HIV Infection
Conditions
Brief summary
In order to define the safe windows for co-dosing of metal-cation antacids with once daily administered raltegravir, this study will evaluate the effect of both calcium carbonate and magnesium/aluminum hydroxide antacids on the pharmacokinetics of raltegravir, due to dosage of 1200 mg raltegravir in HIV-infected participants already taking 400 mg raltegravir twice daily as part of their HIV treatment regimen.
Interventions
DRUGRaltegravir 1200 mg
Two tablets of 600 mg raltegravir administered orally, once daily, over 5 days of Pre-treatment, and once at the start of Periods 1-4.
DRUGTUMS
Three tablets of TUMS Ultra Strength (US) 1000, taken orally, concomitantly with raltegravir in Period 2, and 12 hours after raltegravir in Period 4
DRUGLeader Antacid
20 mL Leader Antacid Maximum Strength (MS) taken orally 12 hours after raltegravir, in Period 3
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is HIV positive * Is on a stable raltegravir-containing (400 mg every 12hr) antiretroviral (ARV) regimen for at least 1 month prior to study entry, with no changes, including dose adjustments; and agrees to maintain their current ARV therapy throughout the study. * Be male, or a non-pregnant and non-breast feeding female at least 18 years of age at the pre-trial (screening) * Has a Body Mass Index (BMI) =\< 32 kg/m\^2
Exclusion criteria
* Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases (excluding HIV) * Has a history of gastric bypass surgery * Has a history of cancer (malignancy) * Has a history of chronic diarrhea within approximately 3 months prior to the pre-trial visit * Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pre-trial visit * Has participated in another investigational trial within 4 weeks prior to the pre-trial visit * Is currently taking rifampin or atazanavir or is unable to refrain from the use of 1) any proton pump inhibitor from two weeks prior to the study through the completion of Period 4, and 2) any H2-blockers, over-the-counter antacids, calcium supplements or multivitamins from one week prior to the study through the completion of Period 4 * Consumes greater than 3 glasses of alcoholic beverages or distilled spirits per day * Consumes greater than 6 servings of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day * Is currently a regular user (including recreational use) of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 6 months of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of Raltegravir Following Once Daily Administration of Raltegravir | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose | In Period 1 participants were treated with 1200 mg raltegravir alone; followed by Period 2 where participants were treated with 1200 mg raltegravir and three tablets of TUMS Ultra Strength (US) 1000 taken orally concomitantly; followed by Period 3 where participants were treated with 1200 mg raltegravir and 12 hours later with 20 mL Leader Antacid Maximum Strength (MS) taken orally; followed by Period 4 where participants were treated with 1200 mg raltegravir and 12 hours later with three tablets of TUMS US 1000 taken orally. The wait between Periods was a maximum of 7 days, during which participants were treated with 1200 mg raltegravir once daily. To determine the plasma concentration of raltegravir, blood samples were collected from pre-dose up to 24 hours post-dose, and analysis of variance (ANOVA) modeling was performed on natural log-transformed values to derive geometric least-squares means. |
| Maximum Plasma Concentration (Cmax) of Raltegravir Following Once Daily Administration of Raltegravir | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose | In Period 1 participants were treated with 1200 mg raltegravir alone; followed by Period 2 where participants were treated with 1200 mg raltegravir and three tablets of TUMS US 1000 taken orally concomitantly; followed by Period 3 where participants were treated with 1200 mg raltegravir and 12 hours later with 20 mL Leader Antacid MS taken orally; followed by Period 4 where participants were treated with 1200 mg raltegravir and 12 hours later with three tablets of TUMS US 1000 taken orally. The wait between Periods was a maximum of 7 days, during which participants were treated with 1200 mg raltegravir once daily. To determine the plasma concentration of raltegravir, blood samples were collected from pre-dose up to 24 hours post-dose, and ANOVA modeling was performed on natural log-transformed values to derive geometric least-squares means. |
| Plasma Concentration at 24 Hrs Post-dose (C24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 24 hours post-dose | In Period 1 participants were treated with 1200 mg raltegravir alone; followed by Period 2 where participants were treated with 1200 mg raltegravir and three tablets of TUMS US 1000 taken orally concomitantly; followed by Period 3 where participants were treated with 1200 mg raltegravir and 12 hours later with 20 mL Leader Antacid MS taken orally; followed by Period 4 where participants were treated with 1200 mg raltegravir and 12 hours later with three tablets of TUMS US 1000 taken orally. The wait between Periods was a maximum of 7 days, during which participants were treated with 1200 mg raltegravir once daily. To determine the plasma concentration of raltegravir, blood samples were collected at 24 hours post-dose, and ANOVA modeling was performed on natural log-transformed values to derive geometric least-squares means. |
Participant flow
Recruitment details
Males or females, at least 18 years of age, with HIV infection were enrolled in this trial.
Pre-assignment details
Starting five days prior to Period 1 participants were treated with 1200 mg raltegravir (MK-0518), once daily for five days.
