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Pharmacokinetic Study of Super-boosted Lopinavir/Ritonavir Given With Rifampin

Primary Purpose

AIDS, Tuberculosis

Status
Terminated
Phase
Phase 4
Locations
Brazil
Study Type
Interventional
Intervention
Lopinavir/ritonavir and ritonavir
Sponsored by
University of Miami
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for AIDS focused on measuring HIV, AIDS, Tuberculosis, Rifampin, Lopinavir, Pharmacokinetic

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • Antiretroviral naive

  • If not antiretroviral naïve they must meet the following criteria:

    • Taking Kaletra containing regimen with suppressed viral load.
    • Taking an NNRTI or integrase containing regimen without prior history of use of PI for more than 2 weeks
    • Taking an NNRTI or integrase containing regimen with prior exposure to PI greater than 2 weeks. It must be clearly stated in the source document that PI was switched to another agent for convenience.
    • Taking another PI containing regimens with suppressed viral load. It must be clearly stated in source document that if another PI was used for greater than 2 weeks the regimen was switched to another agent for convenience. Subjects with prior history of PI use may be enrolled, if there is a genotype showing no resistance to Kaletra Other Inclusion criteria
  • Be at least 18 years of age and able to give informed consent.
  • Diagnosed with TB by criteria per Brazilian Ministry of Health
  • Have a good clinical response to TB.
  • Tolerating tuberculosis therapy containing rifampin for the 2 weeks prior to screening,except for persons taking protease inhibitors at time of diagnosis of TB.,. Subjects taking protease inhibitors will be screened and initiate visit 1 within 3 days of starting TB medication
  • HIV positive with documentation present in source document.
  • Have a CD4 cell count greater than 50 cells/mm3if not taking ART. Persons with cd4 < 50 may be enrolled, if it is felt that in the best interest of the patient, that enrollment in the study will allow for quicker initiation of antiretroviral therapy than referral to another treatment center.

Exclusion Criteria:

  • Non-compliance with DOTPlus. Alternatively DOT can be done by telephoning patient on a daily basis 5 times a week and having patient annotate taking drug in a log which would be reviewed by clinic staff
  • History of being treated for tuberculosis in the prior 2 years unless there is DST, including PCR testing, showing sensitivity to rifamycin.
  • Known hypersensitivity to rifampin or rifabutin.
  • Liver enzymes greater than 2 times ULN.
  • Bilirubin greater than 2 times ULN.
  • Serum creatinine greater than 3 times ULN.
  • Hemoglobin less than 7.0 gms even if receiving erythropoietin.
  • Absolute neutrophil count less than 750 cells/mm3 even if receiving G-CSF.
  • Fasting triglycerides greater than 400 mg/dL.
  • Fasting cholesterol > 1.6 upper limits of normal.
  • GI intolerance of tuberculosis medications requiring discontinuation of tuberculosis medications.
  • Fasting glucose greater 150 mg/dL.
  • Pregnant women.
  • Use of one of the prohibited medications
  • Any condition that the investigators feel could compromise the use of the current medication.
  • Have a CD4 cell count of 50 cells/mm3or less
  • Hepatitis B or C infection
  • Alcohol or illicit drug use, which in the investigators opinion may affect participation in study.

Sites / Locations

  • Instituto Nacional de Infectologia Evandro Chagas - Fiocruz(INI), Laboratorio de Pesquisa Clinica em Micobacterioses(LAPCLINTB)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lopinavir/ritonavir and ritonavir

Arm Description

Two tablets of twice daily of Lopinavir/ritonavir 200 mg/50mg with 3 tablets of ritonavir 100 mg of twice daily given with rifampin 600 mg daily.

Outcomes

Primary Outcome Measures

Proportion of patients with expected pre dose concentration of lopinavir.
The expected pre dose concentration of lopinavir is >1.0 mcg/mL.

Secondary Outcome Measures

Proportion of patients with successful treatment of HIV therapy.
HIV failure will be defined as failure to drop the viral load by 0.5 log 10 copies/mL drop by week 4 of treatment and a viral load drop >1 log 10 copies/ml by week 8.
Proportion of patients with expected AUC of rifampin
The expected AUC of rifampin is 44-70 mcg•h/mL
Proportion of patient with success of tuberculosis therapy
Success of treatment using criteria established by the Brazilian National Ttuberculosis Program.
Proportion of patients with expected Cmax and AUC of lopinavir
The expected Cmax of lopinavir is 6-14 mcg/mL. The expected AUC lopinavir is 56-130 µg•h/mL
Proportion of patients with expected Cmax of rifampin.
Expected maximum concentration of rifampin is 8-24 mcg/mL

Full Information

First Posted
October 2, 2012
Last Updated
May 14, 2019
Sponsor
University of Miami
Collaborators
Oswaldo Cruz Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT01700790
Brief Title
Pharmacokinetic Study of Super-boosted Lopinavir/Ritonavir Given With Rifampin
Official Title
A Pharmacokinetic Study of Super-boosted Lopinavir/Ritonavir in Combination With Rifampin in HIV-1-infected Patients With Tuberculosis.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Terminated
Why Stopped
No Further Funding
Study Start Date
February 2016 (Actual)
Primary Completion Date
November 17, 2018 (Actual)
Study Completion Date
December 31, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Miami
Collaborators
Oswaldo Cruz Foundation

