title: Population pharmacokinetics of peritoneal, plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia.
abstract: OBJECTIVE
  First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity.
  
  
  METHODS
  IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m(2)) at 360 (n = 58) or 460 mg/m(2) (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma.
  
  
  RESULTS
  IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis-Menten equation. The mean (±SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean (±SD) ratio AUC(IP)/AUC(UF) was 5.3 (±2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC(UF) accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUCUF, partly dependent on the extent and rate of oxaliplatin absorption.
  
  
  CONCLUSIONS
  Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.
authors: EA4553, Univ. Toulouse III Paul Sabatier, 31000, Toulouse, France.
authors: Quentin
authors: Q
authors: Chalret du Rieu
authors: Mélanie
authors: M
authors: White-Koning
authors: Laetitia
authors: L
authors: Picaud
authors: Isabelle
authors: I
authors: Lochon
authors: Sabrina
authors: S
authors: Marsili
authors: Laurence
authors: L
authors: Gladieff
authors: Etienne
authors: E
authors: Chatelut
authors: Gwenaël
authors: G
authors: Ferron
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000009:adverse effects*; D006207:Half-Life; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects; D007263:Infusions, Parenteral / Q000009:adverse effects; D008875:Middle Aged; D008962:Models, Theoretical; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced*; D014462:Ultrafiltration
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin