Drug interactions
The 8-aminoquinolines have important pharmacokinetic and pharmacodynamic interactions with other structurally related antimalarial drugs. Coadministration of mepacrine (atebrin, quinacrine) substantially increases plasma concentrations of pamaquine and also reduces tolerability. It substantially increases methaemoglobinaemia associated with pamaquine (33). Chloroquine, piperaquine and pyronaridine all increase plasma concentrations of primaquine by approximately 20%, but they do not affect tolerability (34). Pamaquine and primaquine radical curative activity is increased by concomitant (but not sequential) administration with quinine (35, 36). Chloroquine has also been shown to potentiate the radical curative efficacy of primaquine. During the clinical development of primaquine it was observed that coadministration of primaquine with quinine or chloroquine attenuated the consequent methaemoglobinaemia. This was not observed in comparable studies with pamaquine (plasmoquine) (Figure 5).
However larger, more recent, studies have not confirmed this early finding (Figure 6). They do not suggest any substantial differences between methaemoglobin levels with or without concomitant medicines (quinine, chloroquine, artesunate, artesunate-pyronaridine, dihydroartemisinin-piperaquine have all been evaluated), nor do they suggest differences between methemoglobin levels in the treatment of malaria (in which steady state methaemoglobin levels are reached well after resolution of symptoms), or in healthy subjects. Thus the impact of blood schizontocides on 8-aminoquinoline induced methaemoglobineamia is specific to the drugs and is not a general class effect.