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Effect of Atazanavir-ritonavir on the Pharmacokinetics and Toxicity of Lumefantrine

Sponsor
Fogarty International Center of the National Institute of Health (NIH)
Overall Status
Completed
CT.gov ID
NCT04531072
Collaborator
NIH Office of AIDS Research (OAR) (NIH), National Institute on Minority Health and Health Disparities (NIMHD) (NIH), National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
20
Enrollment
1
Location
2
Arms
10.9
Actual Duration (Months)
1.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A case control pharmacokinetic study evaluating the effects of atazanavir-ritonavir on the pharmacokinetics and toxicity of lumefantrine in people living with HIV attending APIN clinic of the Lagos University Teaching Hospital

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Atazanavir-ritonavir (ATVr) based antiretroviral therapy and artemether-lumefantrine (AL) are commonly used drugs for the treatment of Human Immune Deficiency Virus (HIV) infection and malaria respectively in Nigeria. However, both drugs interact with Cytochrome P 3A4 (CYP 3A4) isoenzymes which may spawn clinically significant pharmacokinetic interactions.

The study was aimed at evaluating the effects of atazanavir-ritonavir on the pharmacokinetics and toxicity of lumefantrine.

In a case control pharmacokinetic study, twenty participants who tested positive for Plasmodium falciparum malaria were recruited and divided into two groups (ATVr-arm, n=10; and Control-arm, n= 10). All the participants were administered with 6 doses of AL 80-480 mg (Coartem). Thereafter, blood samples were collected from them at different time intervals over seven days. The lumefantrine concentration in each sample was determined with high-performance liquid chromatography (HPLC) and entered into WinNonlin® software to determine the pharmacokinetic parameters of lumefantrine which were compared between the test and control groups. Toxicity was evaluated with adverse events monitoring, electrocardiography, haematological and blood chemistry tests at pre and post doses of artemether-lumefantrine.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Two arm study namely: ATVr arm and AL (Control) arm each consisting of 10 participants in a parallel study designTwo arm study namely: ATVr arm and AL (Control) arm each consisting of 10 participants in a parallel study design
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
Effect of Atazanavir-ritonavir on the Pharmacokinetics and Toxicity of Lumefantrine in People Living With HIV Attending Lagos University Teaching Hospital
Actual Study Start Date :
Sep 18, 2018
Actual Primary Completion Date :
May 15, 2019
Actual Study Completion Date :
Aug 15, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: ATVr-arm

10 participants living with HIV and having uncomplicated Falciparum malaria were administered: Atazanavir-ritonavir (300/100 mg) one tablet once daily continuously + tenofovir-lamivudine (300/300 mg) one tablet once daily continuously and artemether-lumefantrine (80/480 mg) one tablet twice daily for three days at 0, 8, 24, 36, 48 and 60 hour.

Drug: Artemether-lumefantrine
Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy
Other Names:
  • Coartem 80/480, P01BF01

    • Drug: Atazanavir-ritonavir 300/100 mg
    Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy
    Other Names:
  • Anzavir-R, J05AR23

    		•
    Active Comparator: AL-arm (Control)

    10 participants who were HIV negative but having uncomplicated Falciparum malaria were administered: Artemether-lumefantrine 80/480 mg, one tablet twice daily for three days at 0, 8, 24, 36, 48 and 60 hour.

    Drug: Artemether-lumefantrine
    Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy
    Other Names:
  • Coartem 80/480, P01BF01

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Drug exposure (Area under the curve) of lumefantrine [2 weeks]

      Change in drug exposure (AUC) of lumefantrine may indicate interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction

    2. Maximum plasma concentration (Cmax) of lumefantrine [2 weeks]

      Change in maximum plasma concentration (Cmax) of lumefantrine may indicate interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction

    3. Day 7 lumefantrine concentration [2 weeks]

      This the plasma concentration of lumefantrine at the seventh day of commencement of the first dose. Efficacy is indicated when it is 280 ng/mL and above.

    4. QTc-interval [One week]

      Change in mean or median QTc-interval above therapeutic range at post-dose of artemether-lumefantrine indicates cardio-toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.

    5. Haemoglobin level [One week]

      Change in mean or median hemoglobin level above therapeutic range at post-dose of artemether-lumefantrine indicates haemotoxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.

    6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels [One week]

      Change in mean or median ALT and AST levels above therapeutic range at post-dose of artemether-lumefantrine indicates liver toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.

    7. Creatinine level [One week]

      Change in mean or median creatinine level above therapeutic range at post-dose of artemether-lumefantrine indicates renal toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.

    8. Adverse events [Two weeks]

      Change in frequency of adverse events post-dose of artemether-lumefantrine indicates toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • Adult male or non-gravid female ≥18 years of age,

    • Informed written consent,

    • Malaria parasitaemia

    • Axillary temperature ≥37.5°C or history of fever within 24 hours before visiting the clinic and with, at least, any of the following signs and symptoms of uncomplicated malaria: chills, sweats, headaches, muscle aches, nausea, vomiting, diarrhoea, body weakness, poor appetite and pallor.

    • Hemoglobin (Hb) ≥8 g/dl

    • Body weight ≥35 kg

    • HIV positive (ATVr arm), HIV negative (AL/control arm)

    Exclusion Criteria:

    • Severe anaemia' (Haemoglobin levels < 8g/dl)

    • Smokers/alcoholics and users of substances which inhibit or induce CYP3A4 iso enzymes

    • Withdrawal of consent

    • Known allergy to any of the study drugs

    • Development of complications or severe adverse effects

    • Smokers/alcoholics and users of caffeine, drugs which induce or inhibit CYP3A4 and CYP2B6

    • Evidence of chronic illnesses such as diabetes, hypertension, psychiatric illnesses

    • Subject taking any drugs or having any condition known to prolong QT-intervals

    • Signs of severe malaria

    • Use of anti-tubercular drugs for at least three months prior to enrolment

    • Being on anti-malarial drugs within four weeks prior to enrolment

    • Pregnant or nursing mother.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Apin (Aids Prevention Initiatives in Nigeria) clinic, Lagos University Teaching Hospital Suru Lere Lagos State Nigeria 001

    Sponsors and Collaborators

    • Fogarty International Center of the National Institute of Health
    • NIH Office of AIDS Research (OAR)
    • National Institute on Minority Health and Health Disparities (NIMHD)
    • National Institute of Neurological Disorders and Stroke (NINDS)

    Investigators

    • Principal Investigator: Sikiru Usman, Ph.D., University of Lagos
    • Study Director: Ibrahim Oreagba, Ph.D., University of Lagos

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Sikiru Olatunji Usman, Principal Investigator, Fogarty International Center of the National Institute of Health
    ClinicalTrials.gov Identifier:
    NCT04531072
    Other Study ID Numbers:
    • D43TW010134
    First Posted:
    Aug 28, 2020
    Last Update Posted:
    Aug 28, 2020
    Last Verified:
    Aug 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Sikiru Olatunji Usman, Principal Investigator, Fogarty International Center of the National Institute of Health
    Drug interaction, artemether-lumefantrine, atazanavir-ritonavir, LUTH
    Additional relevant MeSH terms:
    Ritonavir
    Atazanavir Sulfate
    Lumefantrine
    Artemether
    Artemether, Lumefantrine Drug Combination

    Study Results

    No Results Posted as of Aug 28, 2020