Pharmacokinetic Interactions between Primaquine and Pyronaridine-Artesunate in Healthy Adult Thai Subjects

Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540−180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesunate, or dihydroartemisinin exposures. There were significantly higher primaquine maximum plasma drug concentrations (geometric mean ratio, 30%; 90% confidence interval [CI], 17% to 46%) and total exposures (15%; 6.4% to 24%) during coadministration with pyronaridine-artesunate than when primaquine was given alone. Pyronaridine, like chloroquine and piperaquine, increases plasma primaquine concentrations. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01552330","term_id":"NCT01552330"}}NCT01552330.)     

Impact of Food Rations and Supplements on Micronutrient Status by Trimester of Pregnancy: Cross-Sectional Studies in the Maela Refugee Camp in Thailand

Micronutrient fortified flour (MFF), supplementary food rations and micronutrient (MN) supplements may prevent deficiencies among pregnant women. Objectives of cross-sectional surveys in 2004 (n = 533) and 2006 (n = 515) were to assess the impact of new food rations (flour, oil) and supplements on MN status by trimester of pregnancy in the Maela refugee camp. Hemoglobin, iron status, zinc, retinol, β-carotene and tryptophan decreased, while α-/γ-tocopherol and 5-methyltetrahydrofolate (5-MTHF) increased from first to third trimester. In 2006, mean zinc and α-tocopherol for each trimester was significantly higher than in 2004. The weeks of supplemented thiamine and folic acid were positively correlated with thiamine diphosphate (TDP) and 5-MTHF, but not for ferrous sulfate as iron deficiency was observed in 38.5% of third-trimester women. Frequent consumption of fish paste and owning a garden or animal were associated with significantly higher iron status, retinol, β-carotene, and 5-MTHF. In conclusion, MFF and supplementary oil were most likely to explain improved zinc and α-tocopherol status, while thiamine and folate supplements ensured high TDP and 5-MTHF in late pregnancy. MN supplements, MN-rich staple food, small gardens, and programs to improve iron compliance are promising strategies to prevent MN deficiencies during pregnancy in vulnerable populations.     

Pharmacokinetic Interactions between Primaquine and Chloroquine

Chloroquine combined with primaquine has been the standard radical curative regimen for Plasmodium vivax and Plasmodium ovale malaria for over half a century. In an open-label crossover pharmacokinetic study, 16 healthy volunteers (4 males and 12 females) aged 20 to 47 years were randomized into two groups of three sequential hospital admissions to receive a single oral dose of 30 mg (base) primaquine, 600 mg (base) chloroquine, and the two drugs together. The coadministration of the two drugs did not affect chloroquine or desethylchloroquine pharmacokinetics but increased plasma primaquine concentrations significantly (P ≤ 0.005); the geometric mean (90% confidence interval [CI]) increases were 63% (47 to 81%) in maximum concentration and 24% (13 to 35%) in total exposure. There were also corresponding increases in plasma carboxyprimaquine concentrations (P ≤ 0.020). There were no significant electrocardiographic changes following primaquine administration, but there was slight corrected QT (QTc) (Fridericia) interval lengthening following chloroquine administration (median [range] = 6.32 [−1.45 to 12.3] ms; P < 0.001), which was not affected by the addition of primaquine (5.58 [1.74 to 11.4] ms; P = 0.642). This pharmacokinetic interaction may explain previous observations of synergy in preventing P. vivax relapse. This trial was registered at ClinicalTrials.gov under reference number {"type":"clinical-trial","attrs":{"text":"NCT01218932","term_id":"NCT01218932"}}NCT01218932.     

Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects

Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (C_max), area under the concentration-time curve from 0 h to the end of the study (AUC_0–last), and area under the concentration-time curve from 0 h to infinity (AUC_0–∞) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01525511","term_id":"NCT01525511"}}NCT01525511.)