Adult, Healthy Volunteers, Pharmacokinetics
Conditions
Keywords
Adult, Pharmacokinetic
Brief summary
The purpose of this study is to compare if two forms of study medicine, Ritlecitinib, get processed differently in healthy adults. This study is seeking participants who are: * aged 18 or older; * male or female who are healthy as determined by medical assessment ; * Body-mass Index (BMI) of 16 to 32, and a total body weight \> 45kg. The study will take up to 2.5 months, including the screening period. There will be 5 periods in total for this study. Participants will have to stay at the study clinic for at least 11 days. Participants will take Riltecitinib either as sprinkled in Soft Food or as Intact Blend-In Capsule. On day 1 of each period, participants will take Riltecitinib and have blood samples taken both before and afterwards. Participants will also answer questions for taste assessment purpose. A follow-up phone call will be made at 28 to 35 days after the last study period.
Detailed description
Ritlecitinib is a covalent and irreversible inhibitor of JAK3 with high selectivity over the other JAK isoforms (JAK1, JAK2, and TYK2). Ritlecitinib also inhibits irreversibly the tyrosine kinase expressed in TEC family kinases with selectivity over the broader human kinome. Treatment with ritlecitinib is expected to inhibit the inflammatory pathways mediated by IL 7, IL 15 and IL 21, all implicated in UC, CD, AA, RA, and vitiligo. Moreover, due to lack of activity against the other JAK isoforms, ritlecitinib is expected to spare immunoregulatory cytokines such as IL 10, IL 27 and IL 35, which are critical to the maintenance of immunosuppressive functions and immune homeostasis. The objective of this study is to estimate the impact of administration methods on the bioavailability of the pediatric ritlecitinib intact BiC formulation. The study will be conducted as a Phase 1, open-label, single dose, randomized, 4-crossover periods and 1-fixed period design in a single cohort of approximately 12 healthy male or female participants at a single center. Participants will be randomized into 1 of 4 sequences of treatment. Blood samples will be collected for PK analysis. A taste assessment will be also conducted. Participants will participate in the study for up to approximately 2.5 months, with the inclusion of the screening and follow-up period. On Day 1 of each period, participants will receive a single dose of IP. Administration of IP will be via dosing using intact BiCs with water or by emptying the capsule contents on soft food as per dosing instructions. Participants will be confined in the CRU for a total of at least 11 days and discharged at the discretion of the investigator. A follow-up phone call will be made at least 28 calendar days and up to 35 calendar days after the last administration of the study intervention to capture any potential AE and confirm appropriate contraceptive usage. Tolerability and safety will be assessed for all treatments by monitoring AEs.
Interventions
DRUGRitlecitinib
ritlecitinib 1 x 30 mg intact BiC (Treatment Arms A, E) ritlecitinib 1 x 30 mg intact BiC sprinkled on soft foods (Treatment Arms B, C, D)
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: 1. Aged 18 or older. 2. Male or female who are healthy as determined by medical assessment. 3. Body-mass Index (BMI) of 16 to 32, and a total body weight \> 45kg. Key
Exclusion criteria
1. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). 2. 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). 3. Known immunodeficiency disorder, including positive serology for HIV, or a first degree relative with a hereditary immunodeficiency, or infections (acute or chronic).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours post-dose on Day 1 of each period. Each treatment period lasted 24 hours. Dosing of each period was separated by at least a 48-hour washout interval. | AUCinf was defined as area under the plasma-concentration time profile from time zero extrapolated to infinite time. AUCinf for ritlecitinib was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. |
| Maximum Observed Concentration (Cmax) of Ritlecitinib | 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours post-dose on Day 1 of each period. Each treatment period lasted 24 hours. Dosing of each period was separated by at least a 48-hour washout interval. | Cmax was defined as maximum observed plasma concentration. Cmax for ritlecitinib was observed directly from data. |
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 28-35 days after last dose of study treatment (ie, up to 45 days) | An adverse event (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 events were events between first dose of study treatment and up to approximately 35 days that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Laboratory Abnormalities | From the first dose of study treatment up to 28-35 days after last dose of study treatment (ie, up to 45 days) | Hematology included hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet and white blood cell count, total neutrophils, eosinophils, etc. Chemistry included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein, etc. Urinalysis included pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy. Laboratory abnormalities were judged by the investigator. Laboratory abnormalities reported for at least 1 participant in the whole study are presented here. |
Countries
Belgium
Participant flow
Pre-assignment details
This is a phase 1, open-label, single dose, randomized 4-crossover periods (periods 1-4) and 1-fixed period (period 5) design study. A total of 12 participants were randomized and assigned to receive the study intervention.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who were enrolled in the study. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 5 | Adverse Event | 0 | 0 | 0 | 1 |
| Period 5 | Not completing the meal | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 40.4 Years STANDARD_DEVIATION 12.99 |
| Age, Customized 26-35 years | 6 Participants |
| Age, Customized 36-45 years | 3 Participants |
| Age, Customized >45 years | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 10 |
| other Total, other adverse events | 5 / 12 | 2 / 12 | 4 / 12 | 4 / 12 | 2 / 10 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 10 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib
AUCinf was defined as area under the plasma-concentration time profile from time zero extrapolated to infinite time. AUCinf for ritlecitinib was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours post-dose on Day 1 of each period. Each treatment period lasted 24 hours. Dosing of each period was separated by at least a 48-hour washout interval.
