A pharmacokinetic–pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration–time curve (AUC) values of 21 or 20 mg ml −1 .min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum–DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80–126% of target AUC values, as compared to estimated exposures of 65–213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum–DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug–target interaction.

Kostmann syndrome is a congenital disorder of myelopoeisis characterized by an absolute neutropaenia and severe bacterial infections. The introduction of G-CSF has dramatically changed the prognosis of these patients in recent years; though in G-CSF refractory patients, haemopoeitic stem cell transplant is still the only effective treatment. We describe the first case report of a patient who, unresponsive to escalating doses of G-CSF, underwent reduced intensity conditioning, Matched Unrelated Donor (MUD) allograft and has been cured from this condition. A male child presented shortly after birth with infection of the umbilicus. He developed repeated infections in the first six weeks of his life including pneumonia and scrotal abscess. Investigations at this stage included a bone marrow examination, which confirmed a diagnosis of severe congenital neutropaenia and he was started on treatment with G-CSF at 5μg/kg/day. Since diagnosis, he had numerous episodes of ear and skin infections and recurrent abscesses, most often with Methicillin resistant Staphylococcus aureus (MRSA) that required repeated hospitalisations. As the patient did not have a matched related donor, dose escalations were tried with G-CSF at 14-day intervals though he did not respond to doses up to 160μg/kg/day. At this stage, we had a child who was not responding to G-CSF injections, had several infections and was a carrier of MRSA and also Vancomycin Resistant Enterococci, who did not have a matched sibling donor. It was decided then to proceed with a MUD transplant with a non-myeloablative prepatory regimen. The pre transplant conditioning included fludarabine 30mg/m2 from day −8 to day −5, CAMPATH-1H 0.2 mg/kg from day -6 to day −2 and thiotepa 250 mg/m2 from day −4 to −2. Ciclosporin was started from day −1 and GCSF (Lenograstim) at 5μg/kg from day +7. A total of 10.4×106 CD 34+ cells/kg recipient's weight of stem cells was infused. The patient successfully engrafted with a neutrophil count greater than 0.5×109/L on day 12 with an unsupported platelet count reaching above 50×109/L on day 33. The post transplant period was complicated with grade II skin and gut GVH that responded well to increased doses of ciclosporin alone. Slight falls in neutrophil count were noted on days 28 and 113 after transplant, which resolved by adjusting ciclosporin dosage. He is now ten months post transplant and has not had any infections needing hospitalization and maintains his neutrophil count.

The glycophorin A (GPA) mutation assay was used to examine the risk of in vivo somatic mutation in infants following neonatal administration of vitamin K. The assay assesses damage to erythroid stem cells by measuring the frequency of NO and NN variant red cells of MN blood group heterozygotes using FACS analysis. Blood samples were obtained from 178 infants aged between 10 and 183 days. Twenty-six children were excluded from study having received a blood transfusion. Sixty-four of the remaining 152 infants were of the MN phenotype, samples from whom were analysed using the assay system, providing the first data of NO and NN variant frequencies (vfs) in children aged less than 1 year. Twenty of these 64 infants received vitamin K orally (group A), 17 intramuscularly (group B) and 25 intravenously (group C). Results were compared with those from a reference population of children aged 1-15 years. There were no significant differences in NO, NN and total vf between any of groups A, B and C. For all groups both NO and total vf were significantly lower than those for the control population. This result is of some interest and clearly warrants further investigation. NN and total vfs were greater than the 95th percentile for the pooled data from groups A, B and C in three instances, one in each group. It was thus not possible to demonstrate an association between the route of vitamin K administration and an increase in mutation at the GPA locus.