Human Immunodeficiency Virus Type 1 (HIV-1) Infection
Conditions
Brief summary
The goal of this clinical study is to learn more about the impact of cobicistat (COBI) (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and strong cytochrome P450 enzyme \[CYP\]3A inhibitor), voriconazole (VOR) (strong CYP3A inhibitor), and rifabutin (RFB) (moderate CYP3A inducer) on the study drug, vesatolimod (VES), in people with HIV-1 on antiretroviral therapy (ART).
Interventions
DRUGVesatolimod
Administered orally
DRUGCobicistat
Administered orally
DRUGVoriconazole
Administered orally
DRUGRifabutin
Administered orally
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * On an antiretroviral therapy (ART) regimen for at least 6 consecutive months, with no change in the ART regimen within 2 months prior to screening. Permitted ARTs are as follows: * Cohort 1: A regimen of (bictegravir \[BIC\], dolutegravir \[DTG\], raltegravir \[RAL\], or doravirine \[DOR\]) plus Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Examples of acceptable regimens include BIC/emtricitabine/tenofovir, DTG/ abacavir (ABC)/3TC, DTG/3TC, DTG + emtricitabine/tenofovir, or DOR/3TC/tenofovir * Cohort 2: A DTG-based regimen is required (DTG/ABC/3TC), (DTG/3TC), or (DTG + NRTIs) * Plasma HIV-1 RNA levels less than 50 copies/mL at screening * Have normal hematologic function with an absolute neutrophil count greater than or equal to 1.5 × 10\^9/L, platelets greater than or equal to 150 × 10\^9/L; hemoglobin greater than or equal to 10.5 g/dL for females and greater than or equal to 11.5 g/dL for males * Clusters of differentiation (CD) 4 T cell count greater than or equal to 350 cells/μL * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN) and total bilirubin less than or equal to 1.5 mg/dL, or normal direct bilirubin and creatinine less than or equal to 1.25 x ULN * Have a calculated creatinine clearance (CLcr) of at least 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening and upon admission * Individuals assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception * Must be willing and able to comply with all study requirements and available to complete the study schedule of assessments * In the judgment of the investigator, be in good general health, based on review of the results from a screening visit Key
Exclusion criteria
* Have received any study drug within 30 days prior to study dosing * Participation in any other clinical study (including observation studies) without prior approval from the sponsor is prohibited while participating in this study * Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual compliance or individual safety, or a positive drug or alcohol test at screening or baseline * No Evidence of chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen \[HBsAg\] and/or positive HBV core antibody with positive reflex HBV DNA polymerase chain reaction (PCR)). Note: positive HBV core antibody with negative reflex HBV DNA PCR results are acceptable * No Evidence of active hepatitis C virus (HCV) infection (defined as positive hepatitis C antibody and HCV RNA above lower limit of quantitation). Note: positive anti-HCV antibody and negative HCV PCR results are acceptable * Acute febrile illness within 35 days prior to Day 1 * Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study * Received any vaccine or immunomodulatory medication within 4 weeks prior to screening. Elective vaccination (eg, flu shot, hepatitis A or B vaccine) during the course of the study will require prior approval from the sponsor * Coronavirus disease of 2019 (COVID-19) vaccinations are allowed, with the requirement that they should not be administered within 7 ± 2 days of receiving VES * Have a history of any of the following: * Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria * Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity) * Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients * Autoimmune disease * Significant cardiac disease or a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years * Syncope, palpitations, or unexplained dizziness * Implanted defibrillator or pacemaker * Liver disease, including Gilbert syndrome * Severe peptic ulcer disease requiring prolonged (≥ 6 months) medical treatment * Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary * Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with individual treatment, assessment, or compliance with the protocol * For Cohort 1, individuals with CYP2C19 genotype of CYP2C19\*2/\*2, CYP2C19\*2/\*3, or CYP2C19\*3/\*3 Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | AUClast is defined as an area under the concentration versus time curve from time zero to the last quantifiable concentration. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : AUCinf of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | AUCinf is defined as an area under the concentration versus time curve extrapolated to infinite time, calculated as AUClast + (Clast/Lambda z). Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : Cmax of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | Cmax is defined as the maximum observed concentration of drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : %AUCexp of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf, calculated as (\[AUCinf-AUClast\]/AUCinf)\*100. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : Tmax of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | Tmax is defined as the time (observed time point) of Cmax. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : Clast of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | Clast is defined as the last observed quantifiable concentration of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : Tlast of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | Tlast is defined as the time (observed time point) of Clast. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : Lambda z of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | Lambda z is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log concentration of drug versus time curve of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : t1/2 of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | t1/2 is defined as the terminal elimination half-life. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : CL/F of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | CL/F is defined as an apparent oral clearance. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| PK Parameter : Vz/F of VES | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6 | Vz/F is defined as an apparent volume of distribution of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline. |
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | First dose date up to last dose date plus 30 days (up to 77 days for Cohort 1, and up to 54 days for Cohort 2) | An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can, therefore, be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. Adverse events may also include pretreatment or posttreatment complications that occur as a result of protocol-specified procedures, or special situations. TEAES included all AEs began on or after the study drug start date. |
| Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | First dose date up to last dose date plus 30 days (up to 77 days for Cohort 1, and up to 54 days for Cohort 2) | A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose at any time postdose. Data for participants with post baseline toxicity grade 1 or higher is reported. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States.
Pre-assignment details
59 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Vesatolimod + Cobicistat + Voriconazole Participants received a single dose of vesatolimod (VES) 2 mg on Day 1 of Period 1. In Period 2, participants received cobicistat (COBI) 150 mg once daily on Days 1 to 5 along with a single dose of VES 2 mg on Day 2. In Period 3, participants received a loading dose of voriconazole (VOR) 400 mg twice daily on Day 1, then VOR 200 mg twice daily on Days 2 to 6, and a single dose of VES 2 mg in the morning on Day 3. There was a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1. | 15 |
| Cohort 2: Vesatolimod + Rifabutin Participants received a single dose of VES 6 mg on Day 1. In Period 2, participants received Rifabutin (RFB) 300 mg once daily on Days 1 to 9 along with a single dose of VES 6 mg on Day 6. There was a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1. | 2 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Enrolled but never treated | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrew consent | 2 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Vesatolimod + Cobicistat + Voriconazole | Cohort 2: Vesatolimod + Rifabutin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 2 Participants | 16 Participants |
| Age, Continuous | 47 years STANDARD_DEVIATION 14.5 | 45 years STANDARD_DEVIATION 14.8 | 47 years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 0 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 15 Participants | 2 Participants | 17 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 13 Participants | 0 Participants | 13 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 13 | 0 / 13 | 0 / 11 | 0 / 11 | 0 / 11 | 0 / 1 | 0 / 2 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 15 | 5 / 13 | 0 / 13 | 4 / 11 | 1 / 11 | 1 / 11 | 0 / 0 | 0 / 2 | 1 / 2 | 1 / 2 |
| serious Total, serious adverse events | 0 / 15 | 0 / 13 | 0 / 13 | 0 / 11 | 0 / 11 | 0 / 11 | 0 / 0 | 0 / 2 | 0 / 2 | 0 / 2 |
Outcome results
Primary
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can, therefore, be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. Adverse events may also include pretreatment or posttreatment complications that occur as a result of protocol-specified procedures, or special situations. TEAES included all AEs began on or after the study drug start date.
Time frame: First dose date up to last dose date plus 30 days (up to 77 days for Cohort 1, and up to 54 days for Cohort 2)
Population: Participants in Safety Analysis Set were analyzed. Per planned analysis, the data for adverse events were summarized by study treatments administered in Cohorts 1 and 2 per period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Vesatolimod 2 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 13.3 percentage of participants |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 38.5 percentage of participants |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 0 percentage of participants |
| Cohort 2: Vesatolimod 6 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 36.4 percentage of participants |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 9.1 percentage of participants |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 9.1 percentage of participants |
| Cohort 2: Vesatolimod 6 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 0 percentage of participants |
| Cohort 2: Rifabutin 300 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 50.0 percentage of participants |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) | 50.0 percentage of participants |
Primary
Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities
A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose at any time postdose. Data for participants with post baseline toxicity grade 1 or higher is reported.
Time frame: First dose date up to last dose date plus 30 days (up to 77 days for Cohort 1, and up to 54 days for Cohort 2)
Population: Participants in Safety Analysis Set with available data were analyzed. Per planned analysis, the data for adverse events were summarized by study treatments administered in Cohorts 1 and 2 per period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Vesatolimod 2 mg | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | 35.7 percentage of participants |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | 53.8 percentage of participants |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | 63.6 percentage of participants |
| Cohort 2: Vesatolimod 6 mg | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | 50.0 percentage of participants |
| Cohort 2: Rifabutin 300 mg | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | 100.0 percentage of participants |
Primary
Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES)
AUClast is defined as an area under the concentration versus time curve from time zero to the last quantifiable concentration. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: The VES PK Analysis Set included participants who received at least 1 dose of VES and had at least 1 nonmissing PK concentration value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | 13500 h*pg/mL | Standard Deviation 9500 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | 61900 h*pg/mL | Standard Deviation 35400 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | 14600 h*pg/mL | Standard Deviation 11000 |
| Cohort 2: Vesatolimod 6 mg | Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | 16400 h*pg/mL | Standard Deviation 17900 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | 86300 h*pg/mL | Standard Deviation 16000 |
90% CI: [414, 757]
90% CI: [99.5, 189]
Primary
PK Parameter : %AUCexp of VES
%AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf, calculated as (\[AUCinf-AUClast\]/AUCinf)\*100. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set with available data were analyzed. Data for Cohort 2 Vesatolimod 6mg are not reported due to participant's confidentiality reasons as there was only 1 participant in this cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : %AUCexp of VES | 14.6 percentage of AUCexp | Standard Deviation 6.97 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : %AUCexp of VES | 6.16 percentage of AUCexp | Standard Deviation 3.91 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : %AUCexp of VES | 14.7 percentage of AUCexp | Standard Deviation 6.75 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : %AUCexp of VES | 1.92 percentage of AUCexp | Standard Deviation 0.602 |
Primary
PK Parameter : AUCinf of VES
AUCinf is defined as an area under the concentration versus time curve extrapolated to infinite time, calculated as AUClast + (Clast/Lambda z). Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set with available data were analyzed. Data for Cohort 2 Vesatolimod 6mg are not reported due to participant's confidentiality reasons as there was only 1 participant in this cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : AUCinf of VES | 17600 h*pg/mL | Standard Deviation 9220 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : AUCinf of VES | 68000 h*pg/mL | Standard Deviation 36600 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : AUCinf of VES | 17800 h*pg/mL | Standard Deviation 11600 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : AUCinf of VES | 88000 h*pg/mL | Standard Deviation 16800 |
90% CI: [347, 540]
90% CI: [93.5, 150]
Primary
PK Parameter : Clast of VES
Clast is defined as the last observed quantifiable concentration of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : Clast of VES | 84.2 pg/mL | Standard Deviation 19.4 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : Clast of VES | 103 pg/mL | Standard Deviation 42.2 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : Clast of VES | 74.2 pg/mL | Standard Deviation 17.4 |
| Cohort 2: Vesatolimod 6 mg | PK Parameter : Clast of VES | 75.9 pg/mL | Standard Deviation 30.5 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : Clast of VES | 74.3 pg/mL | Standard Deviation 27.2 |
Primary
PK Parameter : CL/F of VES
CL/F is defined as an apparent oral clearance. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set with available data were analyzed. Data for Cohort 2 Vesatolimod 6mg are not reported due to participant's confidentiality reasons as there was only 1 participant in this cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : CL/F of VES | 156 L/h | Standard Deviation 92.9 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : CL/F of VES | 42.4 L/h | Standard Deviation 28.5 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : CL/F of VES | 176 L/h | Standard Deviation 137 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : CL/F of VES | 69.4 L/h | Standard Deviation 13.3 |
