title: Integrative population pharmacokinetic and pharmacodynamic dose finding approach of the new camptothecin compound namitecan (ST1968).
abstract: OBJECTIVE
  Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development.
  
  
  METHODS
  Plasma concentration-time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1-3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations.
  
  
  RESULTS
  Clearance was estimated to be 0.15 l h(-1), with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration-time curve (AUC) and the percentage drop of neutrophils (r(2) = 0.51, P < 10(-4)) or thrombocytes (r(2) = 0.49, P < 10(-4)). With a target for haematological dose-limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1-3 regimen.
  
  
  CONCLUSIONS
  This is the first integrated population PK-PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently undergoing early clinical development. A distinct relationship was found between drug exposure and haematological toxicity, supporting flat-dosing once every 3 weeks as the most adequate dosing regimen.
authors.affiliation: Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland.|Clinical Research Facility, Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland.|Clinical Research Facility, Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Hess
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Delmonte
authors.affiliation: IOSI Oncology Insitute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Gallerani
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele, IRCCS, Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fasolo
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele, IRCCS, Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
authors.affiliation: IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cresta
authors.affiliation: Sigma-Tau Research Switzerland S.A., Mendrisio, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Barbieri
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite SpA, Pomezia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pace
authors.affiliation: IOSI Oncology Insitute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; C531200:namitecan; D002166:Camptothecin
keywords: Namitecan; neutropenia; pharmacodynamics; pharmacokinetics; thrombocytopenia; toxicity