TY - JOUR
T1 - Fixed dose artesunate amodiaquine - A phase IIb, randomized comparative trial with non-fixed artesunate amodiaquine
AU - Ogutu, Bernhards
AU - Juma, Elizabeth
AU - Obonyo, Charles
AU - Jullien, Vincent
AU - Carn, Gwenaelle
AU - Vaillant, Michel
AU - Taylor, Walter Robert John
AU - Kiechel, Jean René
N1 - Funding Information:
We are grateful to the patients for participating in the study and the study nurses for their invaluable help. We thank Dr Piero Olliaro for helpful discussions during protocol development; Dr Julie Simpson for help with the population PK sampling; Cardinal Systems for data management and analyses; SYNEXEL Research International SAS for the bioanalytical report; Sanofi-Aventis (now Sanofi) for supplying both ASAQ formulations; Quintiles for reading the ECGs and writing the ECG report and Susan Wells, Karly Louie and Graciela Diap for valuable editorial contributions to this manuscript. DNDi thanks the following donors for supporting this study: the Department for International Development (DFID), UK; Spanish Agency for International Development Cooperation (AECID), Spain; Dutch Ministry of Foreign Affairs (DGIS), The Netherlands; Médecins Sans Frontières, International; French Development Agency (AFD), France.
Publisher Copyright:
© 2014 Ogutu et al.
PY - 2014
Y1 - 2014
N2 - 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 AUCO-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 (δ = 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.
AB - 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 AUCO-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 (δ = 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.
KW - Amodiaquine
KW - ECG
KW - Kenya
KW - Malaria
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=84924283120&partnerID=8YFLogxK
U2 - 10.1186/1475-2875-13-498
DO - 10.1186/1475-2875-13-498
M3 - Article
C2 - 25515698
AN - SCOPUS:84924283120
SN - 1475-2875
VL - 13
JO - Malaria Journal
JF - Malaria Journal
IS - 1
M1 - 498
ER -