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

Effect of Atazanavir-ritonavir on the Pharmacokinetics and Toxicity of Lumefantrine in People Living With HIV Attending Lagos University Teaching Hospital

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

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: Artemether-lumefantrine; Drug: Atazanavir-ritonavir 300/100 mg

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 Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Nigeria
  • Lagos State
    • Suru Lere, Lagos State, Nigeria, 001
      • Apin (Aids Prevention Initiatives in Nigeria) clinic, Lagos University Teaching Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Fogarty International Center of the National Institute of Health
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Minority Health and Health Disparities (NIMHD); NIH Office of AIDS Research (OAR)
• Investigators: Principal Investigator: Sikiru Usman, Ph.D., University of Lagos; Study Director: Ibrahim Oreagba, Ph.D., University of Lagos

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2018
• Primary Completion (Actual): May 15, 2019
• Study Completion (Actual): August 15, 2019

Study Registration Dates

• First Submitted: August 16, 2020
• First Submitted That Met QC Criteria: August 26, 2020
• First Posted (Actual): August 28, 2020

Study Record Updates

• Last Update Posted (Actual): August 28, 2020
• Last Update Submitted That Met QC Criteria: August 26, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Drug interaction, artemether-lumefantrine, atazanavir-ritonavir, LUTH
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; HIV Protease Inhibitors; Viral Protease Inhibitors; Antimalarials; Ritonavir; Lumefantrine; Artemether; Atazanavir Sulfate; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: D43TW010134 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: IPD would not be made available to other researchers

Drug and device information, study documents

• 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