Pharmacokinetics, Healthy Volunteers
Conditions
Keywords
Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Nirmatrelvir, Paxlovid, Rosuvastatin
Brief summary
The purpose of this study is to learn about the effect of the study medicine (called nirmatrelvir/ritonavir) on the pharmacokinetics of the medicine rosuvastatin in healthy volunteers. Pharmacokinetics helps us understand how the drug is changed and eliminated from your body after you take it. This study is seeking participants who: * are male and female participants who are overtly healthy * are 18 years of age or older * have a Body mass Index (BMI) of 16-32 kg/m2 and total body weight \>50 kg (110 lb). All participants in this study will receive nirmatrelvir/ritonavir, a standard treatment for mild-to-moderate COVID-19. All participants will also receive rosuvastatin. Nirmatrelvir/ritonavir will be given by mouth at the study clinic 2 times a day. Rosuvastatin will be given by mouth at the study clinic once (as a single dose). We will compare participant experiences to help us determine the effect of nirmatrelvir/ritonavir on the pharmacokinetics of rosuvastatin. Participants will take part in this study for approximately 11 weeks. During this time, they will have 10 days at the study clinic and 1 follow-up phone call. Blood samples will be collected during participants' time at the study clinic.
Interventions
DRUGRosuvastatin
Single oral dose of rosuvastatin tablets
Twice daily oral doses of nirmatrelvir/ritonavir tablets
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Male and female participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. * BMI of 16-32 kg/m2; 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, lifestyle considerations, and other study procedures.
Exclusion criteria
* Positive test result for SARS-CoV-2 infection on Day -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). * Clinically relevant abnormalities requiring treatment (eg, acute myocardial infarction, unstable ischemic conditions, evidence of ventricular dysfunction, serious tachy or brady arrhythmias) or indicating serious underlying heart disease (eg, prolonged PR interval, cardiomyopathy, heart failure greater than NYHA 1, underlying structural heart disease, Wolff Parkinson-White syndrome). * Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). * History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. * Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention. * Participants who have received a COVID-19 vaccine within 7 days before screening or admission, or who are to be vaccinated with a COVID-19 vaccine at any time during the study confinement period. * A positive urine drug test.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the Concentration-Time Curve From Time Zero (0) Extrapolated to Infinity (AUCinf) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 |
| Maximum Observed Concentration (Cmax) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Half-Life (t1/2) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 | t1/2 was calculated as loge (2) per kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Apparent Clearance (CL/F) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Apparent Volume of Distribution (Vz/F) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
| Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 | — |
| Number of Participants With Laboratory Abnormalities | Day 1 of dosing up to 35 days up to last dose of study intervention (maximum of 45 days) | Laboratory abnormalities criteria: a) Hematology: monocytes \>1.2\* upper limit of normal (ULN); b) Urinalysis: urine hemoglobin were \>=1 and leukocyte esterase were \>=1. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Day 1 of dosing up to 35 days up to last dose of study intervention (maximum of 45 days) | An adverse event (AE) was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. |
| Number of Participants With Clinically Significant Findings in Vital Signs | Days 1 and 3 of each period | Vital signs included blood pressure, pulse rate and temperature. Temperature was measured by orally. Blood pressure was measured with the participant in a supine position after 5 minutes of rest for the participant. Clinically significant findings were determined by the investigator. |
| Time for Cmax (Tmax) of Rosuvastatin in Period 1 and 2 | Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2 | — |
Countries
Belgium
Participant flow
Pre-assignment details
A total of 12 healthy male and/or female participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Rosuvastatin Then Rosuvastatin + Nirmatrelvir/ Ritonavir Period 1: Participants received a single oral dose of rosuvastatin 10 milligram (mg) on Day 1 of Period 1 in the morning (AM dose). Period 1 was followed by Period 2. Period 2: Participants received nirmatrelvir 100 mg and ritonavir 100 mg every 12 hours (BID) for 2 days (Day 1 of Period 2: morning \[AM\] and evening \[PM\]; Day 2 of Period 2: morning \[AM\]; total 3 doses) along with a single oral administration of rosuvastatin 10 mg on Day 2 of Period 2 in the morning (AM dose). Participants were followed-up to a maximum of 35 days from final dose of study intervention. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Rosuvastatin Then Rosuvastatin + Nirmatrelvir/ Ritonavir |
|---|---|
| Age, Continuous | 36.75 Years STANDARD_DEVIATION 11.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 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 | 9 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 10 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 | 5 / 12 | 10 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Time Zero (0) Extrapolated to Infinity (AUCinf) of Rosuvastatin in Period 1 and 2
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: Pharmacokinetic (PK) parameter set 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. Here, Number of Participants analyzed signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Rosuvastatin 10 mg | Area Under the Concentration-Time Curve From Time Zero (0) Extrapolated to Infinity (AUCinf) of Rosuvastatin in Period 1 and 2 | 58.62 Nanogram*hour per milliliter | Geometric Coefficient of Variation 46 |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Area Under the Concentration-Time Curve From Time Zero (0) Extrapolated to Infinity (AUCinf) of Rosuvastatin in Period 1 and 2 | 72.78 Nanogram*hour per milliliter | Geometric Coefficient of Variation 48 |
Comparison: Analysis was performed using mixed effect model with treatment as a fixed effect and participant within sequence as a random effect. Ratio of adjusted geometric means of test to reference was reported; where test treatment is Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg and reference treatment is Rosuvastatin 10 mg. Ratio and associated 90% CIs were reported in percentage.90% CI: [115.89, 148.48]
Primary
Maximum Observed Concentration (Cmax) of Rosuvastatin in Period 1 and 2
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: PK parameter set 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: Rosuvastatin 10 mg | Maximum Observed Concentration (Cmax) of Rosuvastatin in Period 1 and 2 | 5.691 Nanogram per milliliter | Geometric Coefficient of Variation 66 |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Maximum Observed Concentration (Cmax) of Rosuvastatin in Period 1 and 2 | 12.09 Nanogram per milliliter | Geometric Coefficient of Variation 60 |
Comparison: Analysis was performed using mixed effect model with treatment as a fixed effect and participant within sequence as a random effect. Ratio of adjusted geometric means of test to reference was reported; where test treatment is Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg and reference treatment is Rosuvastatin 10 mg. Ratio and associated 90% CIs were reported in percentage.90% CI: [174.31, 258.9]
Secondary
Apparent Clearance (CL/F) of Rosuvastatin in Period 1 and 2
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: PK parameter set 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. Here, Number of Participants analyzed signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Rosuvastatin 10 mg | Apparent Clearance (CL/F) of Rosuvastatin in Period 1 and 2 | 170.6 Liter per hour | Geometric Coefficient of Variation 46 |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Apparent Clearance (CL/F) of Rosuvastatin in Period 1 and 2 | 137.4 Liter per hour | Geometric Coefficient of Variation 48 |
Secondary
Apparent Volume of Distribution (Vz/F) of Rosuvastatin in Period 1 and 2
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: PK parameter set 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. Here, Number of Participants analyzed signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Rosuvastatin 10 mg | Apparent Volume of Distribution (Vz/F) of Rosuvastatin in Period 1 and 2 | 3828 Liter | Geometric Coefficient of Variation 53 |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Apparent Volume of Distribution (Vz/F) of Rosuvastatin in Period 1 and 2 | 4685 Liter | Geometric Coefficient of Variation 59 |
Secondary
Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin in Period 1 and 2
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: PK parameter set 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: Rosuvastatin 10 mg | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin in Period 1 and 2 | 51.27 Nanogram*hour per milliliter | Geometric Coefficient of Variation 61 |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Rosuvastatin in Period 1 and 2 | 71.13 Nanogram*hour per milliliter | Geometric Coefficient of Variation 47 |
Secondary
Number of Participants With Clinically Significant Findings in Vital Signs
Vital signs included blood pressure, pulse rate and temperature. Temperature was measured by orally. Blood pressure was measured with the participant in a supine position after 5 minutes of rest for the participant. Clinically significant findings were determined by the investigator.
Time frame: Days 1 and 3 of each period
Population: Safety analysis set included all participants who took at least 1 dose of study intervention. Participants were analyzed according to the product they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Period 1: Rosuvastatin 10 mg | Number of Participants With Clinically Significant Findings in Vital Signs | Day 1 | 0 Participants |
| Period 1: Rosuvastatin 10 mg | Number of Participants With Clinically Significant Findings in Vital Signs | Day 3 | 0 Participants |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Number of Participants With Clinically Significant Findings in Vital Signs | Day 1 | 0 Participants |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Number of Participants With Clinically Significant Findings in Vital Signs | Day 3 | 0 Participants |
Secondary
Number of Participants With Laboratory Abnormalities
Laboratory abnormalities criteria: a) Hematology: monocytes \>1.2\* upper limit of normal (ULN); b) Urinalysis: urine hemoglobin were \>=1 and leukocyte esterase were \>=1.
Time frame: Day 1 of dosing up to 35 days up to last dose of study intervention (maximum of 45 days)
Population: Safety analysis set included all participants who took at least 1 dose of study intervention. Participants were analyzed according to the product they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Rosuvastatin 10 mg | Number of Participants With Laboratory Abnormalities | 4 Participants |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Number of Participants With Laboratory Abnormalities | 2 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.
Time frame: Day 1 of dosing up to 35 days up to last dose of study intervention (maximum of 45 days)
Population: Safety analysis set consisted of all participants who received at least 1 dose of study intervention. Participants were analyzed according to the product they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Period 1: Rosuvastatin 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 5 Participants |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 10 Participants |
Secondary
Terminal Half-Life (t1/2) of Rosuvastatin in Period 1 and 2
t1/2 was calculated as loge (2) per kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: PK parameter set 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. Here, Number of Participants analyzed signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Rosuvastatin 10 mg | Terminal Half-Life (t1/2) of Rosuvastatin in Period 1 and 2 | 16.37 Hours | Standard Deviation 6.0655 |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Terminal Half-Life (t1/2) of Rosuvastatin in Period 1 and 2 | 24.69 Hours | Standard Deviation 8.269 |
Secondary
Time for Cmax (Tmax) of Rosuvastatin in Period 1 and 2
Time frame: Period 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 1; Period 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post dose on Day 2
Population: PK parameter set 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 (MEDIAN) |
|---|---|---|
| Period 1: Rosuvastatin 10 mg | Time for Cmax (Tmax) of Rosuvastatin in Period 1 and 2 | 5.00 Hours |
| Period 2: Rosuvastatin 10 mg + Nirmatrelvir 300 mg/ Ritonavir 100 mg | Time for Cmax (Tmax) of Rosuvastatin in Period 1 and 2 | 2.00 Hours |