title: Pharmacokinetics of satraplatin (JM216), an oral platinum (IV) complex under daily oral administration for 5 or 14 days.
abstract: BACKGROUND
  Satraplatin (JM216; bis-acetatoammine-dichlorocyclohexylamine platinum (IV)) is a platinum (Pt) complex developed in an attempt to circumvent tumour resistance and which can be administered by the oral route. The fate of platinum delivered by this oral formulation administered at various doses under the 5 or 14 days schedule, has been studied to a limited extent.
  
  
  METHODS
  Total (Ptot) and ultrafilterable (PtUF) platinum were determined in 19 patients enrolled in phase I (PI) and II (PII) studies (PI, n = 14, advanced cancer; PII, n = 5, untreated small cell lung carcinoma). JM216 doses were 10 to 50 mg m-2 day-1 x 14 d (days) (dose escalation in PI) and 120 mg m-2 day-1 x 5d (fixed dose in PII), administered to fasted patients in a standardized way. Ptot and PtUF levels were determined by atomic absorption spectrometry on d1 and d14, followed over 28 days in PI; and on d1, followed over 5 days in PII. Pharmacokinetic parameters were derived by a noncompartmental approach.
  
  
  RESULTS
  JM216 is rapidly absorbed with a Tmax obtained within 2.5-3 hours and 1-2 hours for Ptot and PtUF, respectively. The pharmacokinetics of JM216 was linear across the tested doses in PI, with the exposure of Ptot on d14 being better correlated with dose per BSA (Body surface area) (r = 0.91) than that of PtUF (r = 0.61). In PI, Cmax on d1 increased proportionally to the dose (r = 0.82 and r = 0.72 for Ptot and PtUF, respectively). Apparent clearances in PI were 1.1 +/- 0.5 L h-1 and 37.0 +/- 33 L h-1 for Ptot and PtUF, respectively. Prolonged terminal half-lives were observed after the last JM216 administration with mean values of 216 +/- 37 hours and 107 +/- 89 hours, for Ptot and PtUF respectively. The accumulation ratio (Cmaxd14/Cmaxd1) indicated a higher accumulation of Ptot (3.5 +/- 1.6) than of PtUF (1.8 +/- 1) under multiple dose regimen. The apparent volumes of distribution (terminal phase) were similar in the PI and PII studies: 326 +/- 112 L and 3094 +/- 1493 L, and 557 +/- 267 L and 4154 +/- 2147 L, for Ptot and PtUF, respectively. In PI, the nadir of thrombocytopenia was related both to the cumulated dose of JM216 (r = 0.81) and to the AUC of Ptot on d14 (r = 0.77), whereas the AUC of PtUF was not predictive (r = 0.48). The Cmax of Ptot and PtUF on d1 was related to neutropenia (r = 0.61 and r = 0.65, respectively) and to thrombocytopenia (r = 0.77 and r = 0.74, respectively). No relationships were found between leukocytes or neutrophils percent decrease and the AUCs or total, dose of JM216.
  
  
  CONCLUSIONS
  JM216 is an orally bioavailable platinum-containing chemotherapeutic agent yielding predictable total levels of platinum which appears to accumulate in plasma after multiple administration over 14 days. These results should be set in relation to clinical efficacy and tolerance, to optimise the dose regimen of JM216 in further studies.
authors.affiliation: Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Vouillamoz-Lorenz
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Ferdy
authors.initials: F
authors.lastname: Lejeune
authors.forename: Jean
authors.initials: J
authors.lastname: Bauer
authors.forename: Serge
authors.initials: S
authors.lastname: Leyvraz
authors.forename: Laurent Arthur
authors.initials: LA
authors.lastname: Decosterd
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D010984:Platinum / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; C081294:satraplatin