Healthy
Conditions
Brief summary
This is a Phase 1, open label, fixed sequence study of the effect of multiple dose PF-06650833 on single dose OC PK in healthy female subjects.
Interventions
DRUGPF-06650833
400 mg by mouth (PO) Once daily (QD) for 11 days
Single dose of Oral tablet containing 30 ug EE and 150 ug of LN
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study: 1. Healthy female subjects 2. Female subjects of non childbearing potential must meet at least 1 of the following criteria: 1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state; 2. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 3. Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential and will be eligible with adequate contraceptive usage. 3. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb).
Exclusion criteria
Subjects with any of the following characteristics/conditions will not be included in the study: 1. 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). 2. History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine). 3. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). 4. Any current evidence of untreated active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB). 5. History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive testing 6. Benign ethnic (cyclic) neutropenia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Ethinyl Estradiol | Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2 | AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. AUClast for EE was determined using linear/Log trapezoidal method. |
| Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration for Levonorgestrel | Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2 | AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. AUClast for LN was determined using linear/Log trapezoidal method. |
| Maximum Plasma Concentration (Cmax) for Ethinyl Estradiol | Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2 | Cmax was defined as maximum plasma concentration. Cmax for EE was observed directly from data. |
| Maximum Plasma Concentration for Levonorgestrel | Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2 | Cmas was defined as maximum plasma concentration. Cmax for LN was observed directly from data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Treatment-Related Adverse Events | From the first dose up to 35 days after the last dose of study intervention | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. Treatment-emergent are events between first dose of study intervention 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 up to 35 days after the last dose of study intervention | An AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. 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. Only those categories in which at least 1 participant had data were reported. |
| Number of Participants With Categorical Vital Signs Data of Potential Clinical Concern | Day 1 for Period 1 and Day 1, Day 10, Day 12 for Period 2 | Systolic blood pressure (BP), diastolic BP and supine pulse rate measurements meeting the criteria of potential clinical concern were summarized by treatment using categories as defined: Systolic BP min. \<90 mmHg; Systolic BP max. decrease ≥30 or max. increase ≥30; Diastolic BP min. \<50 mmHg; Diastolic BP max. decrease ≥20 or max. increase ≥20; Supine pulse rate min. \<40 bpm or max. \>120 bpm. |
| Number of Participants With Laboratory Abnormalities of Potential Clinical Concern | Day 10, Day 12 for Period 2 | Hematology (hemoglobin, hematocrit, erythrocytes \[Ery.\], Ery.mean corpuscular volume, Ery.mean corpuscular hemoglobin, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes); clinical chemistry (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, bicarbonate, glucose, creatine kinase); and urinalysis (pH, glucose, ketones, protein, hemoglobin, urobilinogen, bilirubin, nitrite, leukocyte esterase, Ery., leukocytes, epithelial cells, casts and bacteria) tests were assessed. Only those categories, in which at least 1 participant had data were reported. |
Countries
United States
Participant flow
Recruitment details
Participants were screened 28 days prior to the first dose of study intervention in Period 1 and reported to the clinical research unit the day prior to Day 1 dosing in Period 1.
Pre-assignment details
The study consisted of 2 periods in a single fixed sequence. Period 1 was immediately followed by Period 2 with no washout. A total of 10 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| OC Then PF-06650833+ OC Participants received a single oral dose of OC, containing EE 30 mcg and LN 150 mcg on Day 1 Period 1. After completion of Period 1, participants orally received PF-06650833 400 mg QD on Days 1-11 of Period 2 and a single oral dose of OC, containing of EE 30 mcg and LN 150 mcg on Day 10 Period 2. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | OC Then PF-06650833+ OC |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 10 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 2 / 10 | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Ethinyl Estradiol
AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. AUClast for EE was determined using linear/Log trapezoidal method.
Time frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2
Population: The PK parameter analysis population was defined as all participants that received at least 1 dose of study intervention and had at least 1 of the PK parameters of primary interest reported in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Contraceptive | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Ethinyl Estradiol | 812.3 picogram*hour per milliliter (pg*hr/mL) | Geometric Coefficient of Variation 25 |
| Period 2: PF-06650833 + Oral Contraceptive | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Ethinyl Estradiol | 823.9 picogram*hour per milliliter (pg*hr/mL) | Geometric Coefficient of Variation 26 |
Comparison: OC alone as the Reference and co-administration of PF-06650833 and OC as the Test. Natural log transformed AUClast was analyzed using a mixed effects model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% confidence intervals (CIs) were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [93.01, 110.61]
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration for Levonorgestrel
AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. AUClast for LN was determined using linear/Log trapezoidal method.
Time frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2
Population: The PK parameter analysis population was defined as all participants that received at least 1 dose of study intervention and had at least 1 of the PK parameters of primary interest reported in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Contraceptive | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration for Levonorgestrel | 31510 pg*hr/mL | Geometric Coefficient of Variation 39 |
| Period 2: PF-06650833 + Oral Contraceptive | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration for Levonorgestrel | 34190 pg*hr/mL | Geometric Coefficient of Variation 41 |
Comparison: OC alone as the Reference and co-administration of PF-06650833 and OC as the Test. Natural log transformed AUClast was analyzed using a mixed effects model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [98.85, 119.11]
Primary
Maximum Plasma Concentration (Cmax) for Ethinyl Estradiol
Cmax was defined as maximum plasma concentration. Cmax for EE was observed directly from data.
