title: Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia.
abstract: Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.).
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand Pattarapornv.fsn@afrims.org.
authors.forename: Pattaraporn
authors.initials: P
authors.lastname: Vanachayangkul
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Chanthap
authors.initials: C
authors.lastname: Lon
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Michele
authors.initials: M
authors.lastname: Spring
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Sommethy
authors.initials: S
authors.lastname: Sok
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Winita
authors.initials: W
authors.lastname: Ta-Aksorn
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Chanikarn
authors.initials: C
authors.lastname: Kodchakorn
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Sut-Thang
authors.initials: ST
authors.lastname: Pann
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Soklyda
authors.initials: S
authors.lastname: Chann
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Mali
authors.initials: M
authors.lastname: Ittiverakul
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Sabaithip
authors.initials: S
authors.lastname: Sriwichai
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Nillawan
authors.initials: N
authors.lastname: Buathong
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Worachet
authors.initials: W
authors.lastname: Kuntawunginn
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Mary
authors.initials: M
authors.lastname: So
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Theng
authors.initials: T
authors.lastname: Youdaline
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Milner
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Wojnarski
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lanteri
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Jessica
authors.initials: J
authors.lastname: Manning
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Satharath
authors.initials: S
authors.lastname: Prom
authors.affiliation: F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Haigney
authors.affiliation: F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Cantilena
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: David
authors.initials: D
authors.lastname: Saunders
mesh_terms: D000962:Antimalarials / Q000009:adverse effects* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D037621:Artemisinins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002160:Cambodia; D066126:Cardiotoxicity; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
keywords: POPPK; QT prolongation; antimalarial agents; cardiac safety; piperaquine