title: Effect of food on the pharmacokinetics of piperaquine and dihydroartemisinin.
abstract: OBJECTIVE
  Piperaquine-dihydroartemisinin combination therapy has established efficacy for the treatment of malaria; however, a more comprehensive understanding of the pharmacokinetic properties and factors contributing to inter- and intra-individual variability is critical to optimize clinical use. This study assessed the effects of food on the pharmacokinetics of combination piperaquine-dihydroartemisinin administration in healthy volunteers.
  
  
  METHODS
  This was an open-label, single-dose, parallel-group study. Participants were randomly allocated to receive oral piperaquine-dihydroartemisinin either after an overnight fast or immediately after a standardized, high-fat, high-calorie meal. Blood samples were collected for analysis of plasma piperaquine and dihydroartemisinin concentrations, which were utilized for calculation of pharmacokinetic parameters, using a standard model-independent approach.
  
  
  RESULTS
  Consumption of a high-fat, high-calorie meal resulted in substantial increases in the extent of exposure to piperaquine (ratio between area under the plasma concentration-time curve [AUC] values from 0 to 168 h in the fed and fasted states [AUC0-168 h FED/AUC0-168 h FASTED] = 299 %, 90 % confidence interval [CI] 239-374 %). This likely reflects an increase in the oral bioavailability of the drug, directly related to the fat content of the meal. Co-administration of food was also found to result in both delayed and enhanced absorption of dihydroartemisinin (ratio between AUC values from time zero to infinity in the fed and states [AUC∞ FED/AUC∞ FASTED] = 142 %, 90 % CI 113-178 %; ratio between mean transit time [MTT] values in the fed and fasted states [MTTFED/MTTFASTED] = 135 %, 90 % CI 114-160 %).
  
  
  CONCLUSIONS
  Although food was found to significantly impact on the pharmacokinetics of piperaquine and dihydroartemisinin, given the low fat content of standard meals within endemic regions and the anorexic effects of malaria infection, these results are unlikely to impact on the clinical utility of these drugs. However, co-administration of food with these anti-malarials by populations consuming a typical Western diet should be avoided to reduce the risk of toxic side effects. It is therefore a general recommendation that piperaquine-dihydroartemisinin not be administered within ±3 h of food consumption.
authors: School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia, stephanie.reuter@unisa.edu.au.
authors: Stephanie E
authors: SE
authors: Reuter
authors: Allan M
authors: AM
authors: Evans
authors: Sepehr
authors: S
authors: Shakib
authors: Yvonne
authors: Y
authors: Lungershausen
authors: Barbara
authors: B
authors: Francis
authors: Giovanni
authors: G
authors: Valentini
authors: Antonella
authors: A
authors: Bacchieri
authors: David
authors: D
authors: Ubben
authors: Silvia
authors: S
authors: Pace
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D037621:Artemisinins / Q000493:pharmacokinetics*; D001682:Biological Availability; D002149:Energy Intake; D005215:Fasting; D005502:Food; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D011804:Quinolines / Q000493:pharmacokinetics*; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines