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Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.) [ABSTRACT FROM AUTHOR]

Background and Objectives: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. Methods: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. Results: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. Conclusion: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0−∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. (www.clinicaltrials.gov, NCT01117441, first submitted date: May 3, 2010). [ABSTRACT FROM AUTHOR]

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Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration. [ABSTRACT FROM AUTHOR]

The GMALL07/2003 protocol introduced pegylated E. coli asparaginase (PEG-ASNase) frontline for adults with acute lymphoblastic leukemia (ALL). PEG-ASNase (500 U/m2, 1000 U/m2, or 2000 U/m2) was given once in induction and as part of three HD-MTX/PEG-ASNase cycles with two PEG-ASNase doses every other week in consolidation. PEG-ASNase activities were monitored in 1363 serum samples from 304 ALL patients. The overall rate of silent inactivation was low (5%) and did not differ between induction and consolidation. The successful targeting of PEG-ASNase activities ≥100 U/L depended on protocol and dose. Overall PEG-ASNase activities were higher during consolidation compared to induction. To target PEG-ASNase activities ≥100 U/L for 14 day with a single dose in induction, 2000 U/m2 was more preferable than 1000 U/m2 or 500 U/m2. During consolidation with two administrations every other week, 1000 U/m2 and 2000 U/m2 were similarly effective in sustaining PEG-ASNase ≥100 U/L activities over 14 days. [ABSTRACT FROM AUTHOR]

Background and Objectives: The pharmacokinetics of the polyethylene glycol (PEG)-conjugated asparaginase Oncaspar are characterized by an increase in elimination over time. The focus of our analysis is the better understanding of this time-dependency. Methods: In paediatric acute lymphoblastic leukemia therapy (AIEOP-BFM ALL 2009), two administrations of Oncaspar (2500 U/m intravenously) in induction phase (14-day interval) and one single administration in reinduction were followed by weekly monitoring of asparaginase activity. Non-linear mixed-effects modeling techniques (NONMEM) were used. Samples indicating immunological inactivation were excluded to describe the pharmacokinetics under standard conditions. Models with time-constant or time-varying clearance (CL) as well as transit compartment models with an increase in CL over a chain of compartments were investigated. Results: Models with time-constant elimination could not adequately describe 6107 asparaginase activities from 1342 patients. Implementing a time-varying CL improved the fit. Modeling an increase of CL over time after dose (E- and Weibull-functions) were superior to models with an increase of CL over time after the first administration. However, a transit compartment model came out to be the best structural model. Conclusion: The increase in elimination of PEGylated asparaginase appears to be driven by physicochemical processes that are drug-related. The observed hydrolytically in vitro instability of the drug leads to the hypothesis that this increase in CL might be due to an in vivo hydrolysis of the instable ester bond between PEG and the enzyme combined with an increased elimination of the partly de-PEGylated enzyme (Trial registered at , NCT0111744). [ABSTRACT FROM AUTHOR]

Following the publication of our paper regarding a population-based model of doxorubicin pharmacokinetics in children in Clinical Pharmacokinetics last year (Voller et al. 54:1139-1149, 2015), we have received many inquiries on the practical clinical consequences of this model; however, a population-based model is only one of the aspects to be taken into account when developing dosing algorithms. In addition, any new method of dose calculation would need clinical validation and, subsequently, a new clinical trial. However, such a trial, especially with regard to burden to the children involved, requires optimal preparation and the selection of the best hypotheses. The European Paediatric Oncology Off-Patent Medicines Consortium (EPOC), represented by the authors, would therefore like to initiate an interdisciplinary discussion on the clinical and pharmacological goals for dose calculation. This current opinion summarizes the existing knowledge on the pharmacokinetics and pharmacodynamics of doxorubicin. Our aim was to define the clinical needs as precisely as possible, with the intention of stimulating discussion between the clinical pediatric oncologist and the pediatric pharmacologist. By doing so, we hope to define surrogates for best practice of a common doxorubicin dose in children. The intent is for a trial to validate a rational dose calculation rule, leading to a regulatory process and subsequent labeling. [ABSTRACT FROM AUTHOR]

Objective: Existing research recognizes low levels of physical activity in pediatric patients with cancer, but much uncertainty exists about their capability to self-reflect physical activity levels. The objective of this study was to compare results of subjective self-reports and objective accelerometers regarding levels of daily walking as well as moderate-to-vigorous physical activities. Methods: Results of the objective assessment tool StepWatchTM Activity Monitor and self-reporting with a standardized questionnaire were compared in 28 children and adolescents during cancer treatment. Results: The patients were 13.8±2.8 years of age and 3.4±2.0 months after cancer diagnosis. The Bland-Altman plots indicated a fairly symmetrical under- and over-estimation for daily minutes of walking with the limits of agreement ranging from -100.8 to 87.3 min (d = -6.7 min). Mean difference for moderate-to-vigorous physical activity was almost zero but limits of agreement are ranging from -126.8 to 126.9 min. The comparison for the days with at least 60 min of moderate-to-vigorous physical activity showed a marked difference with 3.0±2.6 self-reported days versus only 0.1±0.4 measured days. Conclusions: These findings suggest that physical activity in pediatric cancer patients should preferably be assessed with objective methods. Greater efforts are needed to implement supervised exercise interventions during treatment incorporating methods to improve self-reflection of physical activity. [ABSTRACT FROM AUTHOR]

Purpose: Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.Methods: We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m2. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.Results: Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m2) than older children (26.6 ± 6.7 l/h/m2) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.Conclusion: In the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses. [ABSTRACT FROM AUTHOR]

Atypical teratoid rhabdoid tumors ( AT/ RT) are characterized by mutations and subsequent inactivation of SMARCB1 ( INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors ( EU- RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/ II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/ RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations ( GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (±0.10) and 45% (±0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU- RHAB provides the best available basis for phase I/ II clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: The successful use of SMO inhibitors in tumors with activating mutations in hedgehog signaling raised interests in their exploitation against other malignancies. The role of hedgehog signaling in pediatric malignancies remains unclear. Methods: We investigated the hedgehog signaling and its inhibition in a panel of 18 tumor cell lines derived from six of the most common and highly aggressive pediatric tumor types. None of the cell lines was known to stem from tumors with activating hedgehog mutations. Tetrazolium-based assays (MTT and MTS) and BrdU assays were used to analyze cell viability and proliferation after exposure to SANT1 and GANT61. Expression analysis of hedgehog signaling members and cyclins was performed by quantitative real-time PCR and Western blot. Results: Key members of hedgehog signaling (SHH, PTCH1, SMO, GLI1, GLI2 and SUFU) were expressed in all cell lines. In 50% of the cell lines viability was significantly increased by SHH exposure. Stimulation was not restricted to distinct tumor types, but related to cell lines with higher mRNA levels of PTCH1, SMO, GLI1 and GLI2. SMO inhibition by SANT1 moderately decreased cell viability with GI50s between 28 and 93 µmol/l. Sensitivity to SANT1 was not related to distinct tumor types. The GLI inhibitor GANT61 inhibited cell viability and proliferation more effectively than SANT1. Conclusions: Our preclinical data provide evidence that hedgehog signaling is active and can be stimulated by PTCH1 ligands in various pediatric tumors. We suggest further evaluation of GLI inhibitors as inhibitors of hedgehog signaling for the treatment of the investigated tumor types. [ABSTRACT FROM AUTHOR]

Background and Objective: Knowledge on the pharmacokinetics of doxorubicin, especially in children, is very limited with conflicting evidence concerning a possible age dependency in the pharmacokinetics. The aim of the current investigation was to assess, by using population pharmacokinetics, whether an age dependency in the clearance (CL) of doxorubicin exists.Methods: Pharmacokinetic data of doxorubicin and its main metabolite doxorubicinol from 94 children (aged 0-18 years) from the EPOC-MS-001-Doxo trial were available. A population pharmacokinetic model was developed in NONMEM(®) 7.2.0.Results: A linear three-compartment model for doxorubicin, with one additional compartment for doxorubicinol, gave the best fit to the data. All model parameters were linearly scaled on body surface area. Including a power function of age as a covariate for CL led to a further improvement of the model. Variation in genes encoding for enzymes involved in the metabolism or active transport of doxorubicin had no influence on the pharmacokinetics. Estimates of CL were lower (26.6 L/h/m(2) in children aged >3 years and 21.1 L/h/m(2) in children aged ≤3 years, p = 0.0004) in children aged <3 years, compared with older children.Conclusions: This is the first model to describe the pharmacokinetics of doxorubicin in children, with a specific focus on infants and children aged <3 years. The lower CL in younger children should be considered together with the pharmacodynamics, especially the cardiotoxicity, when selecting the dose for future protocols. [ABSTRACT FROM AUTHOR]

Reduced motor performance may particularly limit reintegration into normal life after cessation of treatment in pediatric cancer patients. This study aimed at analyzing motor performance at the end of the acute treatment phase and reveals potential risk factors for motor deficits. A childhood cancer population with different tumor entities was assessed with the MOON test, which allows for comparison with age- and gender-matched reference values of healthy children, at the end of the acute treatment phase. Forty-seven patients were tested at 7.0 ± 2.6 months after diagnosis. Significant reductions of motor performance affected muscular explosive strength ( P < 0.001), handgrip strength ( P < 0.001), muscular endurance of legs ( P = 0.035), hand-eye coordination ( P < 0.001), static balance ( P = 0.003), speed ( P = 0.012), and flexibility ( P < 0.001). Loss of upper extremity coordination did not achieve statistical significance. Associations between single motor deficits and the tumor entity, age, body mass index, and inactivity during treatment were revealed, whereas no associations were found for gender and vincristine application. Conclusion: Overall, motor performance was low in the patient group studied. We recommend that individualized exercise interventions to attenuate motor deficits and promote physical activity are needed during cancer treatment in order to enhance motor performance and improve social participation during and after cancer therapy. [ABSTRACT FROM AUTHOR]

Aim: Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity. Patients & methods: Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults. Results: The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02). Conclusion: These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014 [ABSTRACT FROM AUTHOR]

A physiologically based pharmacokinetic (PBPK) model of the DNA-alkylating agent busulfan was slightly modified and scaled from adults to children in order to predict the systemic busulfan drug exposure in children. Capitalizing on the recent major software release of PK-Sim®, we refined our PBPK model by implementing glutathione S transferase (GST) in 11 organs using the software integrated enzyme expression database. In addition, two irreversible binding processes (i.e., DNA and plasma protein binding) were applied by using Koff and KD values. The model was scaled from adults to children. Simulations were computed and compared to concentration-time data after intravenous (i.v.) busulfan administration to 36 children. Based on the results, an age-dependent enzyme activity and maturation ratio was tailored and evaluated with an external dataset consisting of 23 children. Initial adult to children scaling indicated lower clearance values for children in comparison to adults. Subsequent age-dependent maturation ratio resulted in three different age groups: Activity of busulfan-glutathione conjugate formation was 80%, 61%, and 89% in comparison to adults for children with an age of up to 2 years, > 2-6 years, and > 6-18 years, respectively. Patients of the evaluation dataset were simulated with a mean percentage error (MPE) for all patients of 3.9% with 3/23 children demonstrating a MPE of > ±30%. The PBPK model parameterization sufficiently described the observed concentration-time data of the validation dataset while showing an adequate predictive performance. This PBPK model could be helpful to determine the first dose of busulfan in children. [ABSTRACT FROM AUTHOR]

