We conclude that both intrapatient and interpatient variability in vincristine pharmacokinetics is large in pediatric cancer patients and that variability, although significantly influenced by diagnosis, largely remains unpredictable.

We studied vincristine pharmacokinetics in 70 children newly diagnosed with acute lymphoblastic leukemia, after a single dose of vincristine as monotherapy. Vincristine plasma concentrations were measured by HPLC analysis. A two-compartment, firstorder pharmacokinetic model was fitted to the data by maximum a posteriori parameter estimation. In this group of children pharmacokinetic factors were highly variable: median (25th and 75th percentiles) total body clearance, 228 (128 -360) Vincristine, one of the naturally occurring vinca alkaloids extracted from the leaves of the periwinkle plant Catharanthus roseus, continues to play a key role in the treatment of childhood ALL since its introduction in 1962 (1). Vincristine exerts an antimitotic effect (2-4) and induces apoptosis in various hematologic cell lines (5-8). Its antileukemic effect in vivo is determined by both variability in exposure of the leukemic cells and variability in sensitivity of the cells to the effect of vincristine. In vitro sensitivity of leukemic cells has been well studied (9), but the variability in exposure of leukemic cells in vivo has received less attention. Therefore, we studied vincristine pharmacokinetics in children newly diagnosed with ALL, after a single dose of vincristine.Vincristine-induced cell kill in a human lymphoblastic leukemia cell line was proportional to saturation of cellular binding sites (10), suggesting that the concentration of vincristine to which the cell is exposed is an important determinant of the antileukemic effect of vincristine. In vitro, vincristine accumulates in cells to concentrations as high as 500 times extracellular concentrations and is slowly released from the cells after restoration in drug-free medium (11, 12). Tissue distribution of vincristine was studied with 3 H-labeled vincristine in the rat and revealed accumulation in spleen, adrenal and thyroid glands, large and small intestines, heart, lung, kidney, liver, and marrow. Penetration in rat eye, fat, and brain tissue and in human cerebrospinal fluid appears to be very poor (13)(14)(15).The first pharmacokinetic studies on vincristine in man were performed when 3 H-labeled vincristine became available, 15 y after the introduction of vincristine in clinical practice. It was found that urinary excretion accounts for up to 12% of excreted radioactivity (16, 17). The biliary system appeared to be the principal route of excretion (13, 18 -20

Aim: To investigate whether there is any pharmacokinetic rationale for the common practice of administering vincristine to adolescents at relatively lower doses than those to younger children. Methods: A total of 98 children, aged 1.3–17.3 y, with acute lymphoblastic leukaemia (ALL) were studied on day 1 of induction therapy. Plasma samples were drawn before and 10, 30, 360 and 1380 min after injection of vincristine 2.0 mg/m2 (maximum dose 2.0 mg) and analysed by high‐performance liquid chromatography. Results: The median value (and range) for distribution half‐life was 6.4 min (0.8–11.8), elimination half‐life 1014 min (258–2570), volume of distribution 445 L/m2 (137–1241) and total body clearance 362 ml/min/m2 (134–2553). No correlation was found between age and any of these pharmacokinetic parameters. The area under the concentration time curve (AUC) was significantly correlated to age (p= 0.002; ρ– 0.31), as expected from the dosage of vincristine. The lower AUC in children with a body surface area > 1 m2, which is reached at 8–9 y of age, indicates that they received a less intense treatment because of the capping of the vincristine dose at 2.0 mg. Conclusions: Vincristine pharmacokinetics were not age dependent in this paediatric population. Thus, we found no pharmacokinetic rationale for dose reduction in adolescents. The common practice of limiting the vincristine dose to 2.0 mg should be carefully reconsidered.

Bi2Te3 nanosheets have been synthesized on Si substrates by surface‐assisted chemical vapor transport. The crumpled Bi2Te3 sheets grow in the basal plane of the hexagonal structure and are typically ≤3 nm in thickness (see picture; Te purple, Bi green). Raman studies found that modes involving atom displacement along the c axis that are inactive in the bulk material become Raman‐active in the Bi2Te3 nanosheets.

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