title: Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients.
abstract: Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day(-1), respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and NCT00541385, NCT00403260, NCT00422084, and NCT00440999 [phase III studies]. The most recent phase III study was registered at pactr.org under registration no. PACTR201105000286876.).
authors.affiliation: College of Pharmacy, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Ayyoub
authors.affiliation: College of Pharmacy, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Janthima
authors.initials: J
authors.lastname: Methaneethorn
authors.affiliation: Centre de Recherches Médicales de Lambaréné, Hôpital Albert Schweitzer, Lambaréné, Gabon Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Ramharter
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimde
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Mamadou
authors.initials: M
authors.lastname: Tekete
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Borghini-Fuhrer
authors.affiliation: Shin Poong Pharmaceuticals Co., Ltd., Seoul, Republic of Korea.
authors.forename: Jang-Sik
authors.initials: JS
authors.lastname: Shin
authors.affiliation: College of Pharmacy, University of Iowa, Iowa City, Iowa, USA l-fleckenstein@uiowa.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fleckenstein
mesh_terms: D000293:Adolescent; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D037621:Artemisinins / Q000493:pharmacokinetics; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D016780:Malaria, Vivax / Q000188:drug therapy; D008297:Male; D008962:Models, Theoretical; D009287:Naphthyridines / Q000493:pharmacokinetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D009287:Naphthyridines; D000077332:Artesunate; C027871:pyronaridine