title: Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department I of Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: J J
authors.initials: JJ
authors.lastname: Vehreschild
authors.forename: C
authors.initials: C
authors.lastname: Müller
authors.forename: F
authors.initials: F
authors.lastname: Farowski
authors.forename: M J G T
authors.initials: MJ
authors.lastname: Vehreschild
authors.forename: O A
authors.initials: OA
authors.lastname: Cornely
authors.forename: U
authors.initials: U
authors.lastname: Fuhr
authors.forename: K-A
authors.initials: KA
authors.lastname: Kreuzer
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.forename: V
authors.initials: V
authors.lastname: Kohl
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015331:Cohort Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology; D008875:Middle Aged; D008954:Models, Biological; D009181:Mycoses / Q000517:prevention & control; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000382:microbiology; D013535:Suspensions / Q000008:administration & dosage / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D013535:Suspensions; D014230:Triazoles; C101425:posaconazole