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

Drug Interaction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04531072
• Other study ID #: D43TW010134
• Status: Completed
• Phase: Phase 4
• Start date: September 18, 2018
• Est. completion date: August 15, 2019

Study information

• Verified date: August 2020
• Source: Fogarty International Center of the National Institute of Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: August 15, 2019
• Est. primary completion date: May 15, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Drug Interaction

Intervention

Drug:
• Artemether-lumefantrine
Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy
• Atazanavir-ritonavir 300/100 mg
Safety and efficacy evaluation during concurrent use of artemether-lumefantrine and atazanavir-ritonavir based antiretroviral therapy

Locations

Country	Name	City	State
Nigeria	Apin (Aids Prevention Initiatives in Nigeria) clinic, Lagos University Teaching Hospital	Suru Lere	Lagos State

Sponsors (4)

Lead Sponsor	Collaborator
Fogarty International Center of the National Institute of Health	National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Minority Health and Health Disparities (NIMHD), NIH Office of AIDS Research (OAR)

Country where clinical trial is conducted

Nigeria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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