Healthy
Conditions
Brief summary
The purpose of this study is to understand if ARV-471 affects how a BCRP substrate (rosuvastatin) gets into the body in healthy adults. All participants in this study will receive one dose of rosuvastatin alone by mouth in Period 1. In Period 2, everyone will receive one dose of ARV-471 by mouth 90 min before one dose of rosuvastatin by mouth. The levels of rosuvastatin in Period 1 will be compared to the levels of rosuvastatin in Period 2 to determine if ARV-471 affects how rosuvastatin gets into the body differently in healthy adults. All participants will stay at the study clinic for 10 days and 9 nights.
Interventions
DRUGARV-471
Experimental
DRUGRosuvastatin
Probe substrate
Sponsors
Arvinas Estrogen Receptor, Inc.
Pfizer
Study design
Allocation
NA
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Male and/or female participants of non-childbearing potential must be 18 to 65 years of age, inclusive at the time of signing informed consent document. * Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical exam, laboratory tests, vital sign and standard 12-lead ECGs. * BMI of 17.5 to 32 kg/m2; and a total body weight ≥45 kg.
Exclusion criteria
* 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). * Pregnant female participants; breastfeeding female participants; Male participants with partners currently pregnant; fertile male participants who have partners of childbearing potential and are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for 90 days after the last dose of investigational product. * Participants with known history of hypersensitivity to statin medication, sensitivity to ARV-471 or rosuvastatin or any of the formulation components of ARV-471 or rosuvastatin. * Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality or other conditions or situations related to COVID-19 pandemic that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. * Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). * A positive urine drug test. * History of use of tobacco or nicotine-containing products in excess of the equivalent of 5 cigarettes/day or 2 chews of tobacco/day. * History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. * Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Rosuvastatin | 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 hours post dose on Day 1 in Periods 1 and 2 | Cmax was defined as maximum plasma concentration. Cmax of rosuvastatin was observed directly from data. |
| Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin | 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 hours post dose on Day 1 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 of rosuvastatin was determined using Linear/Log trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose (Day 1) up to 35 days after the last dose (Day 6) of study intervention (up to 41 days) | An AE is any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship with the study intervention. SAE is defined as one of the following: is fatal or life threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs. |
| Number of Participants With Clinical Laboratory Abnormalities (Without Regard to Baseline Abnormality) | Baseline (Period 1 Day -1) up to Period 2 Day 4 (10 days) | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid, cystatinC); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (dipstick \[decimal logarithm of reciprocal of hydrogen ion activity {pH} of urine, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, bilirubin\], microscopy. Abnormality was determined at the investigator's discretion. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline (Period 1 Day 1) up to Period 2 Day 4 (9 days) | ECG abnormalities criteria include a) a postdose QTc corrected using Fridericia's formula (QTcF) increased by \>60 millisecond (ms) from the baseline and the absolute QTcF value \>450 ms; or b) an absolute QTcF value \>500 ms for any scheduled ECG. |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Baseline (Period 1 Day 1) up to Period 2 Day 4 (9 days) | Vital signs (blood pressure and pulse rate) were obtained with participant following at least a 5-minute rest in a supine position. Clinical significance of vital signs was determined at the investigator's discretion. |
Countries
United States
Participant flow
Pre-assignment details
The study consisted of 2 Periods in a single fixed sequence. A total of 12 participants were enrolled in the study and received study intervention.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received a single oral dose of rosuvastatin 10 milligram (mg) on Period 1 Day 1. A minimum washout period of 5 days was required after rosuvastatin administration in Period 1. After completion of Period 1, participants received a single oral dose of ARV-471 (PF-07850327) 200 mg followed by a single oral dose of rosuvastatin 10 mg on Period 2 Day 1. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 50.5 Years STANDARD_DEVIATION 9.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 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 | 3 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 1 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin
AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. AUClast of rosuvastatin was determined using Linear/Log trapezoidal method.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 hours post dose on Day 1 in Periods 1 and 2
Population: All participants enrolled and who took at least 1 dose of study intervention and had at least 1 PK parameter of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Rosuvastatin | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin | 31.40 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 40 |
| Period 2: ARV-471 + Rosuvastatin | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin | 34.71 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 40 |
Comparison: Rosuvastatin administered alone as the Reference and ARV-471 coadministered with rosuvastatin as the Test. Natural log transformed AUClast was analyzed using a mixed effect model with treatment as fixed effects 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: [103.53, 118.06]
Primary
Maximum Plasma Concentration (Cmax) of Rosuvastatin
Cmax was defined as maximum plasma concentration. Cmax of rosuvastatin was observed directly from data.
Time frame: 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 hours post dose on Day 1 in Periods 1 and 2
Population: All participants enrolled and who took at least 1 dose of study intervention and had at least 1 PK parameter of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Rosuvastatin | Maximum Plasma Concentration (Cmax) of Rosuvastatin | 2.178 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 53 |
| Period 2: ARV-471 + Rosuvastatin | Maximum Plasma Concentration (Cmax) of Rosuvastatin | 2.625 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 48 |
Comparison: Rosuvastatin administered alone as the Reference and ARV-471 coadministered with rosuvastatin as the Test. Natural log transformed Cmax was analyzed using a mixed effect model with treatment as fixed effects 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: [104.77, 138.59]
Secondary
Number of Participants With Clinical Laboratory Abnormalities (Without Regard to Baseline Abnormality)
Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid, cystatinC); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (dipstick \[decimal logarithm of reciprocal of hydrogen ion activity {pH} of urine, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, bilirubin\], microscopy. Abnormality was determined at the investigator's discretion.
Time frame: Baseline (Period 1 Day -1) up to Period 2 Day 4 (10 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Rosuvastatin | Number of Participants With Clinical Laboratory Abnormalities (Without Regard to Baseline Abnormality) | 2 Participants |
| Period 2: ARV-471 + Rosuvastatin | Number of Participants With Clinical Laboratory Abnormalities (Without Regard to Baseline Abnormality) | 4 Participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs (blood pressure and pulse rate) were obtained with participant following at least a 5-minute rest in a supine position. Clinical significance of vital signs was determined at the investigator's discretion.
Time frame: Baseline (Period 1 Day 1) up to Period 2 Day 4 (9 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Rosuvastatin | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
| Period 2: ARV-471 + Rosuvastatin | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
Secondary
Number of Participants With Electrocardiogram (ECG) Abnormalities
ECG abnormalities criteria include a) a postdose QTc corrected using Fridericia's formula (QTcF) increased by \>60 millisecond (ms) from the baseline and the absolute QTcF value \>450 ms; or b) an absolute QTcF value \>500 ms for any scheduled ECG.
Time frame: Baseline (Period 1 Day 1) up to Period 2 Day 4 (9 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Rosuvastatin | Number of Participants With Electrocardiogram (ECG) Abnormalities | 0 Participants |
| Period 2: ARV-471 + Rosuvastatin | Number of Participants With Electrocardiogram (ECG) Abnormalities | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant who received study intervention without regard to possibility of causal relationship with the study intervention. SAE is defined as one of the following: is fatal or life threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; is medically significant; requires inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE is defined as an AE with onset date occurring during the on-treatment period. AEs include all SAEs and non-SAEs.
Time frame: From the first dose (Day 1) up to 35 days after the last dose (Day 6) of study intervention (up to 41 days)
Population: All participants enrolled and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Rosuvastatin | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent AEs | 1 Participants |
| Period 1: Rosuvastatin | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent SAEs | 0 Participants |
| Period 2: ARV-471 + Rosuvastatin | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent AEs | 3 Participants |
| Period 2: ARV-471 + Rosuvastatin | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-emergent SAEs | 0 Participants |