HIV Infections
Conditions
Brief summary
This study evaluated the effect of single doses of a magnesium/aluminum antacid (MAALOX) given 4 and 6 hours before or after administration of raltegravir, on the pharmacokinetics of raltegravir in human immunodeficiency virus (HIV)-infected participants. The study consisted of Part 1 (Periods 1, 2, and 3) and Part 2 (Periods 4 and 5), with each study period separated by a washout period of at least 2 days; Part 1 was separated from Part 2 by a Pause. Each study period had a duration of ≥2 days, and paused for evaluation of Part 1 pharmacokinetics results before continuing to Part 2. The same participants participated in Parts 1 and 2. The primary hypothesis tested (in Part 1) was that raltegravir plasma concentration 12 hours after administration (C 12 hrs) would not differ significantly from raltegravir C 12 hrs when antacid is administered 4 hours before or 4 hours after raltegravir.
Interventions
DRUGRaltegravir (ISENTRESS™)
Raltegravir 400 mg oral tablet once every 12 hours. Participants will continue with their other prescribed antiretroviral agents throughout the study.
DRUGMAALOX (MAL)
MAL (or generic equivalent) 20 mL oral single dose on Day 1
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* On a stable raltegravir dose as part of a stable antiretroviral regimen for ≥1 month before the study * If female, is not pregnant or breast feeding * Body mass index ≤32 kg/m\^2
Exclusion criteria
* Mentally or physically incapacitated, has significant emotional problems, or history of clinically significant psychiatric disorder within ≤10 years * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological abnormalities or disease (excluding HIV) * History of gastric bypass surgery * History of cancer, except adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated ≥10 years before the study * History of chronic diarrhea within ≤3 months before the study * History of significant multiple and/or severe allergies (food, drug, latex), or had an anaphylactic reaction or significant intolerability to drugs or food * Had major surgery or donated or lost ≥1 unit of blood (500 mL) ≤4 weeks before the study * Participated in another investigational trial ≤4 weeks before the study * Taking rifampin or is unable to refrain from the use of 1) any proton pump inhibitor from 2 weeks before and throughout the study, or 2) any histamine H2-blockers, antacids, calcium supplements, or multivitamins from 2 weeks before and throughout the study * Consumes \>3 glasses of alcoholic beverages per day * Consumes excessive amounts of caffeine beverages (coffee, tea, cola, energy drinks, or other caffeinated drinks) per day * Currently uses or has a history of drug abuse within ≤6 months before the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 1 | 12 hours after dosing on Day 1 of each period | Blood was drawn 12 hours after dosing with raltegravir in order to determine the geometric mean plasma concentration. |
| Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 1 | Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period | Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir in order to determine the geometric mean area under the curve plasma concentration versus time. |
| Maximum Plasma Concentration (C Max) of Raltegravir in Part 1 | Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period | Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir, in order to determine the geometric mean maximum plasma concentration. |
| Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 2 | 12 hours after dosing on Day 1 of each period | Blood was drawn 12 hours after dosing with raltegravir in order to determine the geometric mean plasma concentration. |
| Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 2 | Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period | Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir, in order to determine the geometric mean area under the curve plasma concentration versus time. |
| Maximum Plasma Concentration (C Max) of Raltegravir in Part 2 | Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period | Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir, in order to determine the geometric mean maximum plasma concentration. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All enrolled participants | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Pause (up to 37 Days) | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
| Pause (up to 37 Days) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 48.7 Years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 14 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 1 / 17 | 1 / 18 | 2 / 16 | 0 / 16 |
| serious Total, serious adverse events | 0 / 18 | 0 / 17 | 0 / 18 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 1
Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir in order to determine the geometric mean area under the curve plasma concentration versus time.
Time frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period
Population: The per-protocol population consisting of participants from Part 1 only, who complied with the study procedure and had available data from at least one treatment. One participant did not complete one period of Maalox-4 hour-Raltegravir treatment, resulting in an n = 17.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir | Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 1 | 17055.21 hr.nM |
| Maalox → 4 Hours → Raltegravir | Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 1 | 13881.87 hr.nM |
| Raltegravir → 4 Hours → Maalox | Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 1 | 11602.02 hr.nM |
90% CI: [0.63, 1.05]
90% CI: [0.5, 0.92]
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 2
Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir, in order to determine the geometric mean area under the curve plasma concentration versus time.
