.
Time frame: -1 (pre-dose), 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with non-misssing value at the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | 2H | 44.97 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | 8H | 23.17 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | 24H | -4.09 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | 1H | 100.00 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | 48H | -38.98 percentage of occupancy |
| RITLECITINIB 50 MG CAPSULE | Percent Target Occupancy for TXK | 4H | 34.01 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | 48H | 20.34 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | 1H | 100.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | Baseline | 0.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | 4H | 100.00 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | 8H | 82.46 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | 24H | 49.70 percentage of occupancy |
| RITLECITINIB 200 MG CAPSULE | Percent Target Occupancy for TXK | 2H | 100.00 percentage of occupancy |
Secondary
Area Under the Curve From Time 0 to 24 Hours (AUC24) of Ritlecitinib
AUC24 is area under the plasma concentration-time curve from time 0 to 24 hours. AUC24 for ritlecitinib was determined using linear/log trapezoidal method.
Time frame: 0 (pre-dose), 1, 2, 4, 8, 24 hours post-dose
Population: The analysis population included all participants who enrolled and treated with at least 1 concentration measurement of study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Area Under the Curve From Time 0 to 24 Hours (AUC24) of Ritlecitinib | 681.8 ng*hr/mL | Geometric Coefficient of Variation 51 |
| RITLECITINIB 200 MG CAPSULE | Area Under the Curve From Time 0 to 24 Hours (AUC24) of Ritlecitinib | 3475 ng*hr/mL | Geometric Coefficient of Variation 42 |
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Ritlecitinib
AUClast is area under the plasma concentration-time profile from time 0 to the time of the Clast. AUClast for ritlecitinib was determined using linear/log trapezoidal method.
Time frame: 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with at least 1 concentration measurement of study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Ritlecitinib | 651.4 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 50 |
| RITLECITINIB 200 MG CAPSULE | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Ritlecitinib | 3382 nanogram*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 43 |
Secondary
Average Plasma Concentration From Time 0 to 24 Hours (Cav) of Ritlecitinib
Cav is average plasma concentration from time 0 to 24 hours over the 24 hours period. Cav for ritlecitinib was calculated as area under the plasma concentration-time curve from 0 to 24 hours (AUC24) divided by 24.
Time frame: 0 (pre-dose), 1, 2, 4, 8, 24 hours post-dose
Population: The analysis population included all participants who enrolled and treated with at least 1 concentration measurement of study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Average Plasma Concentration From Time 0 to 24 Hours (Cav) of Ritlecitinib | 28.42 ng/mL | Geometric Coefficient of Variation 51 |
| RITLECITINIB 200 MG CAPSULE | Average Plasma Concentration From Time 0 to 24 Hours (Cav) of Ritlecitinib | 144.9 ng/mL | Geometric Coefficient of Variation 42 |
Secondary
Last Quantifiable Plasma Concentration (Clast) of Ritlecitinib
Clast is last quantifiable plasma concentration. Clast for ritlecitinib was observed directly from data.
Time frame: 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with at least 1 concentration measurement of study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Last Quantifiable Plasma Concentration (Clast) of Ritlecitinib | 4.812 ng/mL | Geometric Coefficient of Variation 87 |
| RITLECITINIB 200 MG CAPSULE | Last Quantifiable Plasma Concentration (Clast) of Ritlecitinib | 4.036 ng/mL | Geometric Coefficient of Variation 666 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ritlecitinib
Cmax is maximum observed plasma concentration. Cmax for ritlecitinib was observed directly from data.
