Fixed dose artesunate amodiaquine – a phase IIb, randomized comparative trial with non-fixed artesunate amodiaquineReportar como inadecuado




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Malaria Journal

, 13:498

First Online: 16 December 2014Received: 14 August 2014Accepted: 06 December 2014

Abstract

BackgroundPharmacokinetic PK and pharmacodynamic PD data are limited for artesunate AS and amodiaquine AQ in uncomplicated Plasmodium falciparum.

MethodsFrom 2007-8, 54 P. falciparum-infected, Kenyan adults were assigned randomly fixed dose FD ASAQ n = 26 or non-fixed NF ASAQ n = 28. Total doses were 600 mg AS both arms + 1,620 mg FD or 1,836 mg NFAQ. Follow-up extended over 28 days. PK data were collected for AS, dihydroartemisinin DHA, AS + DHA combined as DHA equivalents DHAeq, AQ, desethylamodiaquine DAQ,and their relationships assessed against the PD collected data consisting of parasitological efficacy, adverse events AEs, and the Bazett’s corrected QTinterval QTcB.

ResultsMean AUC 0-72 of dihydroartemisinin equivalents DHAeq when administered as a fixed dose FD compared to NF dose were similar: 24.2 ±4.6 vs 26.4±6.9 µmol*h-L p = 0.68 Parasite clearance rates were also similar after 24 hrs: 17-25 68% vs 18-2864.3% p = 0.86,as well as at 48 hrs: 25-8 100%vs 26 92.9%-28 p = 0.49. Mean FD vs NF DAQ AUC0-28 were 27.6±3.19 vs 32.7±5.53 mg*h-L p = 0.0005. Two PCR-proven new infections occurred on Day D 28 for estimated, in vivo, DAQ minimum inhibitory concentrations of 15.2 and 27.5 ng-mL. Combining the FD and NF arms, the mean QTcB at D2+4 hrs increased significantly p = 0.0059 vs baseline: 420 vs 410 ms ∆ = 9.02 95% confidence interval 2.72-15.31 ms, explained by falling heart rates, increasing DAQ concentrations and female sex in a general linear mixed effects model. Ten of 108 9.26% AEs 5-arm reported by 37-54 68.5% patients were possibly or probably drug related. Severe, asymptomatic neutropaenia developed in 2-47 4.25% patients on D28: 574-µL vs D0: 5,075-µL, and 777-µL vs D0: 3,778-µL.

ConclusionsTolerability of both formulations was good. For QTcB, a parameter for ECG modifications, increases were modest and due to rising DAQ concentrations and falling heart rates as malaria resolved. Rapid parasite clearance rates and no resistant infections suggest effective pharmacokinetics of both formulations.

KeywordsMalaria Amodiaquine ECG Kenya Pharmacokinetics Electronic supplementary materialThe online version of this article doi:10.1186-1475-2875-13-498 contains supplementary material, which is available to authorized users.

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Autor: Bernhards Ogutu - Elizabeth Juma - Charles Obonyo - Vincent Jullien - Gwenaelle Carn - Michel Vaillant - Walter Robert Joh

Fuente: https://link.springer.com/







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