Renal Impairment
Conditions
Brief summary
This study will evaluate the effect of severe renal impairment on the pharmacokinetics of doravirine.
Interventions
DRUGDoravirine
Following an overnight fast, a single coated tablet of 100 mg doravirine will be administered orally
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 75 Years
Healthy volunteers
Yes
Inclusion criteria
* is a non-smoker or moderate smoker * has a body mass index (BMI) ≥ 18.5 and ≤ 40.0 kg/m\^2 * other than renal impairment, participant is judged to be in good health based on medical history, physical examination, vital signs, and laboratory safety tests * female informed of the risks of pregnancy, agree not to become pregnant while participating in this study. Female of childbearing potential must either be sexually inactive for 14 days prior to dosing and throughout the study, or uses one acceptable birth control method * female of non-childbearing potential must have undergone sterilization procedures at least 6 months prior to dosing. * Participants with severe renal impairment only: has baseline estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m\^2
Exclusion criteria
* is mentally or legally incapacitated or has significant emotional problems * has a history or presence of clinically significant medical or psychiatric condition or disease * has history or presence of alcoholism or drug abuse within the past 2 years * has history or presence of hypersensitivity or idiosyncratic reaction to the study drug, any inactive ingredients, or related compounds * has history or presence of renal artery stenosis * has had a renal transplant or nephrectomy * has rapidly fluctuating renal function as determined by historical measurements * female is pregnant or lactating * has positive results for the urine or saliva drug and urine or breath alcohol screen at screening or check-in * has positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) * is unable to refrain from or anticipates the use of any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to dosing and throughout the study. Certain medications including those to treat kidney disease will be permitted. Other medications may be permitted following consultation with the Sponsor Clinical Monitor. * is unable to refrain from or anticipates the use of inducers of cytochrome P450 3A (CYP3A) or permeability glycoprotein (P-gp) transporters for at least 28 days prior to dosing and throughout the study. * has been on a diet incompatible with the on-study diet, within 28 days prior to dosing, and throughout the study * has donated blood or had significant blood loss within 56 days prior to dosing * has donated plasma within 7 days prior to dosing * has participated in another clinical trial within 28 days prior to dosing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Plasma Concentration of Doravirine at 24 Hours Postdose (C24) | 24 hours postdose | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Maximum Observed Plasma Concentration (Cmax) of Doravirine | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Area Under the Plasma Concentration Versus Time Curve From 0 Hours to the Time of Last Quantifiable Sample of Doravirine (AUC 0-last) | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Doravirine | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Apparent Terminal Half-life (t1/2) of Plasma Doravirine | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Apparent Clearance of Plasma Doravirine After Extravascular Administration (CL/F) | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
| Apparent Volume of Distribution of Plasma Doravirine During the Terminal Phase (Vz/F) | Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Severe Renal Impairment Participants with severe renal impairment received a single oral dose of 100 mg doravirine | 8 |
| Healthy Matched Controls Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Severe Renal Impairment | Healthy Matched Controls | Total |
|---|---|---|---|
| Age, Customized 19 to 49 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 50 to 59 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Customized 60 to 69 years | 4 Participants | 4 Participants | 8 Participants |
| Body Weight | 90.86 Kilogram STANDARD_DEVIATION 17.409 | 90.93 Kilogram STANDARD_DEVIATION 6.086 | 90.89 Kilogram STANDARD_DEVIATION 12.599 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 2 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Apparent Clearance of Plasma Doravirine After Extravascular Administration (CL/F)
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Apparent Clearance of Plasma Doravirine After Extravascular Administration (CL/F) | 3.53 Liter/hour | Geometric Coefficient of Variation 63.9 |
| Healthy Matched Controls | Apparent Clearance of Plasma Doravirine After Extravascular Administration (CL/F) | 5.38 Liter/hour | Geometric Coefficient of Variation 32.8 |
Primary
Apparent Terminal Half-life (t1/2) of Plasma Doravirine
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Apparent Terminal Half-life (t1/2) of Plasma Doravirine | 25.02 Hours | Geometric Coefficient of Variation 36.4 |
| Healthy Matched Controls | Apparent Terminal Half-life (t1/2) of Plasma Doravirine | 16.69 Hours | Geometric Coefficient of Variation 26.1 |
Primary
Apparent Volume of Distribution of Plasma Doravirine During the Terminal Phase (Vz/F)
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Apparent Volume of Distribution of Plasma Doravirine During the Terminal Phase (Vz/F) | 127 Liters | Geometric Coefficient of Variation 40.9 |
| Healthy Matched Controls | Apparent Volume of Distribution of Plasma Doravirine During the Terminal Phase (Vz/F) | 129 Liters | Geometric Coefficient of Variation 28.3 |
Primary
Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Severe Renal Impairment | Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine | 64.5 μM•hr |
| Healthy Matched Controls | Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine | 45.1 μM•hr |
90% CI: [1, 2.04]
Primary
Area Under the Plasma Concentration Versus Time Curve From 0 Hours to the Time of Last Quantifiable Sample of Doravirine (AUC 0-last)
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Area Under the Plasma Concentration Versus Time Curve From 0 Hours to the Time of Last Quantifiable Sample of Doravirine (AUC 0-last) | 60.5 μM•hr | Geometric Coefficient of Variation 56.3 |
| Healthy Matched Controls | Area Under the Plasma Concentration Versus Time Curve From 0 Hours to the Time of Last Quantifiable Sample of Doravirine (AUC 0-last) | 41.0 μM•hr | Geometric Coefficient of Variation 29.9 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Doravirine
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Severe Renal Impairment | Maximum Observed Plasma Concentration (Cmax) of Doravirine | 1580 nM |
| Healthy Matched Controls | Maximum Observed Plasma Concentration (Cmax) of Doravirine | 1900 nM |
90% CI: [0.61, 1.15]
Primary
Plasma Concentration of Doravirine at 24 Hours Postdose (C24)
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Severe Renal Impairment | Plasma Concentration of Doravirine at 24 Hours Postdose (C24) | 943 nM |
| Healthy Matched Controls | Plasma Concentration of Doravirine at 24 Hours Postdose (C24) | 684 nM |
90% CI: [0.99, 1.92]
Primary
Time to Maximum Observed Plasma Concentration (Tmax) of Doravirine
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Severe Renal Impairment | Time to Maximum Observed Plasma Concentration (Tmax) of Doravirine | 2.00 Hours |
| Healthy Matched Controls | Time to Maximum Observed Plasma Concentration (Tmax) of Doravirine | 1.50 Hours |