The Effect of Antacids on the Pharmacokinetics (PK) of Raltegravir in Human Immunodeficiency Virus (HIV)-Infected Participants (MK-0518-824)

A Study to Evaluate the Influence of Metal Cation-Containing Antacids on MK-0518 Pharmacokinetics in HIV-Infected Subjects on a Stable Raltegravir-Containing Regimen

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Raltegravir 1200 mg; Drug: TUMS; Drug: Leader Antacid

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Raltegravir Pre- and 4 Period Sequence; Starting five days prior to Period 1 participants will be treated with 1200 mg raltegravir, once daily for five days. In Period 1 participants will be treated with 1200 raltegravir alone; this is followed by Period 2 where participants will be treated with 1200 mg raltegravir and TUMS concomitantly; this is followed by Period 3 where participants will be treated with 1200 mg raltegravir and 12 hours later with Leader Antacid; followed by Period 4 where participants will be treated with 1200 mg raltegravir and 12 hours later with TUMS. The wait between Periods is 2-7 days.

Drug: Raltegravir 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.; Drug: TUMS; Three tablets of TUMS Ultra Strength (US) 1000, taken orally, concomitantly with raltegravir in Period 2, and 12 hours after raltegravir in Period 4; Drug: Leader Antacid; 20 mL Leader Antacid Maximum Strength (MS) taken orally 12 hours after raltegravir, in Period 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
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.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
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.	24 hours post-dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Krishna R, East L, Larson P, Valiathan C, Butterfield K, Teng Y, Hernandez-Illas M. Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir. J Pharm Pharmacol. 2016 Nov;68(11):1359-1365. doi: 10.1111/jphp.12632. Epub 2016 Sep 27.

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2015
• Primary Completion (Actual): August 29, 2015
• Study Completion (Actual): October 9, 2015

Study Registration Dates

• First Submitted: June 12, 2015
• First Submitted That Met QC Criteria: June 12, 2015
• First Posted (Estimate): June 16, 2015

Study Record Updates

• Last Update Posted (Actual): August 27, 2018
• Last Update Submitted That Met QC Criteria: July 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Gastrointestinal Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Raltegravir Potassium; Antacids
• Other Study ID Numbers: 0518-824

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf