Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children

BACKGROUND Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited PK data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. OBJECTIVES To describe the pharmacokinetics of LAmB in children aged 1-17 years with suspected or documented IFD. METHODS Thirty-five children were treated with LAmB at dosages of 2.5-10 mg kg(-1) daily. Samples were taken at baseline and at 0.5-2.0 hourly intervals for twenty-four hours after receipt of the first dose (n=35 patients) and on the final day of therapy (n=25 patients). LAmB was measured using high performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. RESULTS An evolution in PK was observed during the course of therapy resulting in a proportion of patients (n=13) having significantly higher maximum serum concentration (Cmax) and area under the concentration time curve (AUC0-24) later in the course of therapy, without evidence of drug accumulation (Cmin accumulation ratio, AR < 1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24 and probability of nephrotoxicity (OR 2.37; 95% CI 1.84-3.22, p=0.004). CONCLUSIONS LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation or observed clinical factors

Precision Medicine in Pediatric Oncology

Improvements in outcome have been seen in children and adolescents with cancer. Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer, particularly in patients with metastatic disease or with cancers that are resistant or recur after standard treatment. Precision medicine trials using individualized tumor molecular profiling for selection of targeted therapies are ongoing in adult malignancies. Similar approaches are being applied to children and adolescents with cancer. This article describes how precision medicine is being applied to pediatric oncology and the unique challenges being faced with these efforts

Bilateral synchronous tibial periosteal osteosarcoma with familial incidence

Multifocal or multicentric osteosarcoma (OS) has been described as tumor occurrence at two or more sites in a patient without visceral metastasis. These may be synchronous (more than one lesion at presentation) or metachronous (new tumor developing after the initial treatment). The incidence of multifocal OS has ranged from 1.5 to 5.4% in large series, with the synchronous type being rarer. Similarly, periosteal OS is another rare subtype of surface OS and constitutes less than 2% of all OS. An 11-year-old female was diagnosed with bilateral synchronous tibial periosteal OS, which were confirmed by CT-guided biopsies. After neoadjuvant chemotherapy, the patient underwent a staged wide local resection of the tumors. The defect was reconstructed with a proximal tibial replacement on the left side and autologous bone grafting on the right side. The patient did well after surgery and is free of disease at 5.5 years of follow-up. However, her brother also developed a right tibial periosteal osteosarcoma 4 years after her index surgery. Genetic analysis of blood sample from both patients showed a similar missense mutation in at least one allele of TP53 gene (exon 8). To the best of our knowledge, a case of bilateral \u27synchronous\u27 periosteal OS with a familial incidence has not been reported before. © ISS 2012