title: Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens.
abstract: OBJECTIVE
  Selection of the most appropriate chemotherapy dosing regimens for neonates treated within the first weeks of life represents a significant clinical dilemma. Due to a lack of information relating to the clinical pharmacology of anticancer drugs in these challenging patients, current dosing guidelines are based on limited scientific rationale. In the current study, we investigate the utilisation of therapeutic drug monitoring approaches in neonates with localised hepatoblastoma, Wilms' tumour and stage 4S neuroblastoma, being treated with widely used anticancer drugs.
  
  
  METHODS
  Plasma concentrations of cisplatin, vincristine, etoposide and carboplatin were quantified in two neonates being treated within the first 3 weeks of life and in a 32-week preterm infant treated at a gestational age of 40 weeks. Therapeutic drug monitoring was carried out where appropriate, based on the pharmacokinetic data obtained in conjunction with clinical response and toxicity.
  
  
  RESULTS
  Treatment of a child aged 2 weeks with a recommended cisplatin dose reduction for weight to 1.8 mg/kg resulted in achievement of unbound cisplatin plasma concentrations of 0.01-0.08 µg/mL, markedly lower than exposures previously reported in infants and older children. A dose increase to 2.7 mg/kg was implemented, leading to the achievement of levels more in-line with those previously reported. This increased dose level was well tolerated over six courses of treatment, resulting in a good response to cisplatin monotherapy and the patient remains in remission at 3.5 years. In contrast, a 50 % vincristine dose reduction for weight in a 3-week-old neonate resulted in plasma concentrations comparable to levels observed in older children, leading to successful treatment and continued remission at 2 years. In a third patient, etoposide and carboplatin clearance values normalised to body weight were comparable to those reported in older children, resulting in comparatively lower exposures following reduced dosing.
  
  
  CONCLUSIONS
  The current report provides unique data on the pharmacokinetics of several widely used anticancer drugs in neonates treated within the first few weeks of life. The provision of these data acts as a useful reference point to support future dosing decisions to be made by clinicians in the treatment of these challenging patients.
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. G.J.Veal@ncl.ac.uk.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Errington
authors.affiliation: School of Medicine, Glasgow University, Glasgow, G12 8QQ, UK.
authors.forename: Jairam
authors.initials: J
authors.lastname: Sastry
authors.affiliation: Great Ormond Street Hospital, London, WC1N 3JH, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Chisholm
authors.affiliation: Great Ormond Street Hospital, London, WC1N 3JH, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Brock
authors.affiliation: Great Ormond Street Hospital, London, WC1N 3JH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgenstern
authors.affiliation: Institute of Child Health, University College London, London, WC1N 1EH, UK.
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.affiliation: Great Ormond Street Hospital, London, WC1N 3JH, UK.
authors.forename: Tanzina
authors.initials: T
authors.lastname: Chowdhury
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D016903:Drug Monitoring; D055317:Evidence-Based Practice; D006801:Humans; D007231:Infant, Newborn
chemical_list: D000970:Antineoplastic Agents
keywords: Carboplatin; Chemotherapy; Cisplatin; Etoposide; Hepatoblastoma; Neonates; Neuroblastoma; Therapeutic drug monitoring; Vincristine; Wilms’ tumour