![]() Pyronaridine has demonstrated activity against falciparum parasites resistant to other antimalarials, and PA has displayed consistently high efficacy in multiple large clinical trials ( 2). PA contains the artemisinin derivative artesunate, which effects rapid and profound reductions in parasitemia, and the benzonaphthyridine derivative pyronaridine tetraphosphate, which serves to eliminate residual parasitemia in order to prevent recrudescence, and it helps protect against the loss of artesunate sensitivity ( 1). ![]() Pyramax (pyronaridine-artesunate ) is an artemisinin-based combination therapy indicated for the treatment of acute uncomplicated falciparum and vivax malaria in both children and adults. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing. All such elevations resolved typically within 10 days, and up to 30 days at most. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. No interaction effect of metoprolol with pyronaridine was apparent. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval, 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC 0- t) these increases most likely resulted from pyronaridine-mediated CYP2D6 inhibition. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and pyronaridine. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. Healthy adult subjects were randomized to arm A ( n = 26) or arm B ( n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (pyronaridine-artesunate ) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters.
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