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

Malaria Journal, Dec 2014

Background Pharmacokinetic (PK) and pharmacodynamic (PD) data are limited for artesunate (AS) and amodiaquine (AQ) in uncomplicated Plasmodium falciparum. Methods From 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). Results Mean 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 vs410 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 (vsD0: 5,075/µL), and 777/µL (vsD0: 3,778/µL). Conclusions Tolerability 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.

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

Bernhards Ogutu 2 Elizabeth Juma 1 Charles Obonyo 1 Vincent Jullien 0 6 Gwenaelle Carn 5 Michel Vaillant 4 Walter Robert John Taylor 3 Jean-Ren Kiechel 5 0 INSERM U1129, University Paris Descartes, CEA Gif-sur-Yvette , France 1 Centre for Global Health Research, Kenya Medical Research Institute , Nairobi City , Kenya 2 Centre for Clinical Research, Kenya Medical Research Institute , Kisumu , Kenya 3 Division of Tropical and Humanitarian Medicine, Geneva University Hospitals , Geneva , Switzerland 4 Competence Centre in Methodology and Statistics, Public Research Centre for Health , Strassen , Luxembourg 5 Drugs for Neglected Diseases initiative , Geneva , Switzerland 6 Service de Pharmacologie, Hopital Europeen Georges Pompidou, Assistance Publique-Hopitaux de Paris , Paris , France Background: Pharmacokinetic (PK) and pharmacodynamic (PD) data are limited for artesunate (AS) and amodiaquine (AQ) in uncomplicated Plasmodium falciparum. Methods: From 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). Results: Mean 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 26.46.9 mol*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 27.63.19 vs 32.75.53 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 vs410 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/L (vsD0: 5,075/L), and 777/L (vsD0: 3,778/L). Conclusions: Tolerability 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. - Background Fixed dose (FD)artesunate-amodiaquine (ASAQ)was developed, WHO prequalified, and registered by a consortium coordinated by the Drugs for Neglected Diseases initiative (DNDi)[1,2]. Dosing is straightforward and based on four optimized, age/weight categories [3] which provides greater dosing accuracy than coblistered ASAQ [4] and good adherence [5]. As of 2014, ASAQ is available for use in 35 countries, including 32 in Africa [6]. Where tested in Africa, FD ASAQ has consistently achieved high efficacy, achieving Day 28 cure rates of ~93, 94 and 100% in children 60 months of age from Burkina Faso [6], Benin [5] and Central African Republic [10], respectively; ~98% in children <eight years of age in Cote DIvoire, Cameroon and Senegal [7] and <five years of age in the Democratic Republic of Congo (DRC) [8], as well as 100% in Nigerian children <12 years of age [9]. FD ASAQ was non-inferior to artemetherlumefantrine (AL) in two trials, achieving cure rates exceeding ~95% and non-inferiority margins of 3% [8,11]. Non-fixed (NF) dose ASAQ has also achieved high cure rates across Africa [12-26] with some reports of efficacy <90% in focal parts of DRC, Tanzania, Sierra Leone, and Rwanda [26-29]. ASAQ is generally well tolerated and, across a range of studies, has a broadly similar adverse event (AE) profile as AL [5,9,11,30,31]. However, one study found significantly higher rates of fatigue, nausea, vomiting, and anaemia in the FD ASAQ arm compared to AL [32]. In this study, the relationship between Day (D)7 desethylamodiaquine (DAQ) concentrations and AE varied with age: a higher median D7 DAQ was associated with fatigue in children under the age of five, and vomiting in those aged five years of age. Rates of early vomiting or of rejecting the tablets (i.e., spitting them out) were low (0.2 to 6%) [6,11,32], and more common in children under five years old [DNDi data on file [11,32]]. In the past, AQ as malaria prophylaxis caused significant and sometimes fatal hepatotoxicity, which sometimes occurred with severe neutropaenia [33-35]; AQ is no longer (...truncated)


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Bernhards Ogutu, Elizabeth Juma, Charles Obonyo, Vincent Jullien, Gwenaelle Carn, Michel Vaillant, Walter Robert Taylor, Jean-René Kiechel. Fixed dose artesunate amodiaquine – a phase IIb, randomized comparative trial with non-fixed artesunate amodiaquine, Malaria Journal, 2014, pp. 498, 13, DOI: 10.1186/1475-2875-13-498