Healthy
Conditions
Brief summary
The purpose of this study is to understand if ARV-471 affects how a medicine called, dabigatran etexilate, gets absorbed or processed into the body in healthy adults. All participants in this study will receive one dose of dabigatran etexilate alone by mouth in Period 1. In Period 2, everyone will receive one dose of dabigatran etexilate by mouth approximately 90 minutes after receiving one dose of ARV-471 by mouth. The levels of dabigatran in Period 1 will be compared to the levels of dabigatran in Period 2. This will help us to determine if and how ARV-471 affects dabigatran gets absorbed into the body differently in healthy adults. All participants will stay at the study clinic for approximately 8 days and 7 nights.
Interventions
DRUGARV-471
Experimental
DRUGDabigatran etexilate
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 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and/or female participants of non-childbearing potential who are overtly healthy as determined by medical evaluation and are between the ages of 18 and 70 years, inclusive at the time of signing the informed consent document (ICD). * Body mass index (BMI) of 17.5 to 30.5 kg/m\^2; and a total body weight \>50 kg (110 lb). * Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures.
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, female participants of childbearing potential. Male participants with partners currently pregnant; male participants of childbearing potential who 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. * Active bleeding or risk of bleeding including prior personal or familiar history of abnormal bleeding, hereditary or acquired coagulation or platelet disorder or abnormal coagulation test (PT/INR or PTT/aPTT greater than upper limit of normal) result at screening. Any significant risk factor for major bleeding and this may include but not limited to current or recent GI ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. * 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. * Use of prescription or nonprescription medications, including vitamins, dietary and herbal supplements, grapefruit/grapefruit containing products, and Seville orange/Seville orange containing products within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention or a longer washout is required for those that fall into the categories below: * Moderate or strong cytochrome P450 (CYP) 3A / P-glycoprotein (P-gp) inducers which are prohibited within 14 days plus 5 half-lives prior to the first dose of study intervention. * Moderate or strong CYP3A/P-gp inhibitors which are prohibited within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention. * Standard 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. * History of sensitivity to heparin or heparin-induced thrombocytopenia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran When Dabigatran Etexilate is Administered Alone Versus When Dabigatran Etexilate is Administered With ARV-471 | Period 1 and 2: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose on Day 1 | Cmax was defined as maximum observed plasma concentration. Cmax for total dabigatran was observed directly from data. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Total Dabigatran When Dabigatran Etexilate is Administered Alone vs Dabigatran Etexilate is Administered With ARV-471 | Period 1 and 2: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose on Day 1 | AUCinf was defined as area under the concentration-time curve from time 0 extrapolated to infinity. AUCinf 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; AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | From the first dose (Day 1) up to 35 days after the last dose (Day 5) of study intervention (up to 40 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 Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Baseline (Period 1 Day -1) up to Period 2 Day 3 (8 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 Clinically Significant Vital Signs | Baseline (Period 1 Day 1) up to Period 2 Day 3 (7 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. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline (Period 1 Day 1) up to Period 2 Day 3 (7 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. |
Countries
Belgium
Participant flow
Pre-assignment details
The study consisted of 2 Periods in a single fixed sequence. Twenty-four participants were screened and passed. All 24 participants were assigned to the study treatment and all completed the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received a single oral dose of dabigatran etexilate (as mesylate) 75 milligram (mg) on Period 1 Day 1. A minimum washout period of 4 days was required after dabigatran etexilate (as mesylate) 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 dabigatran etexilate (as mesylate) 75 mg on Period 2 Day 1. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 44.7 Years STANDARD_DEVIATION 15.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized White | 19 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 2 / 24 | 2 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Total Dabigatran When Dabigatran Etexilate is Administered Alone vs Dabigatran Etexilate is Administered With ARV-471
AUCinf was defined as area under the concentration-time curve from time 0 extrapolated to infinity. AUCinf 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; AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration.
Time frame: Period 1 and 2: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose on Day 1
Population: Analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Dabigatran 75 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Total Dabigatran When Dabigatran Etexilate is Administered Alone vs Dabigatran Etexilate is Administered With ARV-471 | 522.3 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 42 |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Total Dabigatran When Dabigatran Etexilate is Administered Alone vs Dabigatran Etexilate is Administered With ARV-471 | 949.6 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 63 |
Comparison: Dabigatran etexilate administered alone as Reference, ARV-471 coadministered with dabigatran etexilate as 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: [177.32, 220.66]
Primary
Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran When Dabigatran Etexilate is Administered Alone Versus When Dabigatran Etexilate is Administered With ARV-471
Cmax was defined as maximum observed plasma concentration. Cmax for total dabigatran was observed directly from data.
Time frame: Period 1 and 2: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose on Day 1
Population: Analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of primary interest were reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Dabigatran 75 mg | Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran When Dabigatran Etexilate is Administered Alone Versus When Dabigatran Etexilate is Administered With ARV-471 | 49.80 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 94 |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran When Dabigatran Etexilate is Administered Alone Versus When Dabigatran Etexilate is Administered With ARV-471 | 95.72 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 66 |
Comparison: Dabigatran etexilate administered alone as Reference, ARV-471 coadministered with dabigatran etexilate as 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: [166.56, 221.79]
Secondary
Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs)
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 5) of study intervention (up to 40 days)
Population: The analysis population included all participants who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Dabigatran 75 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with treatment related SAEs | 0 Participants |
| Period 1: Dabigatran 75 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with all-causality SAEs | 0 Participants |
| Period 1: Dabigatran 75 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with treatment related TEAEs | 3 Participants |
| Period 1: Dabigatran 75 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with all-causality TEAEs | 6 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with treatment related TEAEs | 1 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with all-causality TEAEs | 6 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with treatment related SAEs | 0 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With All-Causality and Treatment-Related Treatment-emergent Adverse Events (TEAEs) | Participants with all-causality SAEs | 0 Participants |
Secondary
Number of Participants With Clinically Significant 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 3 (7 days)
Population: The analysis population included all participants who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Dabigatran 75 mg | Number of Participants With Clinically Significant Vital Signs | 0 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With Clinically Significant 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 3 (7 days)
Population: The analysis population included all participants who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Dabigatran 75 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | 1 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | 2 Participants |
Secondary
Number of Participants With Laboratory Test 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 3 (8 days)
Population: The analysis population included all participants who took at least 1 dose of study intervention and with at least 1 observation of the given laboratory test while on study treatment or during lag time.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Dabigatran 75 mg | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Monocytes/Leukocytes (%) >1.2 × ULN | 2 Participants |
| Period 1: Dabigatran 75 mg | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Leukocyte Esterase >=1 | 0 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Monocytes/Leukocytes (%) >1.2 × ULN | 2 Participants |
| Period 2: Dabigatran 75 mg + ARV-471 200 mg | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Leukocyte Esterase >=1 | 1 Participants |