The effects of antimalarial drugs on ventricular repolarization.

Touze, J E; Héno, P.; Fourcade, Laurent; Deharo, J. C.; Thomas, G; Bohan, SJ; Pelletier, Philippe; Rivière, Pauline; Kouassi, Édouard; Buguet, Alain

doi:10.4269/ajtmh.2002.67.54

Cited by 59 publications

(52 citation statements)

References 30 publications

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“…The ECG findings in these predominantly fit young men were unremarkable and consistent with the good cardiac safety record of mefloquine (34,35). The QTcF interval increase was best explained by the falling heart rate consequent to disease resolution (detailed results will be reported elsewhere).…”

Section: Discussionsupporting

confidence: 72%

New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine

Krudsood

Tangpukdee

Wilairatana

et al. 2010

Antimicrob Agents Chemother

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A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalizedMultidrug-resistant Plasmodium falciparum on the ThaiBurmese border dates back to the mid 1970s and has been treated with artesunate (AS) and mefloquine (MQ) since 1994, 7 years before the WHO recommendation to use artemisininbased combinations (ACTs) as first-line treatment for acute uncomplicated falciparum malaria (17, 23). AS plus MQ, dosed at 12 and 25 mg/kg of body weight over 3 and 2 days, respectively, has achieved sustained cure rates of 95%, reduced P. falciparum transmission, and reversed the progression of the median in vitro mefloquine 50% inhibitory concentration (IC 50 ) (23). More recent data still show high cure rates despite a slowing of the parasite clearance time compared to earlier studies (8).The adequacy of the artesunate dose was supported by a dose-ranging and pharmacodynamic (PD) study in P. falciparum-infected patients from the Thai-Burmese border, which found that 2 mg/kg of oral artesunate was the minimum dose that resulted in maximal parasite killing, the minimum parasiticidal concentration (MPC) (3). Allowing for the interindividual variation of AS absorption (7), 4 mg/kg was recommended. This dose has been adopted widely for other ASbased combinations (1, 2). Artesunate is tolerated remarkably well (25, 31). Serious toxicity is limited to acute anaphylaxis, which occurs at an estimated rate of 1 in 2,833 (15).Mefloquine is associated with nausea, vomiting, and dizziness. When used at a stat dose of 25 mg/kg (MQ25), high rates of early (Յ1 h) vomiting occurred, especially in children Ͻ7 and adults Ͼ50 years old (29,34). Vomiting was reduced by 43% by giving MQ at 15 and 10 mg/kg (MQ15-10) 24 h later and by 2-and 3-fold in those who received an artemisinin derivative on the first day of treatment, followed by MQ25 on the second day of treatment or later (19,34). The 15-to 10-mg/kg split dose alone also increased the mean area under the concentration-time curve from zero hour to infinity (AUC 0-ϱ ) by ϳ50% to 51,020 ng ⅐ day/ml compared to MQ25 alone (34,106 ng ⅐ day/ml), and a 20% increase was seen when MQ was combined with artesunate: 24,343 (MQ15-10) versus 20,292 (MQ25) ng ⅐ day/ml (28). Similar AUC results were found in artesunate-treated children who received MQ25 on day 0 (21,196 ng ⅐ day/ml) or delayed to day 1 (28,196 ng ⅐ day/ml) (24). An increased AUC translates into more

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Section: Discussionsupporting

confidence: 72%

New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine

Krudsood

Tangpukdee

Wilairatana

et al. 2010

Antimicrob Agents Chemother

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“…HF was also found to potentiate the QT interval prolongation induced by mefloquine, which is not known to be toxic on its own in an animal model (21). Clinically, both HF and QN had significant QT interval-prolonging effects compared to those of mefloquine, artemether-lumefantrine (22), and artesunate-amodiaquine (23) which did not.…”

Section: Discussionmentioning

confidence: 99%

Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia

Vanachayangkul

Lon

Spring

et al. 2017

Antimicrob Agents Chemother

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Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slopeintercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.)

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“…Similar rates are reported with other antimalarials. Quinoline antimalarial drugs are potentially cardiotoxic; specifically some members of this class cause prolongation of the electrographic QRS and QT intervals (Hien and White, 1993;Touze et al, 2002). Although piperaquine is structurally related to chloroquine and quinine, no clinically significant electrocardiographic, cardiovascular or metabolic effects (especially on plasma glucose) have been observed .…”

Section: Discussionmentioning

confidence: 99%