title: Excel-Based Tool for Pharmacokinetically Guided Dose Adjustment of Paclitaxel.
abstract: BACKGROUND
  Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 μmol/L (Tc > 0.05 μmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc > 0.05 μmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 μmol/L and give clinicians an easy-to-use tool.
  
  
  METHODS
  Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a posteriori Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 μmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function.
  
  
  RESULTS
  There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 μmol/L values. Tc > 0.05 μmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc > 0.05 μmol/L values between both programs was 1%.
  
  
  CONCLUSIONS
  The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 μmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc > 0.05 μmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.
authors.affiliation: *Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Germany; †SGS Exprimo NV, Mechelen, Belgium; ‡Department of Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland; and §Saladax Biomedical Inc, Bethlehem, Pennsylvania.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kraff
authors.forename: Andreas
authors.initials: A
authors.lastname: Lindauer
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Salamone
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaehde
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001499:Bayes Theorem; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D017711:Nonlinear Dynamics; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel