Cyclophosphamide pharmacokinetics in children.

1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

GM1-gangliosidosis presenting as nonimmune hydrops fetalis: a case report.

We report a new case of GM1-gangliosidosis diagnosed in a 5 months old baby who was admitted at birth to our Neonatology Unit because of congenital ascites. The antenatal diagnostic techniques, including ultrasound, maternal antibody screen and fetoscopy with fetal karyotyping, as well as postnatal exhaustive study, failed to determine the underlying cause. Because of progressive neurologic deterioration a lysosomal storage disease was suspected and confirmed by skin biopsy. We wish to add a new case of a lysosomal storage disease to the growing list of nonimmune hydrops fetalis etiologies, and to highlight the importance of enzymatic studies in chorionic villous sample or amniotic cultured cells, once the most common conditions associated with fetal ascitis have been ruled out.

Cyclophosphamide metabolism in children.

The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide.

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13-29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.

Pharmacokinetics and metabolism of cyclophosphamide in paediatric patients.

The pharmacokinetics and metabolism of cyclophosphamide were studied in nine paediatric patients. Plasma samples were obtained from eight subjects and urine was collected from six children during a 24-h period after drug administration. Cyclophosphamide and its major metabolites phosphoramide mustard (PM), carboxyphosphamide (CX), dechloroethylcyclophosphamide (DCCP) and 4-ketocyclophosphamide (KETO) were determined in plasma and urine using high-performance thin-layer chromatography-photographic densitometry (HPTLC-PD). Cyclophosphamide (CP) was nearly, if not completely, cleared from plasma by 24 h after its administration. The plasma half-life of CP ranged from 2.15 to 8.15 h; it decreased following higher doses and was shorter than that previously reported for adult patients. Both the apparent volume of distribution (0.49 +/- 1.4 l/kg) and the total body clearance (2.14 +/- 1.4 l m-2 h-1) increased with increasing dose. Renal clearance ranged between 0.12 and 0.58 l/h (mean, 0.43 +/- 0.19 l/h). Between 5.4% and 86.1% of the total delivered dose was recovered as unchanged drug in the urine. The major metabolites identified in plasma and urine were PM and CX. One patient appeared to be deficient in CX formation. This study suggests that there is interpatient variability in the pharmacokinetics and metabolism of CP in paediatric patients. The shorter half-life and higher clearance as compared with adult values indicate faster CP metabolism in children.