Time frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2
Population: The PK parameter analysis population was defined as all participants that received at least 1 dose of study intervention and had at least 1 of the PK parameters of primary interest reported in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Contraceptive | Maximum Plasma Concentration (Cmax) for Ethinyl Estradiol | 84.00 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 38 |
| Period 2: PF-06650833 + Oral Contraceptive | Maximum Plasma Concentration (Cmax) for Ethinyl Estradiol | 79.86 picogram per milliliter (pg/mL) | Geometric Coefficient of Variation 26 |
Comparison: OC alone as the Reference and co-administration of PF-06650833 and OC as the Test. Natural log transformed Cmax was analyzed using a mixed effects model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% confidence intervals (CIs) were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [84.44, 107.04]
Primary
Maximum Plasma Concentration for Levonorgestrel
Cmas was defined as maximum plasma concentration. Cmax for LN was observed directly from data.
Time frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36 and 48 hours post OC dose in Periods 1 and 2
Population: The PK parameter analysis population was defined as all participants that received at least 1 dose of study intervention and had at least 1 of the PK parameters of primary interest reported in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Contraceptive | Maximum Plasma Concentration for Levonorgestrel | 3468 pg/mL | Geometric Coefficient of Variation 56 |
| Period 2: PF-06650833 + Oral Contraceptive | Maximum Plasma Concentration for Levonorgestrel | 4092 pg/mL | Geometric Coefficient of Variation 53 |
Comparison: OC alone as the Reference and co-administration of PF-06650833 and OC as the Test. Natural log transformed Cmax was analyzed using a mixed effects model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs were obtained from the model and were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [101.82, 136.73]
Secondary
Number of Participants With Categorical Vital Signs Data of Potential Clinical Concern
Systolic blood pressure (BP), diastolic BP and supine pulse rate measurements meeting the criteria of potential clinical concern were summarized by treatment using categories as defined: Systolic BP min. \<90 mmHg; Systolic BP max. decrease ≥30 or max. increase ≥30; Diastolic BP min. \<50 mmHg; Diastolic BP max. decrease ≥20 or max. increase ≥20; Supine pulse rate min. \<40 bpm or max. \>120 bpm.
Time frame: Day 1 for Period 1 and Day 1, Day 10, Day 12 for Period 2
Population: The safety analysis set was defined as all participants enrolled to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Oral Contraceptive | Number of Participants With Categorical Vital Signs Data of Potential Clinical Concern | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Categorical Vital Signs Data of Potential Clinical Concern | 0 Participants |
Secondary
Number of Participants With Laboratory Abnormalities of Potential Clinical Concern
Hematology (hemoglobin, hematocrit, erythrocytes \[Ery.\], Ery.mean corpuscular volume, Ery.mean corpuscular hemoglobin, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes); clinical chemistry (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, bicarbonate, glucose, creatine kinase); and urinalysis (pH, glucose, ketones, protein, hemoglobin, urobilinogen, bilirubin, nitrite, leukocyte esterase, Ery., leukocytes, epithelial cells, casts and bacteria) tests were assessed. Only those categories, in which at least 1 participant had data were reported.
Time frame: Day 10, Day 12 for Period 2
Population: The safety analysis set was defined as all participants enrolled to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Oral Contraceptive | Number of Participants With Laboratory Abnormalities of Potential Clinical Concern | Leukocyte Esterase ≥1 | 2 Participants |
| Period 1: Oral Contraceptive | Number of Participants With Laboratory Abnormalities of Potential Clinical Concern | Urine Hemoglobin ≥1 | 5 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events by Severity
An AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. 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. Only those categories in which at least 1 participant had data were reported.
Time frame: From the first dose up to 35 days after the last dose of study intervention
Population: The safety analysis set was defined as all participants enrolled to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Nausea (mild) | 0 Participants |
| Period 1: Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Toothache (mild) | 0 Participants |
| Period 1: Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Headache (mild) | 0 Participants |
| Period 1: Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Pruritus (mild) | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Pruritus (mild) | 2 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Nausea (mild) | 1 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Headache (mild) | 1 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Toothache (mild) | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Pruritus (mild) | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Toothache (mild) | 1 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Headache (mild) | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Adverse Events by Severity | Nausea (mild) | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Treatment-Related Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. Treatment-emergent are events between first dose of study intervention 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 up to 35 days after the last dose of study intervention
Population: The safety analysis set was defined as all participants enrolled to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Oral Contraceptive | Number of Participants With Treatment Emergent Treatment-Related Adverse Events | Treatment-related AEs | 0 Participants |
| Period 1: Oral Contraceptive | Number of Participants With Treatment Emergent Treatment-Related Adverse Events | Treatment-related SAEs | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Treatment-Related Adverse Events | Treatment-related AEs | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Treatment-Related Adverse Events | Treatment-related SAEs | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Treatment-Related Adverse Events | Treatment-related AEs | 0 Participants |
| Period 2: PF-06650833 + Oral Contraceptive | Number of Participants With Treatment Emergent Treatment-Related Adverse Events | Treatment-related SAEs | 0 Participants |