title: Fixed dose artesunate amodiaquine - a phase IIb, randomized comparative trial with non-fixed artesunate amodiaquine.
abstract: 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.
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Juma
authors.forename: Charles
authors.initials: C
authors.lastname: Obonyo
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Carn
authors.forename: Michel
authors.initials: M
authors.lastname: Vaillant
authors.forename: Walter Robert John
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Drugs for Neglected Diseases initiative, Geneva, Switzerland. jean-rene.kiechel@wanadoo.fr.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Kiechel
mesh_terms: D000293:Adolescent; D000328:Adult; D000655:Amodiaquine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077332:Artesunate; D004359:Drug Therapy, Combination / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000655:Amodiaquine; D000077332:Artesunate