Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

AIMS: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia. METHODS: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). RESULTS: A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible". CONCLUSIONS: The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.

[The effects of interleukin-11 on high-dose methotrexate (HDMTX) induced mucositis in Wistar rats].

OBJECTIVE: To explore the therapeutic effect of interleukin-11 (IL-11) on high-dose methotrexate (HDMTX) induced mucositis in Wistar's rats, the proliferative effect on CEM leukemia cell line and the antitumor effect on HDMTX. METHODS: Ninety-five 5-week old, 120 - 150 grams weight Wistar rats were randomly divided into five groups. Group A is normal control (n = 15), group B MTX control (n = 20), group C IL-11 pretreatment group before MTX injection (n = 20), group D (n = 20) the high dose IL-11 group (475 microg.kg(-1).d(-1)) after MTX injection, group E (n = 20) the low dose IL-11 group (150 microg.kg(-1).d(-1)) after MTX injection. All rats in group B approximately E were given 1 ml MTX intraperitoneally (100 mg/kg). Rats were killed at day 1, 3, 5, 7 after MTX injection. The mortality rates, changes of small intestine tissue morphology and ultra structure were observed. The proliferation of small intestine crypt cell was assayed by proliferating cell nuclear antigen (PCNA) immunohistochemical staining. MTT method was used to detect the proliferation of CEM cell line. RESULT: IL-11 treatment resulted in a significant increase of survival of HDMTX treated rats, increased of small intestinal villus length and villus/crypt ratio. IL-11 administration was associated with enhancement of small intestine mucosa recovery after HDMTX therapy. Group C showed a greater effect than group B (P < 0.01). IL-11 had no effect on CEM cell proliferation. CONCLUSION: IL-11 has a significant mitigating effect on high-dose MTX induced intestinal mucositis in rat, and significantly increase the survival of the rats. IL-11 could be safely used in the HDMTX treatment of childhood acute lymphocyte leukemia.