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The object of this study is to evaluate the pharmacokinetic interactions, short term safety and efficacy of standard dose lopinavir/ritonavir 200mg/50 (two tablets twice daily) given with ritonavir 100 mg three tablets twice daily given in combination with rifampin in HIV-infected persons with tuberculosis
Detailed Description
This will be an open label non-randomized pharmacokinetic study of 10-12 HIV-infected patients co-infected with Mycobacterium tuberculosis. Enrollment: Potential subjects with active tuberculosis who have tolerated a rifampin containing regimen for at least 2 weeks. Potential subjects will be referred from the surrounding communities to Laboratorio de Pesquisa Clinica em Micobacterioses(LAPCLINTB) Visit 1: Subjects will then be started on lopinavir/ritonavir containing HAART regimen with standard twice daily dosing. Ritonavir 100 mg capsules will be added to the regimen and the dose escalated until the patient is taking 3 capsules twice daily. The time between enrollment and visit 1 will be determined by the treating physician. Visit 2: They will return about 1 week after dose escalation has been completed to sample lopinavir and rifampin concentrations. Visit 3: Subject will return in 2 weeks to have repeat to review results of lopinavir concentrations and response to therapy. Ritonavir will be adjusted as needed. Visit 4: Subject will then return in 4 weeks for last visit for evaluation. Lopinavir and rifampin PK will be done.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
AIDS, Tuberculosis
Keywords
HIV, AIDS, Tuberculosis, Rifampin, Lopinavir, Pharmacokinetic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lopinavir/ritonavir and ritonavir
Arm Type
Experimental
Arm Description
Two tablets of twice daily of Lopinavir/ritonavir 200 mg/50mg with 3 tablets of ritonavir 100 mg of twice daily given with rifampin 600 mg daily.
Intervention Type
Drug
Intervention Name(s)
Lopinavir/ritonavir and ritonavir
Other Intervention Name(s)
Kaletra, Norvir
Intervention Description
Two tablets twice daily of Lopinavir/ritonavir 200 mg/50mg with 3 capsules of ritonavir 100 mg twice daily given with rifampin 600 mg daily
Primary Outcome Measure Information:
Title
Proportion of patients with expected pre dose concentration of lopinavir.
Description
The expected pre dose concentration of lopinavir is >1.0 mcg/mL.
Time Frame
Weeks 2 and 8: lopinavir time points at hours 0, 2, 4, 6 and 8.
Secondary Outcome Measure Information:
Title
Proportion of patients with successful treatment of HIV therapy.
Description
HIV failure will be defined as failure to drop the viral load by 0.5 log 10 copies/mL drop by week 4 of treatment and a viral load drop >1 log 10 copies/ml by week 8.
Time Frame
Approximately 10-12 weeks
Title
Proportion of patients with expected AUC of rifampin
Description
The expected AUC of rifampin is 44-70 mcg•h/mL
Time Frame
Approximatley 10-12 weeks
Title
Proportion of patient with success of tuberculosis therapy
Description
Success of treatment using criteria established by the Brazilian National Ttuberculosis Program.
Time Frame
Approximatly 10-12 weeks
Title
Proportion of patients with expected Cmax and AUC of lopinavir
Description
The expected Cmax of lopinavir is 6-14 mcg/mL. The expected AUC lopinavir is 56-130 µg•h/mL
Time Frame
10-12 weeks
Title
Proportion of patients with expected Cmax of rifampin.
Description
Expected maximum concentration of rifampin is 8-24 mcg/mL
Time Frame
Weeks 2 and 8: rifampin time points at hours 0, 2, 4, 6 and 8.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Antiretroviral naive If not antiretroviral naïve they must meet the following criteria: Taking Kaletra containing regimen with suppressed viral load. Taking an NNRTI or integrase containing regimen without prior history of use of PI for more than 2 weeks Taking an NNRTI or integrase containing regimen with prior exposure to PI greater than 2 weeks. It must be clearly stated in the source document that PI was switched to another agent for convenience. Taking another PI containing regimens with suppressed viral load. It must be clearly stated in source document that if another PI was used for greater than 2 weeks the regimen was switched to another agent for convenience. Subjects with prior history of PI use may be enrolled, if there is a genotype showing no resistance to Kaletra Other Inclusion criteria Be at least 18 years of age and able to give informed consent. Diagnosed with TB by criteria per Brazilian Ministry of Health Have a good clinical response to TB. Tolerating tuberculosis therapy containing rifampin for the 2 weeks prior to screening,except for persons taking protease inhibitors at time of diagnosis of TB.,. Subjects taking protease inhibitors will be screened and initiate visit 1 within 3 days of starting TB medication HIV positive with documentation present in source document. Have a CD4 cell count greater than 50 cells/mm3if not taking ART. Persons with cd4 < 50 may be enrolled, if it is felt that in the best interest of the patient, that enrollment in the study will allow for quicker initiation of antiretroviral therapy than referral to another treatment center. Exclusion Criteria: Non-compliance with DOTPlus. Alternatively DOT can be done by telephoning patient on a daily basis 5 times a week and having patient annotate taking drug in a log which would be reviewed by clinic staff History of being treated for tuberculosis in the prior 2 years unless there is DST, including PCR testing, showing sensitivity to rifamycin. Known hypersensitivity to rifampin or rifabutin. Liver enzymes greater than 2 times ULN. Bilirubin greater than 2 times ULN. Serum creatinine greater than 3 times ULN. Hemoglobin less than 7.0 gms even if receiving erythropoietin. Absolute neutrophil count less than 750 cells/mm3 even if receiving G-CSF. Fasting triglycerides greater than 400 mg/dL. Fasting cholesterol > 1.6 upper limits of normal. GI intolerance of tuberculosis medications requiring discontinuation of tuberculosis medications. Fasting glucose greater 150 mg/dL. Pregnant women. Use of one of the prohibited medications Any condition that the investigators feel could compromise the use of the current medication. Have a CD4 cell count of 50 cells/mm3or less Hepatitis B or C infection Alcohol or illicit drug use, which in the investigators opinion may affect participation in study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Catherine Boulanger, MD.
Organizational Affiliation
University of Miami Miller Medical School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Valeria Calvicanti Rolla, MD
Organizational Affiliation
Oswaldo Cruz Foundation
Official's Role
Principal Investigator
Facility Information:
Facility Name
Instituto Nacional de Infectologia Evandro Chagas - Fiocruz(INI), Laboratorio de Pesquisa Clinica em Micobacterioses(LAPCLINTB)
City
Rio de Janeiro
State/Province
RJ
ZIP/Postal Code
21040-900
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
18197120
Citation
Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, Smith PJ, Maartens G, McIlleron HM. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):566-9. doi: 10.1097/QAI.0b013e3181642257.
Results Reference
background
PubMed Identifier
15105105
Citation
la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004 May;48(5):1553-60. doi: 10.1128/AAC.48.5.1553-1560.2004.
Results Reference
background
PubMed Identifier
31704214
Citation
Boulanger C, Rolla V, Al-Shaer MH, Peloquin C. Evaluation of super-boosted lopinavir/ritonavir in combination with rifampicin in HIV-1-infected patients with tuberculosis. Int J Antimicrob Agents. 2020 Feb;55(2):105840. doi: 10.1016/j.ijantimicag.2019.10.021. Epub 2019 Nov 5.
Results Reference
derived

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Pharmacokinetic Study of Super-boosted Lopinavir/Ritonavir Given With Rifampin

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