Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria.
The disposition of chloroquine (CQ) and the related 4-aminoquinoline, piperaquine (PQ), were compared in Papua New Guinean children with uncomplicated malaria. Twenty-two children were randomized to 3 days of PQ phosphate at 20 mg/kg/day (12 mg of PQ base/kg/day) coformulated with dihydroartemisinin (DHA-PQ), and twenty children were randomized to 3 days of CQ at 10 mg base/kg/day with a single dose of sulfadoxine-pyrimethamine (CQ-SP). After a 42-day intensive sampling protocol, PQ, CQ, and its active metabolite monodesethyl-chloroquine (DECQ) were assayed in plasma by using high-performance liquid chromatography. A two-compartment model with first-order absorption was fitted to the PQ and CQ data. There were no significant differences in age, gender, body weight, or admission parasitemia between the two groups. The PCR-corrected 42-day adequate clinical and parasitological responses were 100% for DHA-PQ and 94% for CQ-SP, but P. falciparum reinfections during follow-up were common (33 and 18%, respectively). For PQ, the median volume of distribution at steady state, allowing for bioavailability (Vss/F), was 431 liters/kg (interquartile range [IQR], 283 to 588 liters/kg), the median clearance (CL/F) was 0.85 liters/h/kg (IQR, 0.67 to 1.06 liters/h/kg), the median distribution half-life (t 1/2 alpha) was 0.12 h (IQR, 0.05 to 0.66 h), and the median elimination half-life (t 1/2 beta) was 413 h (IQR, 318 to 516 h). For CQ, the median Vss/F was 154 liters/kg (IQR, 101 to 210 liters/kg), the median CL/F was 0.80 liters/h/kg (IQR, 0.52 to 0.96 liters/h/kg), the median t 1/2 alpha was 0.43 h (IQR, 0.05 to 1.82 h), and the median t 1/2 beta was 233 h (IQR, 206 to 298 h). The noncompartmentally derived median DECQ t 1/2 beta was 290 h (IQR, 236 to 368 h). Combined molar concentrations of DECQ and CQ were higher than those of PQ during the elimination phase. Although PQ has a longer t 1/2 beta than CQ, its prompt distribution and lack of active metabolite may limit its posttreatment malaria-suppressive properties.
Karunajeewa
Harin A
HA
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
Ilett
Kenneth F
KF
Mueller
Ivo
I
Siba
Peter
P
Law
Irwin
I
Page-Sharp
Madhu
M
Lin
Enmoore
E
Lammey
Jovitha
J
Batty
Kevin T
KT
Davis
Timothy M E
TM
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D011739:Pyrimethamine / Q000008:administration & dosage / Q000627:therapeutic use; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000627:therapeutic use; D013413:Sulfadoxine / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome; D010879:Piperazines
D000962:Antimalarials; D037621:Artemisinins; D002738:Chloroquine; D004338:Drug Combinations; D011739:Pyrimethamine; D011804:Quinolines; D012717:Sesquiterpenes; D013413:Sulfadoxine; C001205:fanasil, pyrimethamine drug combination; C039060:artenimol; C034759:piperaquine; D010879:Piperazines