title: Development of a Limited Sampling Strategy for the Estimation of Exposure to High-Dose Etoposide After Intravenous Infusion in Pediatric Patients.
abstract: Etoposide (VP-16), a podophyllotoxin derivative, is used in conditioning regimens before allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia. The aim of this study was to develop a limited sampling strategy (LSS) suitable for the prediction of exposure to VP-16 defined as area under time-concentration curve (AUC).
  
  
  
  The study included 28 pediatric patients with acute lymphoblastic leukemia, who were administered a 4-hour infusion of 60 mg/kg VP-16. VP-16 concentrations were determined in samples collected 4-124 hours after the beginning of infusion. On obtaining the pharmacokinetic (PK) profiles, a population PK model was developed in NONMEM (ICON Development Solutions, Hanover, MD) with first-order conditional estimation with interaction algorithm. LSSs were chosen by means of a multivariate regression analysis and cross-validated with a leave-one-out approach. Predictive performance of LSSs was assessed by calculating relative prediction error (PE), mean PE, mean absolute PE, and root mean squared PE for model-predicted and observed AUC.
  
  
  
  VP-16 PKs was best described by a 2-compartment first-order model, and a large variability in the PK parameters was observed. A 3-sample strategy allowed the estimation of VP-16 with highest accuracy and precision (mean relative PE = 0.18%, 95% confidence interval, 1.73%-2.09%; mean absolute relative PE = 3.47%, 95% confidence interval, 2.28%-4.66%; root mean squared PE = 4.43%). The final equation was AUC = 6.85 × C6 h + 3.88 × C12 h + 46.11 × C28 h + 282.0 (adjusted R = 0.9540).
  
  
  
  In conclusion, developed LSS allows accurate and precise estimation of VP-16 AUC and might be useful for therapeutic drug monitoring.
authors.affiliation: Departments of *Physical Pharmacy and Pharmacokinetics and †Pediatric Hematology, Oncology and Transplantology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Danielak
authors.forename: Joanna
authors.initials: J
authors.lastname: Sobiak
authors.forename: Jacek
authors.initials: J
authors.lastname: Wachowiak
authors.forename: Franciszek
authors.initials: F
authors.lastname: Główka
authors.forename: Maria
authors.initials: M
authors.lastname: Chrzanowska
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002648:Child; D016903:Drug Monitoring / Q000379:methods; D005047:Etoposide / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D013048:Specimen Handling / Q000379:methods; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D007166:Immunosuppressive Agents; D005047:Etoposide