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants All participants who enrolled in the study | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 4 | Lost to Follow-up | 1 |
| Wait 1 | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Continuous | 49.8 Years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 20 | 4 / 19 | 5 / 19 | 5 / 19 |
| serious Total, serious adverse events | 0 / 20 | 1 / 19 | 0 / 19 | 1 / 19 |
Outcome results
Primary
Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of Raltegravir Following Once Daily Administration of Raltegravir
In Period 1 participants were treated with 1200 mg raltegravir alone; followed by Period 2 where participants were treated with 1200 mg raltegravir and three tablets of TUMS Ultra Strength (US) 1000 taken orally concomitantly; followed by Period 3 where participants were treated with 1200 mg raltegravir and 12 hours later with 20 mL Leader Antacid Maximum Strength (MS) taken orally; followed by Period 4 where participants were treated with 1200 mg raltegravir and 12 hours later with three tablets of TUMS US 1000 taken orally. The wait between Periods was a maximum of 7 days, during which participants were treated with 1200 mg raltegravir once daily. To determine the plasma concentration of raltegravir, blood samples were collected from pre-dose up to 24 hours post-dose, and analysis of variance (ANOVA) modeling was performed on natural log-transformed values to derive geometric least-squares means.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Population: Per-Protocol: Participants who complied with the protocol sufficiently to ensure that generated data would reflect the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Period 1: Raltegravir Only | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 53.7 hr*µM |
| Period 2: Raltegravir + TUMS Concomitantly | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 14.8 hr*µM |
| Period 3: Raltegravir + 12 Hrs Leader Antacid | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 46.3 hr*µM |
| Period 4: Raltegravir + 12 Hrs TUMS | Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hrs (AUC 0-24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 48.5 hr*µM |
90% CI: [0.24, 0.32]
90% CI: [0.73, 1.03]
90% CI: [0.8, 1.03]
Primary
Maximum Plasma Concentration (Cmax) of Raltegravir Following Once Daily Administration of Raltegravir
In Period 1 participants were treated with 1200 mg raltegravir alone; followed by Period 2 where participants were treated with 1200 mg raltegravir and three tablets of TUMS US 1000 taken orally concomitantly; followed by Period 3 where participants were treated with 1200 mg raltegravir and 12 hours later with 20 mL Leader Antacid MS taken orally; followed by Period 4 where participants were treated with 1200 mg raltegravir and 12 hours later with three tablets of TUMS US 1000 taken orally. The wait between Periods was a maximum of 7 days, during which participants were treated with 1200 mg raltegravir once daily. To determine the plasma concentration of raltegravir, blood samples were collected from pre-dose up to 24 hours post-dose, and ANOVA modeling was performed on natural log-transformed values to derive geometric least-squares means.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Population: Per-Protocol: Participants who complied with the protocol sufficiently to ensure that generated data would reflect the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Period 1: Raltegravir Only | Maximum Plasma Concentration (Cmax) of Raltegravir Following Once Daily Administration of Raltegravir | 20000 nM |
| Period 2: Raltegravir + TUMS Concomitantly | Maximum Plasma Concentration (Cmax) of Raltegravir Following Once Daily Administration of Raltegravir | 5240 nM |
| Period 3: Raltegravir + 12 Hrs Leader Antacid | Maximum Plasma Concentration (Cmax) of Raltegravir Following Once Daily Administration of Raltegravir | 17300 nM |
| Period 4: Raltegravir + 12 Hrs TUMS | Maximum Plasma Concentration (Cmax) of Raltegravir Following Once Daily Administration of Raltegravir | 19500 nM |
90% CI: [0.21, 0.32]
90% CI: [0.65, 1.15]
90% CI: [0.81, 1.17]
Primary
Plasma Concentration at 24 Hrs Post-dose (C24hr) of Raltegravir Following Once Daily Administration of Raltegravir
In Period 1 participants were treated with 1200 mg raltegravir alone; followed by Period 2 where participants were treated with 1200 mg raltegravir and three tablets of TUMS US 1000 taken orally concomitantly; followed by Period 3 where participants were treated with 1200 mg raltegravir and 12 hours later with 20 mL Leader Antacid MS taken orally; followed by Period 4 where participants were treated with 1200 mg raltegravir and 12 hours later with three tablets of TUMS US 1000 taken orally. The wait between Periods was a maximum of 7 days, during which participants were treated with 1200 mg raltegravir once daily. To determine the plasma concentration of raltegravir, blood samples were collected at 24 hours post-dose, and ANOVA modeling was performed on natural log-transformed values to derive geometric least-squares means.
Time frame: 24 hours post-dose
Population: Per-Protocol: Participants who complied with the protocol sufficiently to ensure that generated data would reflect the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Period 1: Raltegravir Only | Plasma Concentration at 24 Hrs Post-dose (C24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 75.6 nM |
| Period 2: Raltegravir + TUMS Concomitantly | Plasma Concentration at 24 Hrs Post-dose (C24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 39.6 nM |
| Period 3: Raltegravir + 12 Hrs Leader Antacid | Plasma Concentration at 24 Hrs Post-dose (C24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 32.0 nM |
| Period 4: Raltegravir + 12 Hrs TUMS | Plasma Concentration at 24 Hrs Post-dose (C24hr) of Raltegravir Following Once Daily Administration of Raltegravir | 32.4 nM |
90% CI: [0.45, 0.61]
90% CI: [0.34, 0.52]
90% CI: [0.36, 0.51]