HIV-1 Infection
Conditions
Brief summary
This study aims to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-retroviral therapy (ART) activity of monotherapy with MK-8504 (a tenofovir pro-drug), in ART-naïve Human Immunodeficiency Virus (HIV)-1 infected participants. The primary hypothesis is that MK-8504, at a dose that is sufficiently safe and well tolerated, has superior antiretroviral activity compared to placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) at 168 hours post-dose.
Interventions
DRUGMK-8504
After at least an 8-hour fast, a single oral dose of MK-8504 will be administered in capsule form.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or non-pregnant and non-breast feeding female * Have a Body Mass Index (BMI) ≤35 kg/m\^2 * Other than HIV infection, have stable baseline health based on medical history, physical examination, vital sign measurements, and laboratory safety test * Is documented HIV-1 positive * Is diagnosed with HIV-1 infection 3 months prior to screening * Is ART-naïve * Has not received an investigational agent or marketed ART within 30 days of study drug administration and is willing to receive no other ART for the duration of this study * Agree to follow smoking and other trial restrictions
Exclusion criteria
* Is mentally or legally institutionalized / incapacitated, has significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder of the last 5 years * Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological (outside of HIV-1 infection), renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases * Has a history of cancer (malignancy) * Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food * Is positive for hepatitis B surface antigen * Has a history of chronic Hepatitis C * Has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit. * Has participated in another investigational trial within 4 weeks or 5 half-lives, whichever is greater, prior to the Day 1 Dosing visit * Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of trial drug, throughout the trial, until the post-trial visit * Consumes greater than 3 glasses of alcoholic beverages or distilled spirits per day * Consumes excessive amounts, defined as greater than 6 servings of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day * Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict smoking to ≤10 cigarettes per day * Have clinically significant abnormality on the electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug * Has a positive urine drug screen (except for cannabis) at screening and/or predose, rechecks are allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) at 168 Hours Post-Dose | Baseline, 168 hours post-dose | Plasma samples were collected from participants after a single dose of MK-8504 to assess viral load. The log10 plasma HIV-RNA (copies/mL) measurements from participants in each panel were pooled and analyzed based on a longitudinal data analysis model. Change from baseline to 168 hours post-dose was determined for each treatment group. Results are expressed as change in HIV RNA log10 (copies/mL). |
| Number of Participants Who Experienced At Least One Adverse Event (AE) | From Day 1 through Post-Trial Visit (up to 25 days) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, was also an AE. The number of participants experiencing at least one AE was reported for each arm. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | Day 1 | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, was also an AE. The number of participants that discontinued study treatment due to an AE was reported for each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Concentration of MK-8504 in Plasma (Tmax) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Tmax of plasma MK-8504. Tmax was defined as the time at which maximum concentration of MK-8504 in plasma was observed, following a single dose of MK-8504. |
| Maximum Concentration of MK-8504 in Plasma (Cmax) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Cmax of plasma MK-8504. Cmax was defined as the maximum concentration of MK-8504 in plasma observed, following a single dose of MK-8504. |
| Apparent Terminal Half Life of MK-8504 in Plasma (t½) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine t½ of plasma MK-8504. t½ was defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504. |
| Apparent Total Clearance of MK-8504 in Plasma (CL/F) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine CL/F of plasma MK-8504. CL/F was defined as the apparent total clearance of the drug from plasma after oral administration, following a single dose of MK-8504. |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8504 in Plasma | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Vz/F of plasma MK-8504. Vz/F was defined as the apparent volume of distribution of the drug in plasma during the terminal phase after non-intravenous administration, following a single dose of MK-8504. |
| Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to 168 Hours (Intracellular AUC0-168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose, 4, 12, 24, 48, 72, 96, and 168 hours post-dose | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular AUC0-168hr of TFP-DP in PBMCs. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular AUC0-168hr was defined as the area under the concentration time curve of TFV-DP in PBMCs from time 0 to 168 hours, following a single dose of MK-8504. |
| Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to Infinity (Intracellular AUC0-inf) In Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular AUC0-inf of TFV-DP in PBMCs. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular AUC0-inf was defined as the area under the concentration time curve of TFV-DP in PBMCs from time 0 to infinite time, following a single dose of MK-8504. |
| Intracellular Time to Maximum Concentration (Intracellular Tmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular Tmax of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular Tmax was defined as the time at which maximum intracellular concentration of TFV-DP in PBMCs was observed, following a single dose of MK-8504. |
| Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-last of plasma MK-8504. AUC0-last was defined as the area under the concentration time curve of plasma MK-8504 from time 0 to last measurement, following a single dose of MK-8504. |
| Intracellular Apparent Terminal Half Life (Intracellular t½) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular t½ of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular t½ was defined as the time required to divide the intracellular concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504. |
| Intracellular Concentration of Tenofovir-Diphosphate (TFV-DP) at 168 Hours (Intracellular C168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | 168 hours post-dose | Blood samples were collected in a fasted state, processed for PBMC samples, and used to determine the intracellular C168hr of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular C168hr was defined as the intracellular concentration of TFV-DP in PBMCs at 168 hours, following a single dose of MK-8504. |
| Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-last of plasma tenofovir. AUC0-last was defined as the area under the concentration time curve of plasma tenofovir from time 0 to last measurement, following a single dose of MK-8504. |
| Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Infinity (AUC0-inf) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-inf of plasma tenofovir. AUC0-inf was defined as the area under the concentration time curve of plasma tenofovir from time 0 to infinite time, following a single dose of MK-8504. |
| Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to 168 Hours (AUC0-168hr) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-168hr of plasma tenofovir. Because plasma tenofovir was expected to rapidly disappear from plasma based on prior experience with healthy participants, sampling was done until 72 hrs and AUC0-168 hr was computed from these data assuming 1) a mono-exponential concentration decline after 72hrs; 2) accurate estimation of the elimination rate based on available data; and 3) no involvement of other processes besides elimination after 72 hrs. |
| Time to Maximum Concentration of Tenofovir in Plasma (Tmax) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Tmax of plasma tenofovir. Tmax was defined as the time at which maximum concentration of tenofovir in plasma was observed, following a single dose of MK-8504. |
| Maximum Concentration of Tenofovir in Plasma (Cmax) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Cmax of plasma tenofovir. Cmax was defined as the maximum concentration of tenofovir in plasma observed, following a single dose of MK-8504. |
| Apparent Terminal Half Life of Tenofovir in Plasma (t½) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine t½ of plasma tenofovir. t½ was defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504. |
| Intracellular Maximum Concentration (Intracellular Cmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular Cmax of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular Cmax was defined as the maximum intracellular concentration of TFV-DP in PBMCs observed, following a single dose of MK-8504. |
| Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Infinity (AUC0-inf) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-inf of plasma MK-8504. AUC0-inf was defined as the area under the concentration time curve of plasma MK-8504 from time 0 to infinite time, following a single dose of MK-8504. |
| Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to 168 Hours (AUC0-168hr) | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-168hr of plasma MK-8504. Because plasma MK-8504 was expected to rapidly disappear from plasma based on prior experience with healthy participants, sampling was done until 72 hrs and AUC0-168 hr was computed from these data assuming 1) a mono-exponential concentration decline after 72hrs; 2) accurate estimation of the elimination rate based on available data; and 3) no involvement of other processes besides elimination after 72 hrs. |
Countries
Germany, United Kingdom
Participant flow
Pre-assignment details
Twelve participants infected with Human Immunodeficiency Virus 1 (HIV-1) were enrolled into Panels A and B. Due to an earlier than anticipated achievement of the study primary study objectives, Panels C and D were not conducted and no participants were enrolled in these panels.
