title: Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.
abstract: OBJECTIVE
  Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route.
  
  
  METHODS
  Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model.
  
  
  RESULTS
  A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed.
  
  
  CONCLUSIONS
  We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. a.oosten@erasmusmc.nl.
authors.forename: Astrid W
authors.initials: AW
authors.lastname: Oosten
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: João A
authors.initials: JA
authors.lastname: Abrantes
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Siv
authors.initials: S
authors.lastname: Jönsson
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.
authors.forename: Evelien J M
authors.initials: EJ
authors.lastname: Kuip
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.|CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Amílcar
authors.initials: A
authors.lastname: Falcão
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.|Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
authors.forename: Carin C D
authors.initials: CC
authors.lastname: van der Rijt
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000072716:Cancer Pain / Q000188:drug therapy* / Q000209:etiology*; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D005283:Fentanyl
keywords: Fentanyl; NONMEM; Pharmacokinetics; Subcutaneous; Transdermal