Primary
PK Parameter : Cmax of VES
Cmax is defined as the maximum observed concentration of drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : Cmax of VES | 1130 pg/mL | Standard Deviation 1020 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : Cmax of VES | 6930 pg/mL | Standard Deviation 4650 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : Cmax of VES | 1020 pg/mL | Standard Deviation 895 |
| Cohort 2: Vesatolimod 6 mg | PK Parameter : Cmax of VES | 944 pg/mL | Standard Deviation 928 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : Cmax of VES | 22200 pg/mL | Standard Deviation 7780 |
90% CI: [525, 1080]
90% CI: [80.3, 172]
Primary
PK Parameter : Lambda z of VES
Lambda z is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log concentration of drug versus time curve of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set with available data were analyzed. Data for Cohort 2 Vesatolimod 6mg are not reported due to participant's confidentiality reasons as there was only 1 participant in this cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : Lambda z of VES | 0.0381 per hour |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : Lambda z of VES | 0.0310 per hour |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : Lambda z of VES | 0.0321 per hour |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : Lambda z of VES | 0.0442 per hour |
Primary
PK Parameter : t1/2 of VES
t1/2 is defined as the terminal elimination half-life. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set with available data were analyzed. Data for Cohort 2 Vesatolimod 6mg are not reported due to participant's confidentiality reasons as there was only 1 participant in this cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : t1/2 of VES | 18.4 hours |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : t1/2 of VES | 22.4 hours |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : t1/2 of VES | 21.6 hours |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : t1/2 of VES | 15.8 hours |
90% CI: [104, 138]
90% CI: [95.4, 128]
Primary
PK Parameter : Tlast of VES
Tlast is defined as the time (observed time point) of Clast. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : Tlast of VES | 48.0 hours |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : Tlast of VES | 72.0 hours |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : Tlast of VES | 48.0 hours |
| Cohort 2: Vesatolimod 6 mg | PK Parameter : Tlast of VES | 59.8 hours |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : Tlast of VES | 72.0 hours |
Primary
PK Parameter : Tmax of VES
Tmax is defined as the time (observed time point) of Cmax. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : Tmax of VES | 3.03 hours |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : Tmax of VES | 1.52 hours |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : Tmax of VES | 2.50 hours |
| Cohort 2: Vesatolimod 6 mg | PK Parameter : Tmax of VES | 5.13 hours |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : Tmax of VES | 1.28 hours |
90% CI: [45.5, 103]
90% CI: [42.5, 101]
Primary
PK Parameter : Vz/F of VES
Vz/F is defined as an apparent volume of distribution of the drug. Cohort 1 Period 1 Day 1: Day 1 from Baseline; Cohort 1 Period 2 Day 2: Up to Day 17 from Baseline; Cohort 1 Period 3 Day 3: Up to Day 44 from Baseline; Cohort 2 Period 1 Day 1: Day 1 from Baseline; Cohort 2 Period 2 Day 6: Up to Day 21 from Baseline.
Time frame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours post-dose for Cohort 1 on Period 1 Day 1, Period 2 Day 2, and Period 3 Day 3; and for Cohort 2 on Period 1 Day 1 and Period 2 Day 6
Population: Participants in the VES PK Analysis Set with available data were analyzed. Data for Cohort 2 Vesatolimod 6mg are not reported due to participant's confidentiality reasons as there was only 1 participant in this cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Vesatolimod 2 mg | PK Parameter : Vz/F of VES | 3480 L | Standard Deviation 1530 |
| Cohort 1: Vesatolimod 2 mg + Cobicistat 150 mg | PK Parameter : Vz/F of VES | 1320 L | Standard Deviation 1100 |
| Cohort 1: Vesatolimod 2 mg + Voriconazole 200 mg | PK Parameter : Vz/F of VES | 4330 L | Standard Deviation 2220 |
| Cohort 2: Vesatolimod 6 mg + Rifabutin 300 mg | PK Parameter : Vz/F of VES | 1560 L | Standard Deviation 86.7 |