Pharmacokinetic interactions between primaquine and pyronaridine-artesunate in healthy adult Thai subjects

Abstract

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. NCT01552330.).

FIG 1

Observed mean (±SD) concentration-time profiles for primaquine (A), carboxyprimaquine (B), artesunate (C), dihydroartemisinin (D) and pyronaridine (E). Solid lines indicate when drugs are administered alone and dashed lines indicate when drugs are administered as a combination. The inset in panel E shows the concentration-time profile of pyronaridine during the first day. The drug-sampling matrix was plasma for artesunate, dihydroartemisinin, primaquine, and carboxyprimaquine and whole blood for pyronaridine.

FIG 2

Forest plots of the geometric mean ratios (±90% confidence intervals [CI]) of the drug administered with and without interacting drugs for logarithmically transformed C_max, AUC_0–last, and AUC_0–∞. The vertical dashed lines represent the US FDA criteria of 80 to 125% for assuming bioequivalence.