Pharmacokinetic and Safety Study of Raltegravir and Atazanavir in a Once Daily Dose Regimen in HIV-1 Infected Patients (PRADA)

Pharmacokinetic and Safety Pilotstudy of RAltegravir and Atazanavir in a Once DAily Dose Regimen in HIV-1 Infected Patients (PRADA)

The licensed dose of raltegravir is 400 mg twice daily with or without food. Raltegravir is metabolized predominantly through glucuronidation by UGT1A1. Atazanavir increases the plasma concentrations of raltegravir 400 mg twice daily by 72% due to inhibition of UGT 1A1.

This suggests that combined use of atazanavir and a lower dose frequency of raltegravir, once daily for example, is possible. Another reason why raltegravir most likely can be applied is that its pharmacodynamic effect is not related to Cmin but to AUC which is expected to be similar for an 800mg QD dose when compared to 400mg BD. Phase III clinical trials evaluating QD dosing of raltegravir are currently ongoing and interim results are expected to be published in mid 2009.

A regimen of atazanavir and raltegravir in combination with lamivudine or emtricitabine may be a well tolerated and effective NNRTI-, and ritonavir-sparing regimen that could be an attractive option for both first and second line (after NRTI/NNRTI failure) treatment regimens.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV Infection
• Intervention / Treatment: Drug: raltegravir QD; Drug: atazanavir; Drug: lamivudine (or emtricitabine)

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany
    • University of Bonn
• Netherlands
  • Arnhem, Netherlands
    • Rijnstate Hospital Arnhem
  • Nijmegen, Netherlands
    • Radboud University Medical Centre Nijmegen
  • Rotterdam, Netherlands
    • Erasmus Medical Center Rotterdam

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:

• HIV-infected as documented by positive HIV antibody test and confirmed by Western Blot.
• Subject is at least 18 years of age at the day of screening.
• Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
• HIV-1 RNA < 40 copies/mL for at least 6 months on antiretroviral therapy.
• Subject has no history of previous virological failure or documented resistance mutations

Exclusion Criteria:

• History of sensitivity/idiosyncrasy to the drug or chemically related compounds or excipients, which may be employed in the trial.
• Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
• Inability to understand the nature and extent of the trial and the procedures required.
• Pregnant female (as confirmed by an HCG test performed less than 3 weeks before the first dose) or breast-feeding female.
• Abnormal serum transaminases determined as levels being > 5 times upper limit of normal (see Appendix A for normal ranges of clinical laboratory values).
• Concomitant use of medications that interfere with raltegravir or atazanavir pharmacokinetics: rifampicin, irinotecan, midazolam, triazolam, ergotamine, dihydroergotamine, cisapride, pimozide, lovastatin, simvastatin, indinavir, proton pump inhibitors, H2 receptor antagonists, St. john's wort, Ginkgo Biloba, didanosine, tenofovir, efavirenz, nevirapine, antacids, clarithromycin, phenytoin, phenobarbital, carbamazepine.
• Active hepatobiliary or hepatic disease (including chronic hepatitis B infection).
• Alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Raltegravir BID-QD; Week 1-4; 600 mg of atazanavir to be taken once daily; 400 mg of raltegravir to be taken twice daily; 300 mg of lamivudine (or 200 mg of emtricitabine) to be taken once daily Week 5-8; 600 mg of atazanavir to be taken once daily; 800 mg of raltegravir to be taken once daily; 300 mg of lamivudine (or 200 mg of emtricitabine) to be taken once daily	Drug: raltegravir QD; Raltegravir 800mg QD; Drug: atazanavir; atazanavir; Drug: lamivudine (or emtricitabine); lamivudine (or emtricitabine)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
pharmacokinetics of raltegravir	after two weeks of reference treatment and after two weeks of test treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Viral load	after two weeks treatment with the reference treatment and after two weeks treatment with the test treatment
Adverse events	entire trial

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: David Burger, Radboud University Medical Center

Publications and helpful links

General Publications

• Jansen A, Colbers EP, van der Ven AJ, Richter C, Rockstroh JK, Wasmuth JC, van Luin M, Burger DM. Pharmacokinetics of the combination raltegravir/atazanavir in HIV-1-infected patients. HIV Med. 2013 Aug;14(7):449-52. doi: 10.1111/hiv.12029. Epub 2013 Mar 18.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: July 21, 2009
• First Submitted That Met QC Criteria: July 21, 2009
• First Posted (Estimate): July 22, 2009

Study Record Updates

• Last Update Posted (Actual): November 12, 2020
• Last Update Submitted That Met QC Criteria: November 9, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: pharmacokinetics; Treatment experienced; raltegravir; single dose
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Emtricitabine; Raltegravir Potassium; Lamivudine; Atazanavir Sulfate
• Other Study ID Numbers: UMCN-AKF 08.07