Chemotherapy-Induced Nausea and Vomiting, Postoperative Nausea and Vomiting
Conditions
Brief summary
This 5-part study will evaluate the safety, tolerability, and pharmacokinetics of two formulations of MK-0517 (with and without polysorbate 80) and aprepitant in healthy adults. Parts I to IV of this study will examine different doses of MK-0517 as well as two different formulations of MK-0517 (with and without polysorbate 80). Part V of the study will compare single doses of intravenous non-PS80 MK-0517 to oral 125-mg capsule of aprepitant. The primary hypothesis for Part V of the study is that a single intravenous dose of 100-mg or 115-mg MK-0517 is area under the plasma-time curve (AUC) equivalent to that of the 125-mg oral aprepitant capsule in young healthy participants.
Interventions
DRUG90 mg MK-0517 (PS80)
MK-0517 (PS80 formulation), 1 mg/mL, administered intravenous (IV) over 15 minutes
DRUG100 mg MK-0517 (PS80)
MK-0517 (PS80 formulation), 1 mg/mL, administered IV over 15 minutes
DRUG100 MK-0517 (PS80) + 2 mg midazolam
MK-0517 (Non-PS80 formulation), 1 mg/mL, administered IV over 15 minutes. Midazolam is co-administered as a single oral 2-mg dose of midazolam with MK-0517.
DRUG115 mg MK-0517 (PS80)
MK-0517 (PS80 formulation), 1 mg/mL, administered IV over 15 minutes
DRUG150 mg MK-0517 (PS80)
MK-0517 (PS80 formulation), 1 mg/mL, administered IV over 15 minutes
DRUG40 mg MK-0517 (non-PS80)
MK-0517 (Non-PS80) is administered as single IV dose over 30 seconds.
DRUG100 mg MK-0517 (non-PS80)
MK-0517 (Non-PS80) is administered as single IV dose over 30 seconds.
DRUG150 mg MK-0517 (Non-PS80)
MK-0517 (Non-PS80) is administered as single IV dose over 30 seconds.
DRUGPlacebo
Placebo matching MK-0517
DRUG40 mg Aprepitant
Aprepitant, oral, tablet, single dose
DRUG125 mg Aprepitant
Aprepitant oral tablet, single dose
DRUG2 mg Midazolam
Midazolam oral tablet, single dose
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is neither grossly overweight nor underweight for his/her height and body build * Subject is in good health -Subject is a nonsmoker * Subject is willing to avoid excessive alcohol consumption for the duration of the study * Subject is willing to avoid strenuous physical activity (i.e. unaccustomed weight lifting, running, bicycling) for the duration of the study * Subject agrees to refrain from consumption of grapefruit (and grapefruit products) before and during the study
Exclusion criteria
* Subject has a history of multiple and/or severe allergies to drugs or food * Subject has donated blood or taken an investigational drug in another clinical trial within the last 4 weeks * Subject has an infection, including Human immunodeficiency virus (HIV) infection * Subject is a regular user of any illicit drug * Subject consumes excessive amounts of alcohol * Subject drinks excessive amounts of coffee, tea, cola or other caffeinated beverages * Subject currently uses on a regular basis, any prescription or non prescription medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma-Time Curve (AUC[0 to Infinity]) for Aprepitant and MK-0517 for Study Part V | Up to 72 Hours Post Dose | AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time. The AUC(0-inf) bioequivalence was evaluated for single doses of 100 and 115 mg MK-0517 PS80, IV and that of an oral 125-mg capsule of aprepitant. Period I to IV populations are not included in the outcome analysis because those were formulation and dose-finding/dose confirmation arms. |
Participant flow
Recruitment details
One Investigator in the United States. Primary therapy period: 31-Jan-2005 to 01-Dec-2005.