Time frame: 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with at least 1 concentration measurement of study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Maximum Observed Plasma Concentration (Cmax) of Ritlecitinib | 297.1 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 51 |
| RITLECITINIB 200 MG CAPSULE | Maximum Observed Plasma Concentration (Cmax) of Ritlecitinib | 1275 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 20 |
Secondary
Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs)
An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness to study treatment was assessed by the investigator. A serious adverse event (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 were events between first dose of study treatment and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days)
Population: The analysis population included all participants who took at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with all-causality TEAEs | 3 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with all-causality SAEs | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with treatment-related TEAEs | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with treatment-related SAEs | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with treatment-related SAEs | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with all-causality TEAEs | 2 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with treatment-related TEAEs | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With All-Causality and Treatment-Related Treatment-Emergent Adverse Events (TEAEs) | Number of Participants with all-causality SAEs | 0 Participants |
Secondary
Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality
Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocyte, platelet, neutrophils, eosinophils, monocytes, basophils, lymphocytes, etc), chemistry (glucose, calcium, sodium, potassium, chloride, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, etc), and urinalysis (glucose, protein, hemoglobin, ketones, nitrite, leukocytes, urine bacteria, etc). Baseline = the pre-dose measurement on Day -1. Laboratory abnormalities meeting pre-defined criteria are reported for this outcome measure. Only those categories in which at least 1 participant had data were reported. ULN=upper limit of normal. LPF=low power field.
Time frame: From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days)
Population: The analysis population included all participants who took at least 1 dose of study treatment and with at least one observation of the given laboratory test while on study treatment or during lag time.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Monocytes/Leukocytes (%) >1.2*ULN | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Urine Nitrite >=1 | 1 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Urine Bacteria (/LPF) >20 | 1 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Monocytes/Leukocytes (%) >1.2*ULN | 2 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Urine Nitrite >=1 | 1 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Laboratory Abnormalities Without Regard to Baseline Abnormality | Urine Bacteria (/LPF) >20 | 0 Participants |
Secondary
Number of Participants With Pre-defined Criteria for Vital Signs
Pre-defined criteria included: 1) Diastolic blood pressure (DBP), a) supine DBP: less than (\<) 50 mmHg, b) supine DBP: change of \>= 20mmHg increase, c) supine DBP: change of \>= 20mmHg decrease; 2) Systolic blood pressure (SBP), a) supine SBP: \<90 mmHg, b) supine SBP: change of \>=30mmHg increase, c) supine SBP: change of \>=30mmHg decrease; 3) Supine pulse rate, a) \<40 bpm, b) \>120 bpm. mmHg=millimeters of mercury, bpm=beats per minute.
Time frame: From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days)
Population: The analysis population included all participants who took at least 1 dose of study treatment and who were evaluated against criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine DBP <50 mmHg | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine DBP change >= 20mmHg increase | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine DBP change >= 20mmHg decrease | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine SBP <90 mmHg | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine SBP change >=30mmHg increase | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine SBP change >=30mmHg decrease | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine pulse rate <40 bpm | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine pulse rate >120 bpm | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine pulse rate >120 bpm | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine DBP <50 mmHg | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine SBP change >=30mmHg increase | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine DBP change >= 20mmHg increase | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine pulse rate <40 bpm | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine DBP change >= 20mmHg decrease | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine SBP change >=30mmHg decrease | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Pre-defined Criteria for Vital Signs | Supine SBP <90 mmHg | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events by Severity
An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness to study treatment was assessed by the investigator. Treatment-emergent are events between first dose of study treatment and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs are 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: From the first dose of study treatment up to 35 days after the last dose of study treatment (up to 35 days)
Population: The analysis population included all participants who took at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Mild (all causalities) | 3 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Moderate (all causalities) | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Severe (all causalities) | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Mild (treatment-related) | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Moderate (treatment-related) | 0 Participants |
| RITLECITINIB 50 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Severe (treatment-related) | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Moderate (treatment-related) | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Mild (all causalities) | 2 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Mild (treatment-related) | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Moderate (all causalities) | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Severe (treatment-related) | 0 Participants |
| RITLECITINIB 200 MG CAPSULE | Number of Participants With Treatment-Emergent Adverse Events by Severity | Severe (all causalities) | 0 Participants |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ritlecitinib
Tmax is time for Cmax. Tmax for ritlecitinib was observed directly from data as time of first occurrence.
Time frame: 0 (pre-dose), 1, 2, 4, 8, 24, 48 hours post-dose
Population: The analysis population included all participants who enrolled and treated with at least 1 concentration measurement of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RITLECITINIB 50 MG CAPSULE | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ritlecitinib | 1.00 hour (hr) |
| RITLECITINIB 200 MG CAPSULE | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ritlecitinib | 1.00 hour (hr) |