To Determine if There Are Pharmacokinetic Interactions at Plasma or Intracellular Level Between Nucleosides and Tenofovir

Determination of Plasma and Intracellular Levels of Nucleoside Reverse Transcriptase Inhibitors (NRTI) and of Nucleotide Analog Tenofovir Disoproxil Fumarate (TDF) in Patients Treated With Abacavir and/or Lamivudine Given With or Without TDF.

The purpose of this study is to evaluate if there are pharmacokinetic interactions between the NRTI 3TC and ABV, and the TDF nucleotide. For this purpose, the intracellular and plasma levels of 3TC and ABV will be compared in patients given these nucleosides with TDF and 30 days after the interruption of the TDF.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Patients in treatment with 3TC + TDF + LPV/rtv, stop tenofovir during 4 weeks; Drug: Patients in treatment with ABV + TDF + LPV/rtv, stop tenofovir during 4 weeks; Drug: Patients in treatment with 3TC + ABV + TDF+ LPV/rtv, stop TDF during 4 weeks

Detailed Description

There is clear evidence of pharmacokinetic interaction between ddI+TDF. However, the interaction between TDF and other NRTIs, mainly at intracellular level, has not been so well studied.

Since all the NRTIs are anabolized at intracellular level by numerous kinases, and are transported by passive carrier systems, the interaction may be between TDF and other NRTIs.

This study aims to investigate the pharmacokinetic interactions between the TDF and the nucleosides abacavir (ABV) and lamivudine (3TC) at plasma and intracellular level.

With this objective, intracellular and plasma levels will be analysed in a group of patients that receive the combinations 3TC +TDF, ABV+TDF and 3TC+ABV+TDF together with lopinavir/rtv or nevirapine. Subsequently, in a second phase of the study, in the group of patients given ABV and/or 3TC + TDF + lopinavir/rtv, the pharmacokinetic determinations will be repeated after a 4-week interruption of the TDF .

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. HIV+ patients aged above 18 years.
2. Undetectable HIV viral load in the last determination
3. Patients capable of correct compliance according to clinical criteria.
4. Patients on triple HAART therapy for the previous 3 months including 3TC and/or ABV and TDF, with a PI (Lopinavir/ritonavir) or an NNRTI (Nevirapine)
5. Women may not be of fertile age (defined as at least one year from menopause or undergoing any surgical sterilisation technique), or must undertake to use a barrier contraceptive method during the study.
6. Ability to provide informed consent.

Exclusion Criteria:

1. Incorrect therapeutic compliance over the four weeks before the beginning of the study.
2. Interruption or withdrawal from therapy during follow-up.
3. Concomitant treatment with any drug which according to the clinician's criterion may interact with the investigational antiretrovirals, such as other antiretrovirals.
4. Triple HAART therapy including Nevirapine (for phase II)
5. Documented or suspected resistance to ABV, 3TC or lopinavir/rtv (for phase II).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Phase I: 3TC + TDF + NVP or LPV/rtv Phase II: patients on treatment with LPV/rtv, stop TDF during 4 weeks: 3TC + LPV/rtv	Drug: Patients in treatment with 3TC + TDF + LPV/rtv, stop tenofovir during 4 weeks; 3TC (300 mg/24 h, 1 tablet/24 h) + Lopinavir/ritonavir (400 mg/12 h, 3 tablets/12 h); Other Names: Kaletra; Epivir
Experimental: 2; Phase I: ABV + TDF + NVP or LPV/rtv Phase II: patients on treatment with LPV/rtv, stop TDF during 4 weeks: ABV + LPV/rtv	Drug: Patients in treatment with ABV + TDF + LPV/rtv, stop tenofovir during 4 weeks; ABV (300 mg/12 h, 1 tablet/12 h)+ Lopinavir/ritonavir (400 mg/12 h, 3 tablets/12 h); Other Names: Ziagen; Kaletra
Experimental: 3; Phase I: 3TC + ABV + TDF + NVP or LPV/rtv Phase II: patients on treatment with LPV/rtv, stop TDF during 4 weeks: 3TC + ABV + LPV/rtv	Drug: Patients in treatment with 3TC + ABV + TDF+ LPV/rtv, stop TDF during 4 weeks; 3TC (300 mg/24 h, 1 tablet/24 h)+ ABV (300 mg/12 h, 1 tablet/12 h)+ Lopinavir/ritonavir (400 mg/12 h, 3 tablets/12 h).; Other Names: Ziagen; Kaletra; Epivir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint will be the variation between the intracellular levels of 3TC and ABC before and after the interruption of the treatment with TDF	At baseline and week 4.

Secondary Outcome Measures

Outcome Measure	Time Frame
Variations between the plasma levels of 3TC and ABC before and after interruption of the treatment with TDF.	at baseline and week 4
Correlation between the intracellular and plasma levels of 3TC, ABC and TDF.	at baseline and week 4
Changes in the intracellular levels of TDF following the withdrawal of the drug.	At week 4.

Collaborators and Investigators

• Sponsor: Germans Trias i Pujol Hospital
• Collaborators: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): September 1, 2005

Study Registration Dates

• First Submitted: June 8, 2006
• First Submitted That Met QC Criteria: June 8, 2006
• First Posted (Estimate): June 9, 2006

Study Record Updates

• Last Update Posted (Estimate): September 8, 2008
• Last Update Submitted That Met QC Criteria: September 5, 2008
• Last Verified: September 1, 2008

More Information

Terms related to this study

• Keywords: Tenofovir; Abacavir; Plasma concentration; Intracellular concentrations; Lamivudine (3TC); Pharmacokinetic interactions
• Additional Relevant MeSH Terms: 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; Tenofovir; Lamivudine; Abacavir
• Other Study ID Numbers: INTRANUCS; 2004-000948-25