Drug Interaction
Conditions
Keywords
Drug interaction, artemether-lumefantrine, atazanavir-ritonavir, LUTH
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.
Interventions
DRUGArtemether-lumefantrine
Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy
DRUGAtazanavir-ritonavir 300/100 mg
Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy
Sponsors
NIH Office of AIDS Research (OAR)
National Institute on Minority Health and Health Disparities (NIMHD)
National Institute of Neurological Disorders and Stroke (NINDS)
Fogarty International Center of the National Institute of Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Two arm study namely: ATVr arm and AL (Control) arm each consisting of 10 participants in a parallel study design
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug exposure (Area under the curve) of lumefantrine | 2 weeks | Change in drug exposure (AUC) of lumefantrine may indicate interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction |
| Maximum plasma concentration (Cmax) of lumefantrine | 2 weeks | Change in maximum plasma concentration (Cmax) of lumefantrine may indicate interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction |
| Day 7 lumefantrine concentration | 2 weeks | 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. |
| QTc-interval | One week | 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. |
| Haemoglobin level | One week | 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. |
| Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels | One week | 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. |
| Creatinine level | One week | 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. |
| Adverse events | Two weeks | 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. |
Countries
Nigeria
Outcome results
None listed