Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Uprifosbuvir · 2 trials · 2 indications
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Tlag is a measure of the time delay between drug administration and the onset of absorption, where onset of absorption is defined as "the time point prior to the first observed/measured non-zero plasma concentration". The Tlag of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm (in this study Tlag was only calculated for the M5 uprifosbuvir metabolite).
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
An AE was defined as any untoward medical occurrence in a participant administered study drug, and that does not necessarily have a causal relationship with the study drug(s). An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug(s), whether or not related to study drug(s). The percentage of participants who experienced at least one AE is presented.
An SAE was defined as any untoward medical occurrence that at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. The percentage of participants who experienced at least one SAE is presented.
A DLT was defined as any of the following events: Any SAE considered by the investigator to be at least reasonably or possibly related to study drug; Any Grade 3 clinical AE considered by the investigator to be at least reasonably or possibly related to study drug; Any Grade 3 confirmed laboratory abnormalities considered by the investigator to be at least reasonably or possibly related to study drug, except for asymptomatic Grade ¾ cholesterol and triglyceride; Any clinical or laboratory AE of any intensity that is considered by the investigator to be at least reasonably or possibly related to study drug that necessitates permanent discontinuation of study drug; Confirmed increase in QT interval corrected for heart rate using Fridericia's (QTcF) formula ≥60 msec over Baseline or an absolute QTcF ≥500 msec.
Laboratory abnormalities were graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Treatment-emergent AEs (TEAEs)were graded as: Grade 1: Mild TEAE as Worst Severity; Grade 2: Moderate TEAE as Worst Severity; Grade 3: Severe TEAE as Worst Severity; Grade 4: Potentially Life-Threatening TEAE as Worst Severity; Grade 5: TEAE Leading to Death. The percentage of participants who experienced at least one Grade 1, 2, 3, 4 or 5 laboratory abnormality is presented.
The percentage of participants who discontinued study drug due to an AE is presented.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration. All participants were fasted.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
Maximum observed plasma drug concentration was obtained. All participants were fasted.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained. All participants were fasted.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Time to maximum plasma concentration was obtained. All participants were fasted.
Time to maximum plasma concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
AUC0-t was calculated using linear log trapezoidal summation from time zero to last measurable concentration.
Time to maximum plasma concentration was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained. All participants were fasted.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
Area under the drug concentration-time curve from time zero to infinity for M6, a metabolite of uprifosbuvir, estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only. All participants were fasted.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Area under the drug concentration-time curve from time zero to infinity estimated as AUC0-t + Cest/λz, where λz is the terminal elimination rate constant, calculated for the first dose only.
Maximum observed plasma drug concentration was obtained. All participants were fasted.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Maximum observed plasma drug concentration was obtained.
Time to maximum plasma concentration was obtained. All participants were fasted.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
Time to maximum plasma concentration was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained. All participants were fasted.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
The time measured for the plasma concentration to decrease by one half (t1/2) was obtained.
Cumulative urine excretion of unchanged MK-3682 in healthy participants was obtained. All participants were fasted.
Cumulative urine excretion of unchanged M6 in healthy participants was obtained. All participants were fasted.
Reduction in HCV RNA from baseline on Day 8 following uprifosbuvir 50-450 mg for 7 Days in Genotype 1, 2 and 3, HCV-infected participants was obtained.
Reduction in HCV RNA from baseline on Day 8 following uprifosbuvir 50-450 mg for 7 Days in Genotype (Gt) 1, HCV-infected participants was obtained.
