Pharmacokinetic Study of Primaquine and Dihydroartemisinin-Piperaquine in Healthy Subjects
The observed changes of P. falciparum sensitivity to artemisinin leads to the intensification of early detection as well as treatment monitoring in malaria infection. It is widely accepted that the development of resistance can be delayed by the use of combination therapy, especially artemisinin-based combination therapies (ACTs). The resistance problem is considered extremely serious and as the consequence WHO has recommended that all monotherapy for malaria should be stopped Current WHO guideline recommends the drug combination regimens using ACT with effective partner medicines to decrease the risk of development or spreading of artemisinin resistance.
Dihydroartemisinin-piperaquine (DHA-PQP); the fixed-dose combination of Dihydroartemisinin (DHA) and Piperaquine phosphate (PQP) is now one of the recommended drugs by WHO as the oral treatment for uncomplicated P. falciparum. DHA-PQP composes of both blood schizonticidal drugs, with different mechanism of action and different half-life to improve the therapeutic efficacy and to prevent the development of drug resistance to the individual drug. Moreover, it is beneficial for the mutual protection against resistance and long lasting protection against new infection, due to long half-life of PQP.
Primaquine is an effective gametocytocidal for P. falciparum transmission prevention and as tissue killing for the radical cure in Plasmodium vivax and Plasmodium ovale infection. It will be given only in the presence of other antimalarials, so it is necessary that the data of the potential drugs interaction of primaquine and DHA-PQP should be characterized. It is inevitable that in the near future, Dihydroartemisinin-piperaquine (DHA-PQP) and primaquine combination treatment becomes necessary. These drugs are metabolized by cytochrome P450 enzyme which potentially causes pharmacokinetic alteration, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures because of the suboptimal exposure of the parasite.
This study is planned to evaluate potential pharmacokinetic interaction of orally administered primaquine (PQ) and dihydroartemisinin-piperaquine (DHA-PQP) in healthy adult subjects. The results of these interaction studies are important in order to provide clinical guidance for the optimum combination of primaquine and DHA-PQP treatment regimens in malaria infections.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Open-Label Study to Evaluate Potential Pharmacokinetic Interaction of Orally Administered Primaquine and Dihydroartemisinin-Piperaquine in Healthy Adult Subjects|
- Area Under Curve (AUC) for Primaquine [ Time Frame: 36 days ] [ Designated as safety issue: No ]Area under the concentration-time curve [(AUC(0-∞) and AUC(0-last)] and maximal concentration (Cmax) for primaquine and metabolites when given alone or together with DHA-PQP.
- Area Under Curve (AUC) for Dihydroartemisinin (DHA) and Piperaquine (PQP) [ Time Frame: 36 days ] [ Designated as safety issue: No ]Area under the concentration-time curve [(AUC(0-∞) and AUC(0-last)] and maximal concentration (Cmax) for piperaquine and dihydroartemisinin when given alone as DHA-PQP or together with primaquine.
- Clearance rate and half life of Primaquine and its metabolites [ Time Frame: 36 days ] [ Designated as safety issue: No ]Primaquine, carboxyprimaquine (and other detectable major metabolites) elimination clearance rate (CL/F), terminal elimination half-life (t1/2) and apparent volume of distribution (Vd) Dihydroartemisinin and piperaquine elimination clearance rate (CL/F), terminal elimination half-life (t1/2) and apparent volume of distribution (Vd).
- Safety of Dihydroartemisinin-Piperaquine (DHA-PQP) [ Time Frame: 36 days ] [ Designated as safety issue: Yes ]Safety and tolerability parameters, including adverse events, clinical laboratory, and vital signs assessments, in particular QTc prolongation for DHA-PQP
- Pharmacogenetic polymorphisms [ Time Frame: 36 days ] [ Designated as safety issue: Yes ]Pharmacogenetic polymorphisms in the case of unusually high or low drug levels.
|Study Start Date:||June 2012|
|Study Completion Date:||September 2012|
|Primary Completion Date:||September 2012 (Final data collection date for primary outcome measure)|
Experimental: Group A
Primaquine only followed by Dihydroartemisinin-piperaquine and followed by Primaquine together with Dihydroartemisinin-piperaquine.
Subject will receive primaquine (PQ) then receive dihydroartemisinin-piperaquine (DHA-PQP)after 1 week washout period and receive PQ together with DHA-PQP for the third regimen after 8 weeks washout period.
Active Comparator: Group B
Primaquine only followed by Primaquine together Dihydroartemisinin-piperaquine and followed by Dihydroartemisinin-piperaquine only.
Subject will receive primaquine (PQ) then receive PQ together dihydroartemisinin-piperaquine (DHA-PQP) after 1 week washout period and receive DHA-PQP for the third regimen after 8 weeks washout period.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01525511
|Hospital of Tropical Diseases, Faculty of Tropical Medicine, Mahidol University|
|Bangkok, Thailand, 10400|
|Principal Investigator:||Sasithon Pukrittayakamee, MD||Mahidol University|