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

NCT04531072 | Completed Phase 4

• 1 other identifier: D43TW010134
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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

Conditions

Drug Interaction

Keywords

Drug interaction, artemether-lumefantrine, atazanavir-ritonavir, LUTH

Outcome Measures

Primary Outcomes (8)

• Drug exposure (Area under the curve) of lumefantrine

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

  2 weeks

• Maximum plasma concentration (Cmax) of lumefantrine

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

  2 weeks

• Day 7 lumefantrine concentration

  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.

  2 weeks

• QTc-interval

  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.

  One week

• Haemoglobin level

  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.

  One week

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels

  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.

  One week

• Creatinine level

  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.

  One week

• Adverse events

  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.

  Two weeks

Study Arms (2)

ATVr-arm

EXPERIMENTAL

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; Drug: Atazanavir-ritonavir 300/100 mg

AL-arm (Control)

ACTIVE COMPARATOR

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

Interventions

Artemether-lumefantrine DRUG

Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy

Also known as: Coartem 80/480, P01BF01

AL-arm (Control); ATVr-arm

Atazanavir-ritonavir 300/100 mg DRUG

Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy

Also known as: Anzavir-R, J05AR23

ATVr-arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

Apin (Aids Prevention Initiatives in Nigeria) clinic, Lagos University Teaching Hospital

Surulere, Lagos, 001, Nigeria

Location

Related Publications (1)

• Usman SO, Oreagba IA, Kadri MR, Adewumi OO, Akinyede A, Agbaje EO, Abideen G, Busari AA, Hassan OO, Akinleye MO, Akanmu AS. Evaluation of the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine in patients living with HIV in Lagos University Teaching Hospital, South-Western Nigeria. Eur J Clin Pharmacol. 2021 Sep;77(9):1341-1348. doi: 10.1007/s00228-021-03116-x. Epub 2021 Mar 23.

  PMID: 33755736 DERIVED

MeSH Terms

Interventions

Artemether, Lumefantrine Drug Combination; atazanavir, ritonavir drug combination

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Sikiru Usman, Ph.D.

  University of Lagos

  PRINCIPAL INVESTIGATOR

• Ibrahim Oreagba, Ph.D.

  University of Lagos

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Two arm study namely: ATVr arm and AL (Control) arm each consisting of 10 participants in a parallel study design

Study Record Dates

• First Submitted: August 16, 2020
• First Posted: August 28, 2020
• Study Start: September 18, 2018
• Primary Completion: May 15, 2019
• Study Completion: August 15, 2019
• Last Updated: August 28, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

NG (1)