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

Fogarty International Center of the National Institute of Health

Status and phase: Completed; Phase 4

Conditions: Drug Interaction

Treatments: Drug: Atazanavir-ritonavir 300/100 mg; Drug: Artemether-lumefantrine

Study type: Interventional

Funder types: NIH

Identifiers

NCT04531072

D43TW010134

Details and patient eligibility

About

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

Full 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.

Enrollment: 20 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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20 participants in 2 patient groups

ATVr-arm

Experimental group

Description:

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.

Treatment:

Drug: Artemether-lumefantrine

Drug: Atazanavir-ritonavir 300/100 mg

AL-arm (Control)

Active Comparator group

Description:

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.

Treatment:

Drug: Artemether-lumefantrine