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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Drug Interaction

Intervention / Treatment
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* Drug: Artemether-lumefantrine
* Drug: Atazanavir-ritonavir 300/100 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two arm study namely: ATVr arm and AL (Control) arm each consisting of 10 participants in a parallel study design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATVr-arm<br>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<br>* Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy<br>* Other names: Coartem 80/480, P01BF01;Drug: Atazanavir-ritonavir 300/100 mg<br>* Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy<br>* Other names: Anzavir-R, J05AR23;|
| Active Comparator: AL-arm (Control)<br>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<br>* Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy<br>* Other names: Coartem 80/480, P01BF01;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug interaction, artemether-lumefantrine, atazanavir-ritonavir, LUTH