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

Fogarty International Center of the National Institute of Health20 enrolled

Overview

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

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

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Drug Interaction

Interventions

Artemether-lumefantrineDRUG

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

Atazanavir-ritonavir 300/100 mgDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

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

Surulere, Lagos, Nigeria

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: One week

Creatinine level

Data from ClinicalTrials.gov

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