PMID- 25515698
OWN - NLM
STAT- MEDLINE
DCOM- 20151015
LR  - 20220408
IS  - 1475-2875 (Electronic)
IS  - 1475-2875 (Linking)
VI  - 13
DP  - 2014 Dec 16
TI  - Fixed dose artesunate amodiaquine - a phase IIb, randomized comparative trial 
      with non-fixed artesunate amodiaquine.
PG  - 498
LID - 10.1186/1475-2875-13-498 [doi]
LID - 498
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 micromol*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/microL (vsD0: 5,075/microL), and 777/microL 
      (vsD0: 3,778/microL). 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.
FAU - Ogutu, Bernhards
AU  - Ogutu B
FAU - Juma, Elizabeth
AU  - Juma E
FAU - Obonyo, Charles
AU  - Obonyo C
FAU - Jullien, Vincent
AU  - Jullien V
FAU - Carn, Gwenaelle
AU  - Carn G
FAU - Vaillant, Michel
AU  - Vaillant M
FAU - Taylor, Walter Robert John
AU  - Taylor WR
FAU - Kiechel, Jean-Rene
AU  - Kiechel JR
AD  - Drugs for Neglected Diseases initiative, Geneva, Switzerland. 
      jean-rene.kiechel@wanadoo.fr.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20141216
PL  - England
TA  - Malar J
JT  - Malaria journal
JID - 101139802
RN  - 0 (Antimalarials)
RN  - 0 (Artemisinins)
RN  - 220236ED28 (Amodiaquine)
RN  - 60W3249T9M (Artesunate)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Amodiaquine/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Antimalarials/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Artemisinins/*administration & dosage/adverse effects/*pharmacokinetics
MH  - Artesunate
MH  - Drug Therapy, Combination/methods
MH  - Drug-Related Side Effects and Adverse Reactions/epidemiology/pathology
MH  - Female
MH  - Humans
MH  - Kenya
MH  - Malaria, Falciparum/*drug therapy/parasitology/pathology
MH  - Male
MH  - Middle Aged
MH  - Treatment Outcome
MH  - Young Adult
PMC - PMC4302156
EDAT- 2014/12/18 06:00
MHDA- 2015/10/16 06:00
PMCR- 2014/12/16
CRDT- 2014/12/18 06:00
PHST- 2014/08/14 00:00 [received]
PHST- 2014/12/06 00:00 [accepted]
PHST- 2014/12/18 06:00 [entrez]
PHST- 2014/12/18 06:00 [pubmed]
PHST- 2015/10/16 06:00 [medline]
PHST- 2014/12/16 00:00 [pmc-release]
AID - 1475-2875-13-498 [pii]
AID - 3660 [pii]
AID - 10.1186/1475-2875-13-498 [doi]
PST - epublish
SO  - Malar J. 2014 Dec 16;13:498. doi: 10.1186/1475-2875-13-498.