| Arm | Type | Description |
|---|---|---|
| Moderate HI Participants | EXPERIMENTAL | On Day 1, participants with moderate HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast. |
| Severe HI Participants | EXPERIMENTAL | On Day 1, participants with severe HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast. |
| Healthy Participants | EXPERIMENTAL | On Day 1, participants with normal hepatic function will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast. |
| Group A: Healthy | EXPERIMENTAL | Healthy participants will receive sequentially higher doses of uprifosbuvir (10 mg - 300 mg) capsules or matching placebo capsules once daily (QD) on Day 1 (Cohorts 1a-3a, 5a), Days 1 and 7 (Cohort 4a), or Day 1 - Day 7 (Cohort 6a). Dosing of next cohort will be based on review of available safety and PK data. Dosing will occur under fasted conditions with the exception of Cohort 4a, in which drug administration will occur under both fasted and fed conditions. |
| Group B: GT1 HCV-infected, treatment naive on Day 1 | EXPERIMENTAL | HCV GT1 participants with no prior direct-acting antiviral (DAA) exposure will receive a single dose of uprifosbuvir (10 mg - 300 mg) for 1 day across sequential dose cohorts. Dosing will commence following review of available safety and PK data from respective dose cohorts in Group A. All dosing will occur under fasted conditions. |
| Group C: GT1 HCV-infected on Days 1-7 | EXPERIMENTAL | HCV GT1 participants will receive uprifosbuvir (50 mg - 400 mg in capsules or 300 mg or 450 mg in tablets) or matching placebo capsules QD for 7 days. Dosing will commence following review of available safety and PK data of Group A. Fed vs. fasted dosing will be dependent on food effect results from Group A. |
| Group D: GT2 through GT6 HCV-infected on Days 1-7 | EXPERIMENTAL | HCV GT2 - GT6 participants will receive uprifosbuvir (50 mg - 300 mg) capsules QD for 7 days. Dosing will commence following review of available safety and PK data from Group A. Fed vs. fasted dosing will be dependent on food effect results from Group A. |
| Group E: GT1 HCV-infected on Days 1-7, mild hepatic impairment | EXPERIMENTAL | HCV GT1 participants with mildly impaired hepatic function will receive uprifosbuvir (150 mg - 450 mg) capsules QD for 1 or 7 days. Dosing of subsequent cohorts will be based on review of available safety and PK data. Fed vs. fasted dosing will be dependent on food effect results from Group A. |
| Group F: GT1 HCV-infected on Days 1-7, + Itraconazole | EXPERIMENTAL | HCV GT1 participants will receive itraconazole 200 mg twice daily (BID) on Day -5 and itraconazole 200 mg QD from Day -4 to Day 11. Participants will also be co-administered uprifosbuvir 300 mg from Day 1 to Day 7. |
| Name | Type | Description |
|---|---|---|
| Uprifosbuvir | DRUG | A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth. |
| Ruzasvir | DRUG | A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth. |
| Placebo | DRUG | Matching placebo to uprifosbuvir capsule administered by mouth. |
| Itraconazole | DRUG | Itraconazole is supplied as 10 mg/mL oral solution or 100 mg capsules administered by mouth. |
Inclusion Criteria: HI Participants Only: * Has a diagnosis of chronic (\>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) HI features of cirrhosis; * Part 1 only: Participant's score on the Child-Pugh scale ranges from 7 to 9 (...
Uprifosbuvir is an investigational small molecule being developed for the treatment of chronic hepatitis C, a viral infection of the liver. It is currently in Phase 1 clinical development and has not been approved by regulatory authorities.
Uprifosbuvir is a small molecule antiviral agent. Its specific molecular target has not been disclosed in available information, so its exact mechanism of action is not described here.
Uprifosbuvir is being developed by Merck & Company, Inc., a pharmaceutical company traded on the New York Stock Exchange under the ticker symbol MRK.
Uprifosbuvir is in Phase 1 clinical development. It is an investigational drug and has not been approved by the FDA or any other regulatory agency for the treatment of chronic hepatitis C.
Uprifosbuvir has been studied in two completed Phase 1 trials. NCT01974687 evaluated single and multiple doses in healthy and HCV-infected participants, enrolling 178 subjects. NCT02666352 assessed its pharmacokinetics in participants with moderate and severe hepatic insufficiency, enrolling 24 subjects.