Bioavailability of a Co-formulated Combination of Amodiaquine and Artesunate under Fed and Fasted Conditions

Fitoussi, Serge; Thang, Carole; Lesauvage, Eric; Barré, Jérôme; Charron, Brigitte; Filali-Ansary, Aziz; Lameyre, Valérie

doi:10.1055/s-0031-1296410

Cited by 8 publications

(8 citation statements)

References 7 publications

(13 reference statements)

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“…The impact of such mild or moderate clinical symptoms on real life treatment adherence and effectiveness would be worthy of further study, taking into account also other factors such as concomitant food intake, tablet burden and dosing schedule. In the present studies, ASAQ was not administered with food, since a high fat meal may modify the bioavailability of AS and AQ [32]. Mild or moderate anemia AEs were also more frequent in the ASAQ arm, similar to one recent study [30].…”

Section: Discussionsupporting

confidence: 76%

Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

Schramm¹,

Valeh²,

Baudin³

et al. 2013

Malar J

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BackgroundSafety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal.MethodsTwo open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28.ResultsStudy-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p < 0.001), vomiting (7.1% vs 1.6%, p < 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis).ConclusionBoth ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT.Trial registrationThe protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).

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Section: Discussionsupporting

confidence: 76%

Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

Schramm¹,

Valeh²,

Baudin³

et al. 2013

Malar J

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“…In our experience, administering amounts of fat larger than that used here (6.4 g) in cases of acute malaria is likely to be poorly tolerated; furthermore, giving dihydroartemisinin-piperaquine with large amounts of fat might lead to very high drug concentrations in some patients, with an attendant risk of significant cardiotoxicity (reflected by QT prolongation), which is not seen with current fat-free dose administration. Concomitant food intake does not appear to affect the disposition of artemisinin (9), while it does seem to reduce the C max but not the AUC of artesunate and dihydroartemisinin (11). Taken together, these data do not support the coadministration of dihydroartemisinin-piperaquine with fat.…”

Section: Discussionmentioning

confidence: 99%

A Small Amount of Fat Does Not Affect Piperaquine Exposure in Patients with Malaria

Annerberg

Lwin

Khrutsawadchai

et al. 2011

Antimicrob Agents Chemother

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Dihydroartemisinin-piperaquine is a new, highly effective, and well-tolerated combination treatment for uncomplicated falciparum malaria. The lipophilic characteristic of piperaquine suggests that administration together with fat will increase the oral bioavailability of the drug, and this has been reported for healthy volunteers. This pharmacokinetic study monitored 30 adult patients with uncomplicated falciparum malaria for 4.5 months to evaluate the effects of the concomitant intake of fat on the total piperaquine exposure. The fixed-drug combination of dihydroartemisinin-piperaquine was given with water to fasting patients (n ‫؍‬ 15) or was coadministered with 200 ml milk containing 6.4 g fat (n ‫؍‬ 15). The drug combination was generally well tolerated, and there were no severe adverse effects reported for either group during the study. Total piperaquine exposure (area under the concentration-time curve from zero to infinity [AUC 0-ؕ ]; results are given as medians [ranges]) were not statistically different between fed (29.5 h ⅐ g/ml [20.6 to 58.7 h ⅐ g/ml]) and fasting (23.9 h ⅐ g/ml [11.9 to 72.9 h ⅐ g/ml]) patients, but the interindividual variation was reduced in the fed group. Overall, none of the pharmacokinetic parameters differed statistically between the groups. Total piperaquine exposure correlated well with the day 7 concentrations in the fasted group, but the fed group showed a poor correlation. In conclusion, the coadministration of 6.4 g fat did not have any significant effect on piperaquine pharmacokinetics in the treatment of uncomplicated malaria.

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“…Overall, the PK properties of ARS, DHA, AQ, and DAQ obtained in the present study are in broad agreement with other studies in healthy volunteers, given either ARS or AQ alone or in combination with a longer acting antimalarial drug, including AQ. [40][41][42][43][44][45] Tolerability and safety of ARN-PPQ and ARS-AQ in healthy subjects. Both ACTs were well tolerated by the healthy volunteers with no adverse events reported.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Quang

Chavchich²,

Anh

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin-piperaquine [ARN-PPQ] [Artequick] and artesunate-amodiaquine [ARS-AQ] [Coarsucam]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs. The area under the concentration-time curve (AUC) was 3.6-fold higher for dihydroartemisinin (active metabolite of ARS) than that for ARN, whereas the AUC of desethylamodiaquine (active metabolite of AQ) was 2.0-fold lower than that of PPQ. Based on the 50% inhibitory dilution values of the volunteers' plasma samples collected from 0.25 to 3 hours after the last dose, the ex vivo activity of ARS-AQ was 2.9- to 16.2-fold more potent than that of ARN-PPQ against the drug-sensitive D6 line. In addition, at 1.5, 4.0, and 24 hours after the last dose, the ex vivo activity of ARS-AQ was 20.8-, 3.5-, and 8.5-fold more potent than that of ARN-PPQ against the ARN-sensitive MRA1239 line. By contrast, at 1.5 hours, the ex vivo activity of ARS-AQ was 5.4-fold more active than that of ARN-PPQ but had similar activities at 4 and 24 hours against the ARN-resistant MRA1240 line. The PK-PD data suggest that ARS-AQ possesses superior antimalarial activity than that of ARN-PPQ and would be the preferred ACT for further in vivo efficacy testing in multidrug-resistant falciparum malaria areas.

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Bioavailability of a Co-formulated Combination of Amodiaquine and Artesunate under Fed and Fasted Conditions

Cited by 8 publications

References 7 publications

Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

A Small Amount of Fat Does Not Affect Piperaquine Exposure in Patients with Malaria

Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

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