Population: All participants randomized and treated who had at least 1 of the pharmacokinetic (PK) parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ritlecitinib 30 mg Capsule (Fasted) | Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib | 389.1 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 32 |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib | 398.3 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 31 |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib | 378.0 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 27 |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib | 387.8 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 27 |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Ritlecitinib | 387.0 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 23 |
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Mixed with Strawberry Jam (Fasted)90% CI: [95.81, 109.35]
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Mixed with Yoghurt (Fasted)90% CI: [90.94, 103.79]
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Mixed with Applesauce (Fasted)90% CI: [93.28, 106.46]
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Given with High Fat Meal90% CI: [97.3, 112.96]
Primary
Maximum Observed Concentration (Cmax) of Ritlecitinib
Cmax was defined as maximum observed plasma concentration. Cmax for ritlecitinib was observed directly from data.
Time frame: 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours post-dose on Day 1 of each period. Each treatment period lasted 24 hours. Dosing of each period was separated by at least a 48-hour washout interval.
Population: All participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ritlecitinib 30 mg Capsule (Fasted) | Maximum Observed Concentration (Cmax) of Ritlecitinib | 244.3 ng/mL | Geometric Coefficient of Variation 35 |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Maximum Observed Concentration (Cmax) of Ritlecitinib | 236.1 ng/mL | Geometric Coefficient of Variation 28 |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Maximum Observed Concentration (Cmax) of Ritlecitinib | 206.6 ng/mL | Geometric Coefficient of Variation 24 |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Maximum Observed Concentration (Cmax) of Ritlecitinib | 229.4 ng/mL | Geometric Coefficient of Variation 25 |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Maximum Observed Concentration (Cmax) of Ritlecitinib | 108.0 ng/mL | Geometric Coefficient of Variation 28 |
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Mixed with Strawberry Jam (Fasted)90% CI: [83.66, 111.62]
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Mixed with Yoghurt (Fasted)90% CI: [73.23, 97.7]
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Mixed with Applesauce (Fasted)90% CI: [81.3, 108.48]
Comparison: Reference: Ritlecitinib 30 mg Capsule (Fasted) Test: Ritlecitinib 30 mg Capsule Given with High Fat Meal90% CI: [37.5, 51.23]
Secondary
Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs)
An adverse event (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 events were events between first dose of study treatment and up to approximately 35 days that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the first dose of study treatment up to 28-35 days after last dose of study treatment (ie, up to 45 days)
Population: All participants who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ritlecitinib 30 mg Capsule (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality TEAEs | 5 Participants |
| Ritlecitinib 30 mg Capsule (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related TEAEs | 2 Participants |
| Ritlecitinib 30 mg Capsule (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality TEAEs | 2 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related TEAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related TEAEs | 1 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality TEAEs | 4 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality TEAEs | 4 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related TEAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with treatment-related TEAEs | 1 Participants |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality SAEs | 0 Participants |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Number of Participants With All-Causality and Treatment-Related Treatment Emergent Adverse Events (TEAEs) | Number of participants with all-causality TEAEs | 2 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
Hematology included hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet and white blood cell count, total neutrophils, eosinophils, etc. Chemistry included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein, etc. Urinalysis included pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin and microscopy. Laboratory abnormalities were judged by the investigator. Laboratory abnormalities reported for at least 1 participant in the whole study are presented here.
Time frame: From the first dose of study treatment up to 28-35 days after last dose of study treatment (ie, up to 45 days)
Population: All participants who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ritlecitinib 30 mg Capsule (Fasted) | Number of Participants With Laboratory Abnormalities | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Strawberry Jam (Fasted) | Number of Participants With Laboratory Abnormalities | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Yoghurt (Fasted) | Number of Participants With Laboratory Abnormalities | 0 Participants |
| Ritlecitinib 30 mg Capsule Mixed With Applesauce (Fasted) | Number of Participants With Laboratory Abnormalities | 0 Participants |
| Ritlecitinib 30 mg Capsule Given With High Fat Meal | Number of Participants With Laboratory Abnormalities | 0 Participants |