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In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Feb 26, 2012 • By Franco Borsini, William Crumb, Silvia Pace, David Ubben, Barb Wible, Gan-Xin Yan, and Christian Funck-Brentanof

The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (Cmax), were expressed as the fold of that particular effect with respect to their Cmax. The following tests were used at 37°C: hERG (human ether-a-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (INa and IKs, respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemetherlumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and INa and IKs analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC50) of halofantrine, which was lower than its Cmax, was confirmed. All the other compounds blocked hERG, with IC50s ranging from 3- to 30-fold their Cmaxs. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its Cmax were confirmed and DHA blocked it at a concentration about 300-fold its Cmax. In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the INa ion current and did so at about 30-fold its Cmax. No effect on IKs was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.

Torsade de pointes (TdP) caused by drugs is a life-threatening form of polymorphic ventricular tachycardia which is associated clinically with a long QT interval prolongation. This kind of deleterious effect has been described in several classes of drugs, such as antihistamines, psychotropics, and antibiotics (40). However, QT prolongation is not a strong predictor of the risk of TdP, and several factors may contribute to an individual patient’s risk of TdP. Various models have been developed to assess the potential in vitro cardiac toxicity of drugs and their potential to generate TdP (9). Many antimalarials are associated with prolongation of the corrected QT interval (QTc) at therapeutic concentrations (49). However, despite large-scale use, information on the rate of TdP with these drugs is limited, because these drugs are mostly used in developing countries, where pharmacovigilance data are lacking. Dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) is a fixed-combination antimalarial treatment with excellent efficacy and good tolerance (3, 4, 14, 16, 29, 38, 46). Derivatives of artemisinin are generally considered to be safe in terms of cardiotoxic potential, with no clinically significant changes in QT observed in the treatment of malaria (49). QTc prolongation appears to be limited with DHA and PQP (49). However, PQP is structurally similar to chloroquine, for which significant electrophysiological effects on the heart have been described (43, 45), even if the clinical differences have not been well considered. One common electrophysiological finding for those antimalarial drugs associated with QTc prolongation is blockade of the repolarizing potassium channel hERG (human ether-a-go-go-related gene) (24, 35, 45). To investigate the electrophysiological profile of DHA and PQP, the hERG channel-blocking profile of these compounds, alone and in combination, was characterized in stably expressing human embryonic kidney (HEK-293) cells. For comparison, the hERG channel-blocking effects of chloroquine, dofetilide, halofantrine, lumefantrine, and mefloquine were also evaluated. Previous hERG studies with antimalarials were performed in vitro at room temperature (24, 35, 45). Under our experimental conditions, the hERG assay was evaluated at 37°C, which provides a more conservative safety evaluation of hERG inhibition (27). The potential torsadogenic risk of DHA, PQP, and their combination was evaluated in a rabbit heart wedge preparation (33), an established experimental model for the prediction of druginduced proarrhythmia (26). In this model, the torsadogenic risk score ranges from 2 up to 14, with a higher score being worse (33). The results with the combination of DHA and PQP were compared to those with chloroquine, artemether combined with lumefantrine, and dofetilide. Dofetilide was used as a positive control because of the numerous reports of TdP associated with this medication (1). Additionally, three in vitro tests were performed with DHA, PQP, and their combination: hERG trafficking and sodium and slow potassium ion current interference (INa and IKs, respectively) measurements (11).

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