Time frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period
Population: The per-protocol population consisting of participants from the Raltegravir alone treatment group from Part 1, and the treatment groups from Part 2, who complied with the study procedure and had available data from at least one treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir | Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 2 | 17055.21 hr.nM |
| Maalox → 4 Hours → Raltegravir | Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 2 | 14799.48 hr.nM |
| Raltegravir → 4 Hours → Maalox | Area Under the Plasma Concentration Versus Time Curve (AUC 0-12 Hrs) of Raltegravir in Part 2 | 15104.15 hr.nM |
90% CI: [0.64, 1.18]
90% CI: [0.64, 1.22]
Primary
Maximum Plasma Concentration (C Max) of Raltegravir in Part 1
Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir, in order to determine the geometric mean maximum plasma concentration.
Time frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period
Population: The per-protocol population consisting of participants from Part 1 only, who complied with the study procedure and had available data from at least one treatment. One participant did not complete one period of Maalox-4 hour-Raltegravir treatment, resulting in an n = 17.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir | Maximum Plasma Concentration (C Max) of Raltegravir in Part 1 | 4723.00 nM |
| Maalox → 4 Hours → Raltegravir | Maximum Plasma Concentration (C Max) of Raltegravir in Part 1 | 3690.96 nM |
| Raltegravir → 4 Hours → Maalox | Maximum Plasma Concentration (C Max) of Raltegravir in Part 1 | 3324.84 nM |
90% CI: [0.55, 1.1]
90% CI: [0.48, 1.04]
Primary
Maximum Plasma Concentration (C Max) of Raltegravir in Part 2
Blood was drawn at time 0, and at various intervals up to 12 hours after dosing with raltegravir, in order to determine the geometric mean maximum plasma concentration.
Time frame: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1 of each period
Population: The per-protocol population consisting of participants from the Raltegravir alone treatment group from Part 1, and the treatment groups from Part 2, who complied with the study procedure and had available data from at least one treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir | Maximum Plasma Concentration (C Max) of Raltegravir in Part 2 | 4723.00 nM |
| Maalox → 4 Hours → Raltegravir | Maximum Plasma Concentration (C Max) of Raltegravir in Part 2 | 4268.72 nM |
| Raltegravir → 4 Hours → Maalox | Maximum Plasma Concentration (C Max) of Raltegravir in Part 2 | 4256.01 nM |
90% CI: [0.58, 1.4]
90% CI: [0.58, 1.41]
Primary
Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 1
Blood was drawn 12 hours after dosing with raltegravir in order to determine the geometric mean plasma concentration.
Time frame: 12 hours after dosing on Day 1 of each period
Population: The per-protocol population consisting of participants from Part 1 only, who complied with the study procedure and had available data from at least one treatment. One participant did not complete one period of Maalox-4 hour-Raltegravir treatment, resulting in an n = 17.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir | Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 1 | 241.35 nM |
| Maalox → 4 Hours → Raltegravir | Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 1 | 96.29 nM |
| Raltegravir → 4 Hours → Maalox | Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 1 | 92.22 nM |
Comparison: The hypothesis is that the true Raltegravir C 12 hrs geometric mean ratio (GMR) is not less than 0.4p-value: 0.50790% CI: [0.31, 0.52]Hochberg step-up procedure
Comparison: The hypothesis is that the true Raltegravir C 12 hrs GMR is not less than 0.4p-value: 0.62490% CI: [0.3, 0.49]Hochberg step-up procedure
Primary
Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 2
Blood was drawn 12 hours after dosing with raltegravir in order to determine the geometric mean plasma concentration.
Time frame: 12 hours after dosing on Day 1 of each period
Population: The per-protocol population consisting of participants from the Raltegravir alone treatment group from Part 1, and the treatment groups from Part 2, who complied with the study procedure and had available data from at least one treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir | Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 2 | 241.35 nM |
| Maalox → 4 Hours → Raltegravir | Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 2 | 121.52 nM |
| Raltegravir → 4 Hours → Maalox | Plasma Concentration of Raltegravir at 12 Hours (C 12 Hrs) in Part 2 | 122.39 nM |
Comparison: The hypothesis is that the true Raltegravir C 12 hrs GMR is not less than 0.490% CI: [0.39, 0.65]
Comparison: The hypothesis is that the true Raltegravir C 12 hrs GMR is not less than 0.490% CI: [0.4, 0.64]