Potential pharmacokinetic interactions of primaquine and blood chizontocides healthy thai volunteers

Abstract

Primaquine is a drug widely used with other schizontocides in treating malaria. It has been used with chloroquine for radical treatment of vivax malaria, and with artemisinin-based combination therapy (ACT) as a gametocytocide to contain the spread of artemisinin-resistant Plasmodium falciparum. Since primaquine and many other antimalarials are metabolized by cytochrome P450, drug-drug interactions are likely to occur. We conducted 3 crossover studies in healthy Thai adult volunteers to determine potential pharmacokinetic interactions between primaquine and three other important blood schizontocides, namely chloroquine, dihydroartemisinin-piperaquine, and pyronaridine-artesunate. In each study, all volunteers were randomised into two groups of three sequential hospital admissions to receive 30 mg base primaquine, the blood schizontocide under study (i.e., 600 mg base chloroquine, 120-960 mg dihydroartemisinin-piperaquine or 540-180 mg pyronaridineartesunate) and the combined drugs. The pharmacokinetic properties of all drugs were evaluated using a non-compartmental approach. An analysis of variance (ANOVA) was carried out on the log-transformed pharmacokinetic parameters for exposure to assess the drug-drug interactions. All treatment regimens were well-tolerated and none was associated with significant electrocardiographic QT prolongation. The single oral dose of primaquine did not result in any significant pharmacokinetic alterations of the studied schizontocides. In contrast, the co-administration with these long halflife schizontocides significantly increased plasma primaquine concentrations. These results suggest a synergistic effect of chloroquine and primaquine for curative treatment in vivax malaria. They also confirm the recent WHO guideline that primaquine is to be given in addition to ACT on the first day of treatment of falciparum malaria.