Cargando…

Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients

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 th...

Descripción completa

Detalles Bibliográficos
Autores principales: Ayyoub, Amal, Methaneethorn, Janthima, Ramharter, Michael, Djimde, Abdoulaye A., Tekete, Mamadou, Duparc, Stephan, Borghini-Fuhrer, Isabelle, Shin, Jang-Sik, Fleckenstein, Lawrence
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775925/
https://www.ncbi.nlm.nih.gov/pubmed/26666916
http://dx.doi.org/10.1128/AAC.02004-15
_version_ 1782419076848549888
author Ayyoub, Amal
Methaneethorn, Janthima
Ramharter, Michael
Djimde, Abdoulaye A.
Tekete, Mamadou
Duparc, Stephan
Borghini-Fuhrer, Isabelle
Shin, Jang-Sik
Fleckenstein, Lawrence
author_facet Ayyoub, Amal
Methaneethorn, Janthima
Ramharter, Michael
Djimde, Abdoulaye A.
Tekete, Mamadou
Duparc, Stephan
Borghini-Fuhrer, Isabelle
Shin, Jang-Sik
Fleckenstein, Lawrence
author_sort Ayyoub, Amal
collection PubMed
description 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 (V(2)/F), peripheral volume of distribution (V(3)/F), intercompartmental clearance (Q/F), and absorption rate constant (K(a)) 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 V(2)/F and formulation on K(a). 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.)
format Online
Article
Text
id pubmed-4775925
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher American Society for Microbiology
record_format MEDLINE/PubMed
spelling pubmed-47759252016-04-04 Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients Ayyoub, Amal Methaneethorn, Janthima Ramharter, Michael Djimde, Abdoulaye A. Tekete, Mamadou Duparc, Stephan Borghini-Fuhrer, Isabelle Shin, Jang-Sik Fleckenstein, Lawrence Antimicrob Agents Chemother Pharmacology 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 (V(2)/F), peripheral volume of distribution (V(3)/F), intercompartmental clearance (Q/F), and absorption rate constant (K(a)) 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 V(2)/F and formulation on K(a). 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.) American Society for Microbiology 2016-02-26 /pmc/articles/PMC4775925/ /pubmed/26666916 http://dx.doi.org/10.1128/AAC.02004-15 Text en Copyright © 2016 Ayyoub et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacology
Ayyoub, Amal
Methaneethorn, Janthima
Ramharter, Michael
Djimde, Abdoulaye A.
Tekete, Mamadou
Duparc, Stephan
Borghini-Fuhrer, Isabelle
Shin, Jang-Sik
Fleckenstein, Lawrence
Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
title Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
title_full Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
title_fullStr Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
title_full_unstemmed Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
title_short Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
title_sort population pharmacokinetics of pyronaridine in pediatric malaria patients
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775925/
https://www.ncbi.nlm.nih.gov/pubmed/26666916
http://dx.doi.org/10.1128/AAC.02004-15
work_keys_str_mv AT ayyoubamal populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT methaneethornjanthima populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT ramhartermichael populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT djimdeabdoulayea populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT teketemamadou populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT duparcstephan populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT borghinifuhrerisabelle populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT shinjangsik populationpharmacokineticsofpyronaridineinpediatricmalariapatients
AT fleckensteinlawrence populationpharmacokineticsofpyronaridineinpediatricmalariapatients