Participants by arm
| Arm | Count |
|---|---|
| MK-8504 100 mg (Panel A) Participants receive a single oral dose of MK-8504 100 mg. | 6 |
| MK-8504 240 mg (Panel B) Participants receive a single oral dose of MK-8504 240 mg. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | MK-8504 100 mg (Panel A) | MK-8504 240 mg (Panel B) | Total |
|---|---|---|---|
| Age, Continuous | 31.7 Years STANDARD_DEVIATION 6 | 35.5 Years STANDARD_DEVIATION 7 | 33.6 Years STANDARD_DEVIATION 6.6 |
| Baseline Plasma HIV-1 Ribonucleic Acid (RNA) | 4.31 Log10 copies/mL STANDARD_DEVIATION 0.34 | 4.60 Log10 copies/mL STANDARD_DEVIATION 0.64 | 4.45 Log10 copies/mL STANDARD_DEVIATION 0.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 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 | 6 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 5 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) at 168 Hours Post-Dose
Plasma samples were collected from participants after a single dose of MK-8504 to assess viral load. The log10 plasma HIV-RNA (copies/mL) measurements from participants in each panel were pooled and analyzed based on a longitudinal data analysis model. Change from baseline to 168 hours post-dose was determined for each treatment group. Results are expressed as change in HIV RNA log10 (copies/mL).
Time frame: Baseline, 168 hours post-dose
Population: All randomized participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8504 100 mg (Panel A) | Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) at 168 Hours Post-Dose | -1.06 log10 (copies/mL) |
| MK-8504 240 mg (Panel B) | Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) at 168 Hours Post-Dose | -0.95 log10 (copies/mL) |
Comparison: Adjusted by Placebo data pooled from historical placebo data from recent monotherapy studies in HIV-1 infected participants (NCT00100048, NCT01466985, NCT01152255, and NCT01353898) and fitted with a longitudinal data analysis (LDA) model containing fixed effects for study and time, and a random effect for participants. LS mean (95% confidence interval) for change from baseline at 168 hours post dose of pooled historical placebo was -0.03 log10 copies/mL (-0.14, 0.09).
Comparison: Adjusted by Placebo data pooled from historical placebo data from recent monotherapy studies in HIV-1 infected participants (NCT00100048, NCT01466985, NCT01152255, and NCT01353898) and fitted with a longitudinal data analysis (LDA) model containing fixed effects for study and time, and a random effect for participants. LS mean (95% confidence interval) for change from baseline at 168 hours post dose of pooled historical placebo was -0.03 log10 copies/mL (-0.14, 0.09).
Primary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, was also an AE. The number of participants that discontinued study treatment due to an AE was reported for each arm.
Time frame: Day 1
Population: All participants that received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8504 100 mg (Panel A) | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 0 Participants |
| MK-8504 240 mg (Panel B) | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 0 Participants |
Primary
Number of Participants Who Experienced At Least One Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, was also an AE. The number of participants experiencing at least one AE was reported for each arm.
