Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria.
OBJECTIVE
To study the population pharmacokinetics of piperaquine after co-administration with dihydroartemisinin in uncomplicated malaria.


METHODS
The disposition of piperaquine was studied in 85 Cambodian patients with uncomplicated falciparum or vivax malaria treated with the piperaquine-dihydroartemisinin coformulation Artekin. All patients were given Artekin orally at 0, 6, 24 and 32 h with a total piperaquine dose of 32-35 mg base kg-1. Adults were given tablets while children received either tablets or a dispersible granule formulation. Patients underwent either intensive (17-19 samples) or sparse (2-5 samples) blood sampling schedules over 35 days and clinical/parasitological follow-up over > 28 days. Piperaquine in plasma was quantified by high performance liquid chromatography.


RESULTS
All patients achieved fever clearance within 24 h and parasite clearance within 72 h. The 28-day cure rate was 97% in adults and 98% in children. A covariate-free two-compartment population model with first-order absorption and elimination gave the most robust representation of the plasma concentration-time data in both adults and children. In adults (n = 38), the median (interquartile range) derived pharmacokinetic descriptors CL/F, Vss/F and t1/2,z were 0.9 l h-1 kg-1 (0.79-1.02 l h-1 kg-1), 574 l kg-1(371-711 l kg-1) and 23 days (19-28 days), respectively. In children (n = 47), corresponding values were 1.8 l h-1 kg-1 (1.29-2.3 l h-1 kg-1), 614 l kg-1 (332-1205 l kg-1) and 14 days (10-18 days), respectively.


CONCLUSIONS
Piperaquine is a highly lipid-soluble drug with a large Vss/F, long t1/2,z and a clearance that is markedly higher in children than in adults.
Medicine Unit (Fremantle Hospital) and Pharmacology Unit (Queen Elizabeth 2 Medical Centre), School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
Te-Yu
TY
Hung
Timothy M E
TM
Davis
Kenneth F
KF
Ilett
Harin
H
Karunajeewa
Sean
S
Hewitt
Mey Bouth
MB
Denis
Chiv
C
Lim
Doung
D
Socheat
D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy*; D016780:Malaria, Vivax / Q000097:blood / Q000188:drug therapy*; D008297:Male; D011804:Quinolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013607:Tablets; D010879:Piperazines
D000962:Antimalarials; D011804:Quinolines; D013607:Tablets; C034759:piperaquine; D010879:Piperazines