Clinical trial NCT04531072: Effect of Atazanavir-ritonavir on the Pharmacokinetics and Toxicity of Lumefantrine
Official title: Effect of Atazanavir-ritonavir on the Pharmacokinetics and Toxicity of Lumefantrine in People Living With HIV Attending Lagos University Teaching Hospital
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Drug Interaction
Keywords: Drug interaction, artemether-lumefantrine, atazanavir-ritonavir, LUTH
Lead sponsor: Fogarty International Center of the National Institute of Health
Sponsor class: NIH
Collaborators: name: NIH Office of AIDS Research (OAR)
name: National Institute on Minority Health and Health Disparities (NIMHD)
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2020-08-28
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two arm study namely: ATVr arm and AL (Control) arm each consisting of 10 participants in a parallel study design
Primary purpose: BASIC_SCIENCE

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Drug exposure (Area under the curve) of lumefantrine
timeFrame: 2 weeks
measure: Maximum plasma concentration (Cmax) of lumefantrine
timeFrame: 2 weeks
measure: Day 7 lumefantrine concentration
timeFrame: 2 weeks
measure: QTc-interval
timeFrame: One week
measure: Haemoglobin level
timeFrame: One week
measure: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
timeFrame: One week
measure: Creatinine level
timeFrame: One week
measure: Adverse events
timeFrame: Two weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Suru Lere
country: Nigeria
facility: Apin (Aids Prevention Initiatives in Nigeria) clinic, Lagos University Teaching Hospital
state: Lagos State
Study officials:
affiliation: University of Lagos
name: Sikiru Usman, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Lagos
name: Ibrahim Oreagba, Ph.D.
role: STUDY_DIRECTOR
References:
citation: 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.