Participants by arm
| Arm | Count |
|---|---|
| Part I, Panel A 100 mg MK-0517 (non-polysorbate 80 formulation \[non-PS80\]) or placebo → 150 mg MK-0517 (non-PS80) or placebo → 125 mg aprepitant | 14 |
| Part I, Panel B 100 mg MK-0517 (PS80 formulation \[PS80\]) or placebo → 150 mg MK-0517 (PS80) or placebo → 125 mg aprepitant | 16 |
| Part I, Panel C 40 mg MK-0517 (non-PS80) or placebo → 40 mg aprepitant | 14 |
| Part II 2 mg midazolam → 100 mg MK-0517 (PS80) + 2 mg midazolam | 8 |
| Part III, Panel 1, Treatment Sequence 1 125 mg aprepitant → 90 mg MK-0517 (PS80) | 17 |
| Part III, Panel 1, Treatment Sequence 2 40 mg MK-0517 (non-PS80) → 125 mg aprepitant | 17 |
| Part III, Panel 2 40 mg MK-0517 (non-PS80) | 12 |
| Part IV 40 mg MK-0517 (non-PS80 formulation) | 14 |
| Part V, Treatment Sequence 1 125 mg aprepitant → 100 mg MK-0517 (PS80) → 115 mg MK-0517 (PS80 formulation) | 12 |
| Part V, Treatment Sequence 2 100 mg MK-0517 (PS80) → 115 mg MK-0517 (PS80) → 125 mg aprepitant | 14 |
| Part V, Treatment Sequence 3 115 mg MK-0517 (PS80) → 125 mg aprepitant → 100 mg MK-0517 (PS80) | 12 |
| Part V, Treatment Sequence 4 125 mg aprepitant → 115 mg MK-0517 (PS80) → 100 mg MK-0517 (PS80) | 14 |
| Part V, Treatment Sequence 5 100 mg MK-0517 (PS80) → 125 mg aprepitant → 115 mg MK-0517 (PS80) | 12 |
| Part V, Treatment Sequence 6 115 mg MK-0517 (PS80) → 100 mg MK-0517 (PS80) → 125 mg aprepitant | 12 |
| Total | 188 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 | 3 | 3 | 1 | 0 | 0 | 1 | 3 | 5 | 2 | 1 |
Baseline characteristics
| Characteristic | Part I, Panel A | Part I, Panel B | Part I, Panel C | Part II | Part III, Panel 1, Treatment Sequence 1 | Part III, Panel 1, Treatment Sequence 2 | Part III, Panel 2 | Part IV | Part V, Treatment Sequence 1 | Part V, Treatment Sequence 2 | Part V, Treatment Sequence 3 | Part V, Treatment Sequence 4 | Part V, Treatment Sequence 5 | Part V, Treatment Sequence 6 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 31.2 years | 35.2 years | 33.1 years | 36.9 years | 33.2 years | 33.2 years | 32.4 years | 29.4 years | 31.9 years | 33.5 years | 31.3 years | 29.1 years | 30.4 years | 36.5 years | 32.6 years |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 10 Participants | 5 Participants | 11 Participants | 10 Participants | 10 Participants | 10 Participants | 7 Participants | 11 Participants | 6 Participants | 6 Participants | 4 Participants | 6 Participants | 112 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 4 Participants | 3 Participants | 6 Participants | 7 Participants | 2 Participants | 4 Participants | 5 Participants | 3 Participants | 6 Participants | 8 Participants | 8 Participants | 6 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 31 | 8 / 82 | 5 / 8 | 7 / 66 | 3 / 12 | 4 / 36 | 3 / 12 | 6 / 11 | 2 / 11 | 2 / 14 | 6 / 133 | 2 / 8 |
| serious Total, serious adverse events | 0 / 31 | 0 / 82 | 0 / 8 | 0 / 66 | 0 / 12 | 0 / 36 | 0 / 12 | 0 / 11 | 0 / 11 | 0 / 14 | 0 / 133 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma-Time Curve (AUC[0 to Infinity]) for Aprepitant and MK-0517 for Study Part V
AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time. The AUC(0-inf) bioequivalence was evaluated for single doses of 100 and 115 mg MK-0517 PS80, IV and that of an oral 125-mg capsule of aprepitant. Period I to IV populations are not included in the outcome analysis because those were formulation and dose-finding/dose confirmation arms.
Time frame: Up to 72 Hours Post Dose
Population: All participants in Part V who had at least one period of AUC data were included in the evaluation of pharmacokinetics. Participants without sufficient concentration data for an AUC calculation included: 6 participants in the Aprepitant (125 mg) , 8 participants in the MK-0517 (100 mg) group, and 5 participants in the MK-0517 (115 mg) group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aprepitant (125 mg) | Area Under the Plasma-Time Curve (AUC[0 to Infinity]) for Aprepitant and MK-0517 for Study Part V | 29215 ng*hr/mL | Standard Deviation 15731 |
| MK-0517 (100 mg) | Area Under the Plasma-Time Curve (AUC[0 to Infinity]) for Aprepitant and MK-0517 for Study Part V | 24961 ng*hr/mL | Standard Deviation 10477 |
| MK-0517 (115 mg) | Area Under the Plasma-Time Curve (AUC[0 to Infinity]) for Aprepitant and MK-0517 for Study Part V | 31724 ng*hr/mL | Standard Deviation 14287 |