title: Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function.
abstract: OBJECTIVE
  The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy.
  
  
  METHODS
  A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr)  = 50-79 ml min(-1) ], moderate [CLcr  = 30-49 ml min(-1) ], severe [CLcr <30 ml min(-1) ]).
  
  
  RESULTS
  Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m(-2) day(-1) , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m(-2) day(-1) for patients with moderate renal impairment (suggested dose 1.9 mg m(-2) day(-1) for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m(-2) day(-1) in this cohort.
  
  
  CONCLUSIONS
  Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.
authors: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Lot A
authors: LA
authors: Devriese
authors: Department of Medical Oncology, University Medical Center Utrecht, The Netherlands.
authors: Petronella Els O
authors: PE
authors: Witteveen
authors: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Marja
authors: M
authors: Mergui-Roelvink
authors: GlaxoSmithKline, Research Triangle Park, USA.
authors: Deborah A
authors: DA
authors: Smith
authors: Department of Medicine, The Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, USA.
authors: Lionel D
authors: LD
authors: Lewis
authors: Pinnacle Oncology Hematology, Scottsdale, USA.
authors: David S
authors: DS
authors: Mendelson
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors: Yung-Jue
authors: YJ
authors: Bang
authors: Yonsei Cancer Center, Severance Hospital, Seoul, South Korea.
authors: Hyun Choel
authors: HC
authors: Chung
authors: GlaxoSmithKline, Research Triangle Park, USA.
authors: Mohammed M
authors: MM
authors: Dar
authors: Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
authors: Alwin D R
authors: AD
authors: Huitema
authors: Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.|Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors: Jos H
authors: JH
authors: Beijnen
authors: Department of Medical Oncology, University Medical Center Utrecht, The Netherlands.
authors: Emile E
authors: EE
authors: Voest
authors: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors: Jan H M
authors: JH
authors: Schellens
mesh_terms: D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D059004:Topoisomerase I Inhibitors; D019772:Topotecan
keywords: oral topotecan; pharmacodynamics; pharmacokinetics; renal impairment; toxicity