OBJECTIVES: To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting. METHODS: Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity. RESULTS: A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8–60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution). CONCLUSION: We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.
OBJECTIVES: To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting. METHODS:Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity. RESULTS: A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8–60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution). CONCLUSION: We developed a prediction basis for mean posaconazole concentrations in AML/MDSpatients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.
Authors: Ryan K Shields; Cornelius J Clancy; Aniket Vadnerkar; Eun J Kwak; Fernanda P Silveira; Rima C Abdel Massih; Joseph M Pilewski; Maria Crespo; Yoshiya Toyoda; Jay K Bhama; Christian Bermudez; M Hong Nguyen Journal: Antimicrob Agents Chemother Date: 2010-12-28 Impact factor: 5.191
Authors: Andrew J Ullmann; Jeffrey H Lipton; David H Vesole; Pranatharthi Chandrasekar; Amelia Langston; Stefano R Tarantolo; Hildegard Greinix; Wellington Morais de Azevedo; Vijay Reddy; Navdeep Boparai; Lisa Pedicone; Hernando Patino; Simon Durrant Journal: N Engl J Med Date: 2007-01-25 Impact factor: 91.245
Authors: Thomas J Walsh; Elias J Anaissie; David W Denning; Raoul Herbrecht; Dimitrios P Kontoyiannis; Kieren A Marr; Vicki A Morrison; Brahm H Segal; William J Steinbach; David A Stevens; Jo-Anne van Burik; John R Wingard; Thomas F Patterson Journal: Clin Infect Dis Date: 2008-02-01 Impact factor: 9.079
Authors: George R Thompson; Michael G Rinaldi; Gennethel Pennick; Sheryl A Dorsey; Thomas F Patterson; James S Lewis Journal: Antimicrob Agents Chemother Date: 2009-03-02 Impact factor: 5.191
Authors: J J Vehreschild; M J G T Rüping; H Wisplinghoff; F Farowski; A Steinbach; R Sims; A Stollorz; K-A Kreuzer; M Hallek; C Bangard; O A Cornely Journal: J Antimicrob Chemother Date: 2010-04-21 Impact factor: 5.790
Authors: Gopal Krishna; Allen Moton; Lei Ma; Matthew M Medlock; James McLeod Journal: Antimicrob Agents Chemother Date: 2008-12-15 Impact factor: 5.191
Authors: M Mar Rodríguez; F Javier Pastor; Enrique Calvo; Valentina Salas; Deanna A Sutton; Josep Guarro Journal: Antimicrob Agents Chemother Date: 2009-09-28 Impact factor: 5.191
Authors: Annette C Reboli; Coleman Rotstein; Peter G Pappas; Stanley W Chapman; Daniel H Kett; Deepali Kumar; Robert Betts; Michele Wible; Beth P Goldstein; Jennifer Schranz; David S Krause; Thomas J Walsh Journal: N Engl J Med Date: 2007-06-14 Impact factor: 91.245
Authors: Michael J Dolton; Roger J M Brüggemann; David M Burger; Andrew J McLachlan Journal: Antimicrob Agents Chemother Date: 2014-09-08 Impact factor: 5.191
Authors: Michel Laverdiere; Eric J Bow; Coleman Rotstein; Julie Autmizguine; Raewyn Broady; Gary Garber; Shariq Haider; Trana Hussaini; Shahid Husain; Philippe Ovetchkine; Jack T Seki; Yves Théorêt Journal: Can J Infect Dis Med Microbiol Date: 2014 Nov-Dec Impact factor: 2.471
Authors: Lu Chen; Elke H J Krekels; Paul E Verweij; Jochem B Buil; Catherijne A J Knibbe; Roger J M Brüggemann Journal: Drugs Date: 2020-05 Impact factor: 9.546
Authors: Sarah Allegra; Giovanna Fatiguso; Silvia De Francia; Fabio Favata; Elisa Pirro; Chiara Carcieri; Amedeo De Nicolò; Jessica Cusato; Giovanni Di Perri; Antonio D'Avolio Journal: Biomedicines Date: 2017-11-20
Authors: Whitley M Yi; Kelly E Schoeppler; Jaclyn Jaeger; Scott W Mueller; Robert MacLaren; Douglas N Fish; Tyree H Kiser Journal: Ann Clin Microbiol Antimicrob Date: 2017-09-11 Impact factor: 3.944
Authors: Jannik Stemler; Philipp Koehler; Christian Maurer; Carsten Müller; Oliver A Cornely Journal: Ann Hematol Date: 2020-06-08 Impact factor: 3.673
Authors: Roeland E Wasmann; Cornelis Smit; Marieke H van Donselaar; Eric P A van Dongen; René M J Wiezer; Paul E Verweij; David M Burger; Catherijne A J Knibbe; Roger J M Brüggemann Journal: J Antimicrob Chemother Date: 2020-04-01 Impact factor: 5.790