Purpose: We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data. Methods: PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation). Results: The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg] = target AUC[mg × h/L] × 3.04L/h × (ABW/16.1). Compared to other dosing strategies, differences were observed for the very small and obese patients. Conclusions: We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed. [ABSTRACT FROM AUTHOR]

Purpose: We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data. Methods: PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation). Results: The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg] = target AUC[mg × h/L] × 3.04L/h × (ABW/16.1). Compared to other dosing strategies, differences were observed for the very small and obese patients. Conclusions: We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed. [ABSTRACT FROM AUTHOR]

Purpose: A physiologically based pharmacokinetic (PBPK) model was established and evaluated describing the pharmacokinetics (PK) of the DNA-alkylating agent Busulfan in adults in order to predict the systemic Busulfan drug exposure in both plasma and toxicity-related organs. Methods: A generic PBPK model was tailored to describe Busulfan PK by implementing compound-specific physicochemical and metabolism data. With regard to possible influences of glutathione S transferase (GST) variations on Busulfan PK, two different PBPK model parameterizations were investigated: a first parameterization with individual GST activity (expressed as different estimated V values) for each patient, and a resulting second model parameterization with a mean GST activity for all patients. Simulations were computed and compared to concentration-time data after intravenous Busulfan administration to 108 adults serving as development dataset. Subsequently, appropriateness of the PBPK model was evaluated with an external dataset not used for model development, consisting of 95 adults. Results: Both PBPK model parameterizations of Busulfan successfully described the observed plasma concentrations. For the validation dataset, calculated PK parameters were as follows: clearance 0.16 ± 0.03 L/h/kg and volume of distribution 0.65 ± 0.06 L/kg (mean ± standard deviation). Mean absolute percentage error was less than 30 % for each PK parameter. Mass balances for distribution and excretion were in good agreement with the literature data. Conclusions: Both PBPK model parameterizations sufficiently described the observed concentration-time data while showing an adequate predictive performance. The model should be further evaluated for its ability to explain the between-subject variability in intravenous Busulfan PK parameters. [ABSTRACT FROM AUTHOR]

Purpose: N, N-dimethylacetamide (DMA) is administered to children during high-dose chemotherapy as a solubilizer with the intravenous formulation of busulfan (Busilvex). DMA has shown liver toxicity in rats. However, little is known regarding its pharmacokinetics (PK) in humans. The aim of this analysis was to compare the PK of DMA after a once-daily dose of Busilvex with the standard scheme consisting of 3-4 administrations per day in children. Methods: Out of 42 children, aged 0.1-18.9 years, receiving Busilvex, 18 children received the first dose as a loading dose, giving a double dose of 1.4-2.0 mg/kg over a 4 h infusion followed by 15 doses of 0.7-1.0 mg/kg as 2 h infusions every 6 h. The other 24 children received Busilvex as 3 h infusions once-daily for 4 consecutive days with a targeted busulfan AUC of 4,263 μM*min. Using NONMEM™ plasma, concentration-time data were analyzed. Assuming an increase in clearance overtime as found in our previous investigation, separate time factors for the two different dosing schedules included in the dataset were tested. Results: A one-compartment model with clearance increasing over time described the DMA kinetics sufficiently. Peak plasma concentrations of DMA, up to 3.09 mmoL/L (median 0.75 mmoL/L) for the current licensed dose regimen and up to 8.77 mmoL/L (median 3 mmoL/L) for the once-daily application, were observed. The examined increase in clearance was found to be 58 mL/h/kg and 6.1 mL/h/kg per day for the current licensed and the once-daily dose regimen, respectively. Conclusion: N, N-dimethylacetamide as solvent of lipophilic drugs such as busulfan has a linear PK in children of all ages using a dose split into one or four administrations per day. The rapid clearance with different dosing in patients of different body weights indicates that it is safe to use DMA in children in both a once and four times daily regimen. [ABSTRACT FROM AUTHOR]

