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

Malaria Journal

Research

Bernhards Ogutu¹  Charles Obonyo²  Elizabeth Juma²  Michel Vaillant³  Walter Robert John Taylor⁴  Jean-René Kiechel⁵  Gwenaelle Carn⁵  Vincent Jullien⁶ 

[1] Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya;Centre for Global Health Research, Kenya Medical Research Institute, Nairobi City, Kenya;Competence Centre in Methodology and Statistics, Public Research Centre for Health, Strassen, Luxembourg;Division of Tropical and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland;Drugs for Neglected Diseases initiative, Geneva, Switzerland;INSERM U1129, University Paris Descartes, CEA, Gif-sur-Yvette, France;Service de Pharmacologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France;

关键词: Malaria;    Amodiaquine;    ECG;    Kenya;    Pharmacokinetics;   

DOI  :  10.1186/1475-2875-13-498

 received in 2014-08-14, accepted in 2014-12-06,  发布年份 2014

来源: Springer

【 摘 要 】

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 (NF)AQ. 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 18/28(64.3%) (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.

【 授权许可】

Unknown   
© Ogutu et al.; licensee BioMed Central. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.