Time frame: From Day 1 through Post-Trial Visit (up to 25 days)
Population: All participants that received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8504 100 mg (Panel A) | Number of Participants Who Experienced At Least One Adverse Event (AE) | 5 Participants |
| MK-8504 240 mg (Panel B) | Number of Participants Who Experienced At Least One Adverse Event (AE) | 6 Participants |
Secondary
Apparent Terminal Half Life of MK-8504 in Plasma (t½)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine t½ of plasma MK-8504. t½ was defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Apparent Terminal Half Life of MK-8504 in Plasma (t½) | 3.02 hr | Geometric Coefficient of Variation 38.6 |
| MK-8504 240 mg (Panel B) | Apparent Terminal Half Life of MK-8504 in Plasma (t½) | 6.27 hr | Geometric Coefficient of Variation 29.7 |
Secondary
Apparent Terminal Half Life of Tenofovir in Plasma (t½)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine t½ of plasma tenofovir. t½ was defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Apparent Terminal Half Life of Tenofovir in Plasma (t½) | 32.3 hr | Geometric Coefficient of Variation 23.7 |
| MK-8504 240 mg (Panel B) | Apparent Terminal Half Life of Tenofovir in Plasma (t½) | 35.3 hr | Geometric Coefficient of Variation 29 |
Secondary
Apparent Total Clearance of MK-8504 in Plasma (CL/F)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine CL/F of plasma MK-8504. CL/F was defined as the apparent total clearance of the drug from plasma after oral administration, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Apparent Total Clearance of MK-8504 in Plasma (CL/F) | 67.7 liters (L)/hr | Geometric Coefficient of Variation 63 |
| MK-8504 240 mg (Panel B) | Apparent Total Clearance of MK-8504 in Plasma (CL/F) | 67.4 liters (L)/hr | Geometric Coefficient of Variation 32 |
Secondary
Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8504 in Plasma
Plasma samples were collected in a fasted state pre- and post-dose and used to determine Vz/F of plasma MK-8504. Vz/F was defined as the apparent volume of distribution of the drug in plasma during the terminal phase after non-intravenous administration, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8504 in Plasma | 295 liters (L) | Geometric Coefficient of Variation 55.1 |
| MK-8504 240 mg (Panel B) | Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8504 in Plasma | 609 liters (L) | Geometric Coefficient of Variation 17.8 |
Secondary
Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to 168 Hours (AUC0-168hr)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-168hr of plasma MK-8504. Because plasma MK-8504 was expected to rapidly disappear from plasma based on prior experience with healthy participants, sampling was done until 72 hrs and AUC0-168 hr was computed from these data assuming 1) a mono-exponential concentration decline after 72hrs; 2) accurate estimation of the elimination rate based on available data; and 3) no involvement of other processes besides elimination after 72 hrs.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to 168 Hours (AUC0-168hr) | 2.61 μM·hr | Geometric Coefficient of Variation 62.4 |
| MK-8504 240 mg (Panel B) | Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to 168 Hours (AUC0-168hr) | 6.26 μM·hr | Geometric Coefficient of Variation 32.5 |
Secondary
Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Infinity (AUC0-inf)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-inf of plasma MK-8504. AUC0-inf was defined as the area under the concentration time curve of plasma MK-8504 from time 0 to infinite time, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Infinity (AUC0-inf) | 2.59 μM·hr | Geometric Coefficient of Variation 63 |
| MK-8504 240 mg (Panel B) | Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Infinity (AUC0-inf) | 6.25 μM·hr | Geometric Coefficient of Variation 32 |
Secondary
Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Last Measurable Concentration (AUC0-last)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-last of plasma MK-8504. AUC0-last was defined as the area under the concentration time curve of plasma MK-8504 from time 0 to last measurement, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma pharmacokinetic (PK) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | 2.58 μM·hr | Geometric Coefficient of Variation 63.4 |
| MK-8504 240 mg (Panel B) | Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | 6.20 μM·hr | Geometric Coefficient of Variation 32.1 |
Secondary
Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to 168 Hours (AUC0-168hr)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-168hr of plasma tenofovir. Because plasma tenofovir was expected to rapidly disappear from plasma based on prior experience with healthy participants, sampling was done until 72 hrs and AUC0-168 hr was computed from these data assuming 1) a mono-exponential concentration decline after 72hrs; 2) accurate estimation of the elimination rate based on available data; and 3) no involvement of other processes besides elimination after 72 hrs.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to 168 Hours (AUC0-168hr) | 2.13 μM·hr | Geometric Coefficient of Variation 25.7 |
| MK-8504 240 mg (Panel B) | Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to 168 Hours (AUC0-168hr) | 5.72 μM·hr | Geometric Coefficient of Variation 17.3 |
Secondary
Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Infinity (AUC0-inf)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-inf of plasma tenofovir. AUC0-inf was defined as the area under the concentration time curve of plasma tenofovir from time 0 to infinite time, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Infinity (AUC0-inf) | 2.19 μM·hr | Geometric Coefficient of Variation 27.6 |
| MK-8504 240 mg (Panel B) | Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Infinity (AUC0-inf) | 6.00 μM·hr | Geometric Coefficient of Variation 19.6 |
Secondary
Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Last Measurable Concentration (AUC0-last)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-last of plasma tenofovir. AUC0-last was defined as the area under the concentration time curve of plasma tenofovir from time 0 to last measurement, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma pharmacokinetic (PK) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | 1.71 μM·hr | Geometric Coefficient of Variation 19.5 |
| MK-8504 240 mg (Panel B) | Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | 4.47 μM·hr | Geometric Coefficient of Variation 14.2 |
Secondary
Intracellular Apparent Terminal Half Life (Intracellular t½) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs)
Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular t½ of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular t½ was defined as the time required to divide the intracellular concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504.
Time frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available PBMC PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Intracellular Apparent Terminal Half Life (Intracellular t½) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | 72.4 hour (hr) | Geometric Coefficient of Variation 21.5 |
| MK-8504 240 mg (Panel B) | Intracellular Apparent Terminal Half Life (Intracellular t½) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | 67.5 hour (hr) | Geometric Coefficient of Variation 42.1 |
Secondary
Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to 168 Hours (Intracellular AUC0-168hr) In Peripheral Blood Mononuclear Cells (PBMCs)
Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular AUC0-168hr of TFP-DP in PBMCs. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular AUC0-168hr was defined as the area under the concentration time curve of TFV-DP in PBMCs from time 0 to 168 hours, following a single dose of MK-8504.
Time frame: Pre-dose, 4, 12, 24, 48, 72, 96, and 168 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available PBMC PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to 168 Hours (Intracellular AUC0-168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | 346 μM·hr | Geometric Coefficient of Variation 22.5 |
| MK-8504 240 mg (Panel B) | Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to 168 Hours (Intracellular AUC0-168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | 885 μM·hr | Geometric Coefficient of Variation 17.8 |
Secondary
Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to Infinity (Intracellular AUC0-inf) In Peripheral Blood Mononuclear Cells (PBMCs)
Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular AUC0-inf of TFV-DP in PBMCs. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular AUC0-inf was defined as the area under the concentration time curve of TFV-DP in PBMCs from time 0 to infinite time, following a single dose of MK-8504.
Time frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available PBMC PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to Infinity (Intracellular AUC0-inf) In Peripheral Blood Mononuclear Cells (PBMCs) | 433 μM·hr | Geometric Coefficient of Variation 22.9 |
| MK-8504 240 mg (Panel B) | Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to Infinity (Intracellular AUC0-inf) In Peripheral Blood Mononuclear Cells (PBMCs) | 1020 μM·hr | Geometric Coefficient of Variation 19.3 |
Secondary
Intracellular Concentration of Tenofovir-Diphosphate (TFV-DP) at 168 Hours (Intracellular C168hr) In Peripheral Blood Mononuclear Cells (PBMCs)
Blood samples were collected in a fasted state, processed for PBMC samples, and used to determine the intracellular C168hr of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular C168hr was defined as the intracellular concentration of TFV-DP in PBMCs at 168 hours, following a single dose of MK-8504.
Time frame: 168 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available PBMC PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Intracellular Concentration of Tenofovir-Diphosphate (TFV-DP) at 168 Hours (Intracellular C168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | 0.910 μM | Geometric Coefficient of Variation 19.4 |
| MK-8504 240 mg (Panel B) | Intracellular Concentration of Tenofovir-Diphosphate (TFV-DP) at 168 Hours (Intracellular C168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | 1.35 μM | Geometric Coefficient of Variation 24.7 |
Comparison: PBMC TFV-DP C168hr values pooled, natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. The posterior probability that the true GM of PBMC TFV-DP C168hr level was ≥0.1 μM was calculated for the dose level using flat priors under a normal likelihood assumption. An 80% posterior probability for a dose level that also exhibits acceptable safety and tolerability would satisfy the secondary PK hypothesis.