Background: While research on exercise interventions during anticancer treatment is well-established in adults, only very few studies exist in children. However, pediatric patients experience great limitations to being physically active, and appropriate interventions are desired. Procedure: The present study aimed at investigating the effects of individualized exercise interventions during inpatient stays on pediatric patients with a malignant bone tumor. The parameter of interest was physical activity (PA). Patients' PA during home stays was assessed 6 weeks as well as 3, 6, 12, and 18 months post-surgery. Patients were distinguished into an intervention group and a control group. All patients received endoprosthetic replacement of the affected bone in the same institution. Results: A constant increase in all PA parameters was observed during follow-up. Exercise interventions were possible and appeared worthwhile. The intervention group showed better PA results at all measurements; however, no significant differences between groups were found. Furthermore, differences decreased especially after the cessation of the intervention. General problems in reaching appropriate power and compliance were observed. Conclusions: Individualized exercise interventions in pediatric bone tumor patients are possible and appear to be beneficial. Such interventions should be implemented in adjuvant care; however, future research is needed to understand more about the effects of different interventions. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic veno-occlusive disease (HVOD) is one of the major complications following hematopoietic stem cell transplantation (HSCT). Although high-dose busulfan is associated with the development of HVOD, the underlying molecular mechanisms are still unknown. Methods: Transcriptional gene regulation by busulfan was profiled using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Messenger RNA (mRNA) expression of regulated genes was assessed by TaqMan real-time polymerase chain reaction (PCR), and protein expression and secretion was determined by enzyme-linked immunosorbent assay (ELISA) in cell supernatants, lysates, and patient plasma. Results: Plasma levels of plasminogen activator inhibitor (PAI)-1 significantly increased 48 h after starting busulfan treatment IV in children preconditioned for HSCT. In vitro, busulfan significantly induced plasminogen activator inhibitor-1 (PAI-1) expression in endothelium-like ECV304 cells in a concentration- and time-dependent manner. Comparative transcriptional profiling of busulfan-treated and control ECV304 cells identified differential expression of genes related to coagulation and fibrinolysis, including tissue factor, tissue factor pathway inhibitor-1, protein S, thrombospondin-1, urokinase receptor, and PAI-1, as well as activin A and transforming growth factor beta 1 (TGF-β1). Ingenuity pathway analysis (IPA) suggested TGF-β1 as a central modulator of gene regulation by busulfan. Consequently, expression of tissue factor, urokinase receptor, and PAI-1 mRNA and PAI-1 protein secretion induced by busulfan were significantly reduced by the activin A/TGF-β1 inhibitor SB 431542 in ECV304 and primary endothelial cells. Conclusions: This is the first report that directly relates busulfan exposure to antifibrinolytic activity by PAI-1 and hypercoagulation possibly mediated by members of the TGF-β1 family. This suggests further research to evaluate activin A and TGF-β1 as potential targets for HVOD treatment. [ABSTRACT FROM AUTHOR]

The main aim of this analysis was to characterize the population pharmacokinetics of native Escherichia coli asparaginase (ASNase medac™) in pediatric patients with previously untreated acute lymphoblastic leukemia. Secondary objective was to give further evidence for bioequivalence between ASNase medac™ and a new recombinant ASNase preparation. The authors reanalyzed 233 plasma samples from 16 children treated according to the DCOG-ALL 10 protocol (5000 U/m2 ASNase medac™) using NONMEM. Subsequently, assessment of bioequivalence was performed by including the preparation as a categorical covariate into the PopPK model when analyzing data of both preparations (480 samples, 32 children). A linear 2-compartment model with first-order elimination sufficiently described ASNase medac™ pharmacokinetics. The parameters found were as follows: total body clearance 0.13 L/h ± 12.4%% per 1.73 m2, volume of distribution in the central compartment 4.11 L ± 12.3%% per 70 kg, volume of distribution in the peripheral compartment 1.63 L per 70 kg and intercompartmental clearance 0.106 L/h (mean ± interindividual variability). A visual predictive check procedure and simulation of different dosages ASNase medac™ administered in the ALL-BFM protocol indicated adequate model performance. Assessment of bioequivalence provided a difference of about 14%% in clearance of both preparations being too small to be considered as clinically relevant. A population pharmacokinetic model of ASNase medac™ in pediatric patients with previously untreated acute lymphoblastic leukemia was established. The model was able to describe asparaginase activity of different dosages in the ALL-BFM protocol and provides further evidence for bioequivalence between ASNase medac™ and a new recombinant asparaginase preparation. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data. Methods: Simulations were performed with PK-Sim (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis-Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group. Results: Simulated plasma concentration-time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70 ml/min/kg (Cl: 0.70 ml/min/kg) versus 0.50 ml/min/kg (Cl: 0.60 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated. Conclusions: The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children. [ABSTRACT FROM AUTHOR]

Purpose: The diagnosis of a malignant bone tumor in the lower limb is a risk factor for physical disability, limiting physical performance. Walking ability especially, which is essential for most activities of daily living, is limited in those patients. In the present study, the extent of limitations during the course of treatment was investigated to determine when the assessment of functional parameters is meaningful in those patients.Methods: In the present study, activity levels were determined in 20 patients with a malignant bone tumor in the lower limb who received endoprosthetic replacement of the affected bone and in 20 healthy individuals. A uniaxial accelerometer was used to investigate patients at five different time points after surgery.Results: Patients performed significantly less amounts and intensities of activity than control individuals at all measurements. Significant increases in the volume of activity were observed after cessation of treatment. However, the intensity of activity only showed minor increases. Patients experiencing complications of surgery revealed greater restriction than those without even 18 months after surgery.Conclusions: After cessation of treatment for their disease, patients recovered markedly and showed great improvements in physical activity. However, some limitations appeared to persist. Comparisons with patients with longer follow-up revealed that meaningful functional assessment does not make sense within the first 12 months after surgery. More research is needed to show if longer follow-up periods reveal further improvements. Based on such information, it should be more promising to develop individually tailored activity recommendations and intervention programs. [ABSTRACT FROM AUTHOR]

Purpose: The observation that the orphan drug dichloroacetate (DCA) selectively promotes mitochondria-regulated apoptosis and inhibits tumour growth in preclinical models by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis attracted not only scientists', clinicians' but also patients' interests and prompted us to further evaluate DCA effects against paediatric malignancies. Methods: The effects of DCA on mitochondrial membrane potential (ΔΨm), cell viability and induction of apoptosis were evaluated in paediatric tumour cell lines and the non-malignant cell line HEK293. In addition, combinations of DCA with the standard anticancer drugs cisplatin, doxorubicin, and temozolomide were tested and intra- and extra-cellular platinum species analysed. Results: DCA selectively induced phosphatidylserine externalisation and reduced ΔΨm in paediatric tumour cells compared to HEK293 cells, but DCA concentrations ≤10 mmol/L only moderately inhibited the growth of 18 paediatric tumour cell lines. DCA neither influenced the in vitro stability of cisplatin nor the cellular cisplatin uptake, but it abrogated the cytotoxicity of cisplatin in 7 out of 10 cell lines. DCA also affected the cytotoxicity of doxorubicin but did not influence the cytotoxicity of temozolomide. Despite phosphatidylserine externalisation, DCA failed to activate caspase 3/7 and, moreover, suppressed caspase 3/7 activation by cisplatin and doxorubicin. Conclusions: Our results indicate that apart from the intriguing effects of DCA on the glucose metabolism of cancer cells, the use of DCA for cancer treatment has to be evaluated carefully. Moreover, compassionate use of the orally available drug by patients with cancer themselves without medical supervision is strongly discouraged at present. [ABSTRACT FROM AUTHOR]

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. [ABSTRACT FROM AUTHOR]

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. [ABSTRACT FROM AUTHOR]