Pharmacokinetic and Pharmacodynamic Study of Mefloquine and Dihydroartemisinin-Piperaquine in Healthy Subjects

Healthy Clinical Trial

Official title: Open-Label Study to Evaluate Potential Pharmacokinetic and Pharmacodynamic Interactions of Orally Administered Mefloquine and Dihydroartemisinin-Piperaquine in Healthy Adult Subjects

Status Completed

Clinical Trial Summary

This is an open-label sequential pharmacokinetic study in 16 healthy glucose-6-phosphate dehydrogenase (G6PD) normal Thai subjects at Faculty of Tropical medicine, Mahidol university.

The 16 subjects have already participated in a healthy volunteer studies in the past either i) Open-Label Study to Evaluate Potential Pharmacokinetic Interaction of Orally Administered primaquine and dihydroartemisinin-piperaquine (DHA-PQP) in Healthy Adult Subjects or ii) Comparison of the electrocardiographic effects in relation to Pharmacokinetic profile of chloroquine and piperaquine in healthy Thai subjects

Every subject was administered a single dose of three tablets of DHA-PQP from previous studies. To avoid unnecessary exposure of DHA-PQP again, we propose to include the results of DHA-PQP arm from these previous studies and ask the healthy subjects to participate this study for receiving only single dose of three tablet of DHA-PQP (40mg/320mg) and two tablet of Mefloquine (250mg) on first admission and single dose of two tablet of Mefloquine on second admission.

Clinical Trial Description

Artemisinin resistance poses the greatest threat to current global initiatives to control and eliminate malaria. The World Health Organisation recommends the use of the artemisinin combination therapy (one partner drug combine with artemisinin as the back bone) (ACTs) instead of the single drug. The reduction in artemisinin sensitivity has left partner drugs within ACTs exposed too much larger number of parasites and unsurprisingly cure rates with ACTs have begun to fall substantially.

Recently, the Mahidol Oxford Tropical Medicine Research Unit (MORU) has applied for and received funding for an extension of the TRAC project. The proposed extension project, named TRACII, will further map artemisinin and partner drug resistance in the South-East Asian region. Also, TRACII aims to investigate the safety, pharmacokinetic characteristics and efficacy of a novel combination of an artemisinin-derivative and two long acting partner drugs, piperaquine and mefloquine.

It is necessary that the potential drug-drug interactions of mefloquine and dihydroartemisinin-piperaquine (DHA-PQP) are characterized. Piperaquine and Mefloquine are both metabolized by Cytochrome P450 3A4 (abbreviated CYP3A4) enzyme which potentially results in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures because of the suboptimal drug exposures to the parasite.

The study will evaluate the pharmacokinetic interaction and safety profile focusing on the cardiogenic effect (QTc prolongation) of this triple combinations of DHA-PQP and mefloquine. Piperaquine and Mefloquine are both metabolized by Cytochrome P450 3A4 enzyme which potentially results in clinically significant drug-drug interactions.

These safety and pharmacokinetic data will be translated to support the intervention in the Tracking Resistance to Artemisinin Collaboration II (TRACII) project.

This is an open-label sequential pharmacokinetic study in 16 healthy G6PD normal Thai subjects. The 16 subjects have participated in a healthy volunteer studies in the past either i) Open-Label Study to Evaluate Potential Pharmacokinetic Interaction of Orally Administered primaquine and dihydroartemisinin-piperaquine in Healthy Adult Subjects or ii) Comparison of the electrocardiographic effects in relation to Pharmacokinetic profile of chloroquine and piperaquine in healthy Thai subjects in which they were administered a single dose of three tablets of DHA-PQP. To avoid unnecessary exposure of other healthy subjects to this study, we propose to include the result of these previous studies and ask the healthy subjects to participate from regimen 1 and onward.

Subjects will be admitted in the inpatient ward to receive 2 drug regimens: regimen 1 (Mefloquine with DHA-PQP) and regimen 2 (Mefloquine). Every subject will have 1 screening and 2 admissions in the hospital ;

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Healthy

• NCT number: NCT02324738
• Study type: Interventional
• Source: University of Oxford
• Status: Completed
• Phase: Phase 4
• Start date: January 2015
• Completion date: May 2015