Human Immunodeficiency Virus
Conditions
Brief summary
Study to assess the pharmacokinetics of plasma doravirine once daily over 72 hours following drug intake cessation at steady-state in healthy volunteers
Detailed description
The administration of combination antiretroviral therapy (cART) to HIV-infected patients has been associated with a dramatic reduction in AIDS-related morbidity and mortality. The key to successful HIV drug treatment is adhering to the prescribed combination every day. The approval of single tablet combinations (STRs) provides HIV care providers with a one tablet once a day therapy, making adherence much easier for patients. However, in HIV therapy, successful adherence also means attention to intervals between doses or dietary restrictions. Ideally, to guarantee long-term virological response, HIV-infected patients should take their cART every day at the same time. However, cART is for life and doses can be forgotten or delayed. For this study 14 healthy volunteers will receive Pifeltro® (doravirine 100mg tablets) daily for 7 days to reach steady state. Following the last dose samples will be taken for pharmacokinetic testing over 72 hours. The incidence of adverse events between enrolment to the study (day 1) and last visit (day 20-23) will be recorded. Blood, urine and faecal samples from study subjects will be taken for use in planned exploratory research and for use in future research: Analyses looking at genes which affect drug disposition (pharmacogenomics); the impact of doravirine intake on platelet function and markers of platelet and endothelial cell activation; metabolic changes associated with doravirine.
Interventions
DRUGDoravirine
Non-nucleoside reverse transcriptase inhibitor. Administered as film coated tablet.
Sponsors
Merck Sharp & Dohme LLC
Imperial College London
University of Liverpool
Chelsea and Westminster NHS Foundation Trust
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Single cohort pharmacokinetic (PK) study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements 2. Male or non-pregnant, non-lactating females. 3. Between 18 to 65 years, inclusive 4. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive 5. ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). A single repeat is allowed for eligibility determination. 6. Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 4 weeks after the study. Any contraception method must be used consistently, in accordance with the approved product label and for at least 4 weeks after discontinuation of IMP. 7. Men who have partners who are women of childbearing potential must be using an adequate method of contraception to avoid pregnancy in their partner throughout the study and for a period of at least 4 weeks after the study. Any contraception method must be used consistently, in accordance with the approved product label and for at least four weeks after discontinuation of IMP. 8. Willing to consent to their personal details being entered onto the TOPS database 9. Willing to provide proof of identity by photographic ID at screen and any subsequent visit 10. Registered with a GP in the UK
Exclusion criteria
1. Any clinically significant acute or chronic medical illness 2. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations 3. Positive blood screen for hepatitis B surface antigen or C antibody 4. Positive blood screen for HIV-1 or 2 by antibody/antigen assay 5. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) 6. History or presence of allergy to the study drugs and their components 7. Current or recent (within three months) gastrointestinal disease 8. Known intolerance of lactose monohydrate, sunset yellow aluminium lake (E110), and patients with galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption 9. Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study 10. Exposure to any investigational drug (or placebo) or participation in a clinical study involving the donation of blood samples within three months of first dose of study drug 11. Use of any other drugs (unless approved by the Investigator), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs. 12. Females of childbearing potential without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least four weeks after the end of the treatment period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose. | 72 hours from treatment cessation; days 7-10 inclusive from enrolment | Following cessation of daily doravirine, plasma concentrations of drug to be taken before last dose and at 11 further timepoints over 72 hours. Blood samples were collected pre-dose and at 2, 4, 8, 12, 24, 30, 36, 48, 60 and 72 h post-dose |
| Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72h Post-dose | 72 hours from treatment cessation; days 7-10 inclusive from enrolment | Following cessation of daily dorovirine, plasma concentrations of drug to be taken before last dose and at 11 further timepoints over 72 hours. Blood samples were collected at pre-dose and at 2,4,8,12,24,30,36,47,60 and 72h post-dose |
| Steady State Plasm Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose | 72 hours from treatment cessation; days 7-10 inclusive from enrolment | Following cessation of daily dorovirine, plasma concentrations of drug to be taken before last dose and at 11 further timepoints over 72 hours. Blood samples were collected pre-dose and at 2, 4, 8, 12, 24, 30, 36, 48, 60 and 72h post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events | From enrolment to last visit; last visit will be between days 20-23 from enrolment | All adverse events to be recorded and reported during the study up to last visit. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Intervention Pifeltro® (doravirine 100mg) daily dose for 7 days
Doravirine: Non-nucleoside reverse transcriptase inhibitor. Administered as film coated tablet. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Study Intervention |
|---|---|
| Age, Continuous | 33 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Median BMI | 23.3 kg/m2 |
| Region of Enrollment United Kingdom | 14 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 6 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose.
Following cessation of daily doravirine, plasma concentrations of drug to be taken before last dose and at 11 further timepoints over 72 hours. Blood samples were collected pre-dose and at 2, 4, 8, 12, 24, 30, 36, 48, 60 and 72 h post-dose
Time frame: 72 hours from treatment cessation; days 7-10 inclusive from enrolment
Population: Plasma concentrations of doravirine after drug intake cessation up to 72 hours post-dose were investigated in population of participants for the study
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Study Intervention | Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose. | Doravirine steady-state PK parameters measured over 24h AUC 0-24h | 18354 ng*hr/mL |
| Study Intervention | Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose. | Doravirine steady-state PK parameters measured over 24h AUC 0-72h | 26338 ng*hr/mL |
Primary
Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose.
Following cessation of daily dorivirine, plasm concentrations of drug to be taken were collected pre-dose and at 2,4,8, 12, 24, 30, 36, 48, 60 and 72h post-dose
Time frame: 72 hours from treatment cessation; days 7-10 inclusive from enrolment
Population: Plasma concentrations of doravirine after drug intake cessation up to 72 hours post-dose were investigated in population of participants for the study
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Study Intervention | Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose. | t1/2 0-24h | 14.56 ng*hr/mL |
| Study Intervention | Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose. | t1/2 0-72h | 13.97 ng*hr/mL |
Primary
Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72h Post-dose
Following cessation of daily dorovirine, plasma concentrations of drug to be taken before last dose and at 11 further timepoints over 72 hours. Blood samples were collected at pre-dose and at 2,4,8,12,24,30,36,47,60 and 72h post-dose
Time frame: 72 hours from treatment cessation; days 7-10 inclusive from enrolment
Population: Plasma concentrations of doravirine after drug intake cessation up to 72 hours post-dose were investigated in population of participants for the study
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Study Intervention | Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72h Post-dose | Cmax 0-24h | 1286 ng*hr/mL |
| Study Intervention | Steady State Plasma Concentrations of Doravirine After Drug Intake Cessation up to 72h Post-dose | Cmax 0-72h | 1286 ng*hr/mL |
Primary
Steady State Plasm Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose
Following cessation of daily dorovirine, plasma concentrations of drug to be taken before last dose and at 11 further timepoints over 72 hours. Blood samples were collected pre-dose and at 2, 4, 8, 12, 24, 30, 36, 48, 60 and 72h post-dose
Time frame: 72 hours from treatment cessation; days 7-10 inclusive from enrolment
Population: Plasma concentrations of doravirine after drug intake cessation up to 72 hours post-dose were investigated in population of participants for the study
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Study Intervention | Steady State Plasm Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose | Ctrough at 24 h | 420 ng*hr/mL |
| Study Intervention | Steady State Plasm Concentrations of Doravirine After Drug Intake Cessation up to 72 Hours Post-dose | Ctrough at 72 h | 39 ng*hr/mL |
Secondary
Number of Participants With Treatment-emergent Adverse Events
All adverse events to be recorded and reported during the study up to last visit.
Time frame: From enrolment to last visit; last visit will be between days 20-23 from enrolment
Population: Safety and tolerability of study drug were investigated in population of participants for the study
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Intervention | Number of Participants With Treatment-emergent Adverse Events | Hay Fever | 4 Participants |
| Study Intervention | Number of Participants With Treatment-emergent Adverse Events | Headache | 2 Participants |
| Study Intervention | Number of Participants With Treatment-emergent Adverse Events | No adverse events | 8 Participants |