title: Malnourished Malawian patients presenting with large Wilms tumours have a decreased vincristine clearance rate.
abstract: BACKGROUND
  In developing countries, patients with a Wilms' tumour often present late with a high degree of malnutrition and large tumours. We investigated whether this affects vincristine pharmacokinetics.
  
  
  METHODS
  Patients newly diagnosed with Wilms' tumour in Malawi and the UK were included. We documented anthropometric parameters, nutritional status and tumour size. Vincristine (1.50 mg/m(2)) was administered as part of the standard chemotherapy regimen. Vincristine plasma concentrations were measured at several time points by liquid chromatography-mass spectrometry. Vincristine pharmacokinetic parameters (clearance and area under the curve) were calculated by non-compartmental analysis.
  
  
  RESULTS
  Eleven Malawian and 8 UK patients were included. Mean Z-score of (corrected) weight for height was significantly lower in the Malawian patients than in the UK patients (-2.3 versus 0.42, p<0.0001). Mean tumour weight at diagnosis was significantly larger in Malawian patients (2.8 kg versus 0.7 kg, p=0.007). Mean vincristine logClearance was lower in Malawian as compared to UK patients (2.2 versus 2.6 ml/min, p=0.001). Mean logAUC values were higher in Malawian than in UK patients (3.8 versus 3.5 microg/mlmin, p=0.003). This difference is reflected in the, on average, 1.98-fold larger vincristine AUC values for Malawian patients. The difference in AUC values was statistically significantly explained by nutritional status (p=0.043).
  
  
  CONCLUSIONS
  Malnourished patients in Malawi exhibited lower vincristine clearance rates and thus higher AUC values than a comparable patient population with a better nutritional status in the UK. In malnourished patients, dose reductions may need to be considered to prevent an increased incidence and severity of toxicity.
authors.affiliation: Department of Paediatrics, College of Medicine, University of Malawi, Blantyre, Malawi. t.israels@amc.uva.nl
authors.forename: Trijn
authors.initials: T
authors.lastname: Israels
authors.forename: Carola W N
authors.initials: CW
authors.lastname: Damen
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.forename: Nan
authors.initials: N
authors.lastname: van Geloven
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Molyneux
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
mesh_terms: D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008295:Malawi; D008297:Male; D044342:Malnutrition / Q000150:complications* / Q000378:metabolism; D008657:Metabolic Clearance Rate; D014750:Vincristine / Q000493:pharmacokinetics*; D009396:Wilms Tumor / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine