title: Pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated falciparum malaria.
abstract: Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P = 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P = 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P = 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P = 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P = 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
authors.affiliation: Shoklo Malaria Research Unit, PO Box 46 Mae Sot, Tak 63110, Thailand.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Rijken
authors.forename: Rose
authors.initials: R
authors.lastname: McGready
authors.forename: Aung Phae
authors.initials: AP
authors.lastname: Phyo
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegardh
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Natthapon
authors.initials: N
authors.lastname: Laochan
authors.forename: Hla Hla
authors.initials: HH
authors.lastname: Than
authors.forename: Oh
authors.initials: O
authors.lastname: Mu
authors.forename: Aye Kyi
authors.initials: AK
authors.lastname: Win
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: Nicholas
authors.initials: N
authors.lastname: White
authors.forename: François
authors.initials: F
authors.lastname: Nosten
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D037621:Artemisinins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000188:drug therapy*; D011256:Pregnancy Outcome; D011804:Quinolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013785:Thailand; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines