Pharmacokinetic and Pharmacodynamic Study of Mefloquine and Dihydroartemisinin-Piperaquine in Healthy Subjects
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|ClinicalTrials.gov Identifier: NCT02324738|
Recruitment Status : Completed
First Posted : December 24, 2014
Last Update Posted : November 3, 2015
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.
|Condition or disease||Intervention/treatment||Phase|
|Healthy||Drug: Mefloquine and Dihydroartemisinin-piperaquine Other: Wash-out period Drug: Mefloquine||Phase 4|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||16 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Open-Label Study to Evaluate Potential Pharmacokinetic and Pharmacodynamic Interactions of Orally Administered Mefloquine and Dihydroartemisinin-Piperaquine in Healthy Adult Subjects|
|Study Start Date :||January 2015|
|Actual Primary Completion Date :||May 2015|
|Actual Study Completion Date :||May 2015|
Experimental: Healthy Volunteer
All subjects will receive Mefloquine and Dihydroartemisinin-piperaquine, wash out then will receive Mefloquine
Drug: Mefloquine and Dihydroartemisinin-piperaquine
2 tablets of mefloquine and 3 tablets of dihydroartemisinin-piperaquine single dose
Other: Wash-out period
2 tablets of Mefloquine single dose
- Safety and tolerability parameters (including adverse events, clinical laboratory, and vital signs assessments) [ Time Frame: approximately 4 months ]Safety and tolerability parameters, including adverse events, clinical laboratory, and vital signs assessments, in particular QTc prolongation for DHA-PQP in combination with mefloquine.
- Area under the curve and maximum concentration [ Time Frame: approximately 36 days ]Area under the concentration-time curve [AUC 0-∞ and AUC 0-last] and maximal concentration (Cmax) for mefloquine and metabolites when given alone and together with DHA-PQP.
- Area under the curve and maximum concentration [ Time Frame: approximately 36 days ]Area under the concentration-time curve [AUC0-∞ and AUC0-last] and maximal concentration (Cmax) for piperaquine and dihydroartemisinin when given alone as DHA-PQP and together with mefloquine.
- Pharmacokinetic parameters ((i.e. elimination clearance (CL/F), terminal elimination half-life (t1/2) and apparent volume of distribution (Vd) [ Time Frame: approximately 36 days ]Estimate pharmacokinetic parameters (i.e. elimination clearance (CL/F), terminal elimination half-life (t1/2) and apparent volume of distribution (Vd) for mefloquine, dihydroartemisinin and piperaquine when given alone and in combination.
- Genetic abnormality [ Time Frame: approximately 4 months ]In case of any abnormal metabolisms in individuals, related genetic tests may be performed to determine if there is any genetic abnormality. Such data may be useful in predicting those who may not obtain the full therapeutic or prophylactic benefit of study drugs.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02324738
|Faculty of Tropical Medicine|
|Bangkok, Thailand, 10400|