title: Towards better dose individualisation: metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer.
abstract: BACKGROUND
  Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs. As exposure to cabazitaxel is related to treatment response, it is essential to develop a better individualised dosing strategy.
  
  
  METHODS
  Ten patients with metastatic castration-resistant prostate cancer, who received cabazitaxel dosed on BSA as a part of routine palliative care, were enrolled in this study. Midazolam was administered as phenotyping probe for cytochrome P450 isoenzyme 3A (CYP3A). The relationship between midazolam and cabazitaxel clearance was investigated using non-linear mixed effects modelling.
  
  
  RESULTS
  The clearance of Midazolam highly correlated with cabazitaxel clearance (R=0.74). Midazolam clearance significantly (P<0.004) explained the majority (∼60%) of the inter-individual variability in cabazitaxel clearance in the studied population.
  
  
  CONCLUSIONS
  Metabolic phenotyping of CYP3A using midazolam is a promising strategy to individualise cabazitaxel dosing. Before clinical application, a randomised study is warranted.
authors.affiliation: Laboratory of Translational Immunology, University Medical Center, Utrecht 3584 CX, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Janssen
authors.affiliation: Department of Internal Medicine, St Antonius Hospital, Nieuwegein 3435 CM, The Netherlands.
authors.forename: C P M
authors.initials: CPM
authors.lastname: Verkleij
authors.affiliation: Department of Pulmonology, Jeroen Bosch Hospital, Den Bosch 5223 GZ, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van der Vlist
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center, Rotterdam 3075 EA, The Netherlands.
authors.forename: R H J
authors.initials: RHJ
authors.lastname: Mathijssen
authors.affiliation: Department of Internal Medicine, Meander Medical Center, Amersfoort 3813 TZ, The Netherlands.|Department of Medical Oncology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Bloemendal
authors.affiliation: Department of Pharmacy, Radboud UMC, Nijmegen 6525 GA, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Ter Heine
mesh_terms: D000368:Aged; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001830:Body Surface Area; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D014151:Anti-Anxiety Agents; D000970:Antineoplastic Agents; D043823:Taxoids; C552428:cabazitaxel; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam