Pharmacokinetic interaction between pyronaridine-artesunate and metoprolol

Abstract

The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (pyronaridine-artesunate [PA]) 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. 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 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. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 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 (AUC0-t); these increases most likely resulted from pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with pyronaridine was apparent. 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. All such elevations resolved typically within 10 days, and up to 30 days at most. 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.

FIG 1

Study drug administration per study design in arms A and B.

FIG 2

Plot of mean metoprolol concentration versus time after dose. Only time points with ≥50% of concentrations above the LLOQ are plotted. Each error bar represents one standard deviation.

FIG 3

Plot of mean alpha-hydroxymetoprolol concentration versus time after dose. Only time points with ≥50% of concentrations above the LLOQ are plotted. Each error bar represents one standard deviation.

FIG 4

Forest plot of 90% confidence intervals for the ratios of geometric means for pharmacokinetic results. The dashed lines represent the 0.80 and 1.25 boundaries. The solid diamonds indicate point estimates for the geometric mean ratios of with PA to without PA for the metoprolol parameters. The solid circles (arm A) and triangles (arm B) give the point estimates for the geometric mean ratios of second dosing to first dosing for the pyronaridine (Pyr) parameters. The lines extending from the solid bullets indicate the 90% confidence intervals for the ratios of geometric means.

FIG 5

Ratio of metoprolol AUC_0-t (period 2 to period 1) versus CYP2D6 metabolizer status.