Comparison: PBMC TFV-DP C168hr values pooled, natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. The posterior probability that the true GM of PBMC TFV-DP C168hr level was ≥0.1 μM was calculated for the dose level using flat priors under a normal likelihood assumption. An 80% posterior probability for a dose level that also exhibits acceptable safety and tolerability would satisfy the secondary PK hypothesis.
Secondary
Intracellular Maximum Concentration (Intracellular Cmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs)
Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular Cmax of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular Cmax was defined as the maximum intracellular concentration of TFV-DP in PBMCs observed, following a single dose of MK-8504.
Time frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available PBMC PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Intracellular Maximum Concentration (Intracellular Cmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | 5.89 μM | Geometric Coefficient of Variation 22.3 |
| MK-8504 240 mg (Panel B) | Intracellular Maximum Concentration (Intracellular Cmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | 15.1 μM | Geometric Coefficient of Variation 52.6 |
Secondary
Intracellular Time to Maximum Concentration (Intracellular Tmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs)
Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular Tmax of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular Tmax was defined as the time at which maximum intracellular concentration of TFV-DP in PBMCs was observed, following a single dose of MK-8504.
Time frame: Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available PBMC PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-8504 100 mg (Panel A) | Intracellular Time to Maximum Concentration (Intracellular Tmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | 4.00 hours (hr) |
| MK-8504 240 mg (Panel B) | Intracellular Time to Maximum Concentration (Intracellular Tmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | 12.00 hours (hr) |
Secondary
Maximum Concentration of MK-8504 in Plasma (Cmax)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine Cmax of plasma MK-8504. Cmax was defined as the maximum concentration of MK-8504 in plasma observed, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Maximum Concentration of MK-8504 in Plasma (Cmax) | 2.72 μM | Geometric Coefficient of Variation 81.6 |
| MK-8504 240 mg (Panel B) | Maximum Concentration of MK-8504 in Plasma (Cmax) | 5.32 μM | Geometric Coefficient of Variation 22.5 |
Secondary
Maximum Concentration of Tenofovir in Plasma (Cmax)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine Cmax of plasma tenofovir. Cmax was defined as the maximum concentration of tenofovir in plasma observed, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8504 100 mg (Panel A) | Maximum Concentration of Tenofovir in Plasma (Cmax) | 0.0727 μM | Geometric Coefficient of Variation 25 |
| MK-8504 240 mg (Panel B) | Maximum Concentration of Tenofovir in Plasma (Cmax) | 0.156 μM | Geometric Coefficient of Variation 22.8 |
Secondary
Time to Maximum Concentration of MK-8504 in Plasma (Tmax)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine Tmax of plasma MK-8504. Tmax was defined as the time at which maximum concentration of MK-8504 in plasma was observed, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-8504 100 mg (Panel A) | Time to Maximum Concentration of MK-8504 in Plasma (Tmax) | 1.00 Hour (hr) |
| MK-8504 240 mg (Panel B) | Time to Maximum Concentration of MK-8504 in Plasma (Tmax) | 0.75 Hour (hr) |
Secondary
Time to Maximum Concentration of Tenofovir in Plasma (Tmax)
Plasma samples were collected in a fasted state pre- and post-dose and used to determine Tmax of plasma tenofovir. Tmax was defined as the time at which maximum concentration of tenofovir in plasma was observed, following a single dose of MK-8504.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment, were compliant with the study procedure, and had available plasma PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-8504 100 mg (Panel A) | Time to Maximum Concentration of Tenofovir in Plasma (Tmax) | 2.00 Hour (hr) |
| MK-8504 240 mg (Panel B) | Time to Maximum Concentration of Tenofovir in Plasma (Tmax) | 2.00 Hour (hr) |