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Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione‐s‐transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model‐based, first‐dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu‐based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age‐dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first‐dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, −0.5%; 95% confidence interval [CI], −3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%–20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.

Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration–time curve from 0 to 24 h in pediatric transplant recipients treated with valganciclovir (VGCV) or GCV. Solid organ transplant or stem-cell transplant recipients who received GCV or VGCV and had available GCV concentrations per standard of care were retrospectively included in this study for pharmacokinetic modeling and development of Bayesian estimators using the iterative two-stage Bayesian method. Validation datasets included additional child recipients of a solid organ transplant or stem-cell transplant, and child recipients of a kidney or liver transplant enrolled in a previous study. Various combinations of three or two sampling times, applicable in clinical practice, were assessed based on the relative mean bias, standard deviation, and the root mean square error in a development dataset and three independent validation datasets. In the development dataset, the mean bias/standard deviation/root mean square error for the 1 h/2 h/3 h and 1 h/3 h limited sampling strategies were − 1.4%/9.3%/9.1% and − 3.5%/12.2%/12.3%, respectively for GCV, while for VGCV, the mean bias/standard deviation/root mean square error for the 1 h/2 h/6 h and 1 h/6 h limited sampling strategies were 0.7%/13.5%/13.3% and − 0.1%/12.1%/11.8%, respectively. In the independent validation datasets, seven (13%) and five (14%) children would have had misclassifications of their exposure using these Bayesian estimators and limited sampling strategies for VGCV and GCV, respectively. Three plasma samples collected at 1 h/2 h/3 h and 1 h/2 h/6 h post-dose for GCV and VGCV respectively, are sufficient to accurately determine GCV area under the concentration–time curve from 0 to 24 h for pharmacokinetic-enhanced therapeutic drug monitoring.

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.

Extensive venous malformations (VM) involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. Patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Current pharmacological VM treatments (e.g. sirolimus) are not universally effective as 10% of patients present intractable debilitating and/or critical disease. Novel therapies are therefore highly needed for treatment-resistant VM. Over 70% of sporadic VM are attributed to activating mutations in the TEK gene, encoding the receptor tyrosine kinase TIE2 expressed by venous endothelial cells. Despite in vitro studies showing the superiority of alpelisib over sirolimus in inhibiting TIE2 signalling pathway and vein remodelling, there are currently no clinical reports of alpelisib use in VM. Our aim was therefore to assess the effect of alpelisib in TIE-2 mutated VM and to assess its pharmacokinetics. Three patients with a VM harboring the TEK L914F mutations were treated with alpelisib in an open-label compassionate use study. All patients experienced significant improvement. Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy showed dramatic improvement. Drug exposure was highly variable despite similar weight-adjusted doses, suggesting that alpelisib dosing should be individualized to patient’s characteristics and guided by therapeutic drug monitoring to improve clinical response.

AIMS Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children. METHODS We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC0-24h ) of 40-60 mg.h.L-1 . RESULTS Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg-1 .day-1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg-1 .day-1 divided every 12 hours in children 0

Immunomodulator monotherapy is an important component in the treatment of inflammatory bowel disease (IBD). However, there is conflicting literature about thiopurines maintaining long-term remission in patients with active IBD. To determine the durable clinical remission rate in adults with Crohn’s disease (CD) or ulcerative colitis (UC) on thiopurine monotherapy over 5 years. We performed a retrospective analysis of adult patients identified at McGill University Health Centre from 2009 to 2012. We included IBD patients who initiated thiopurine monotherapy and were in remission for at least 3 months (Harvey–Bradshaw Index (HBI) 5 in CD and pMS > 2 in UC. There were 148 patients included in the study (100 CD; 48 UC). At 5 years, 23% (34/148) patients remained in clinical remission on thiopurine monotherapy (25 CD and 9 UC patients). Thirty-three percent (33/100) of CD and 46% (22/48) of UC patients relapsed while on thiopurines. There was no difference in relapse rates between CD and UC patients. Eighty-four percent (42/50) of patients with CD with side effects and all UC (17/17) patients who experienced side effects discontinued the drug. This analysis demonstrates that there is poor sustainability of clinical remission in IBD patients on thiopurine monotherapy given that a high proportion of patients discontinue thiopurines due to either relapse or side effects.

Sinusoidal obstruction syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease, and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected a set of genes. To get more comprehensive insight in the genetic component, we performed an exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following a busulfan-containing conditioning regimen. Eight lead single-nucleotide polymorphisms (SNPs) were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n = 182). Three SNPs were successfully replicated, including rs17146905 ( P = .001), rs16931326 ( P = .04), and rs2289971 ( P = .03), located respectively in the UGT2B10, BHLHE22, and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in a multivariable model while controlling for nongenetic covariates and previously identified risk variants in the GSTA1 promoter. The modulation of associations by conditioning regimens was noted; KIAA1715 was dependent on the intensity of the conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed ( P = .00006) with a genotype-related SOS risk of 9.8. To our knowledge, this is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring a higher risk of SOS, which might be useful for personalized prevention and treatment strategies. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient–donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2–4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.

Off-label drug prescribing, frequent in the treatment of vascular anomalies (VA), relies on the quality of the literature reporting drug efficacy and safety. Our objective is to review the level of evidence (LOE) surrounding drug use in VA, which is more prevalent in pediatric care. A list of drugs used in VA was created with a literature review in July 2020. For each drug listed, the article displaying the highest LOE was determined and then compared between efficacy/safety data, routes of administration, pharmacological categories and a subset of VA. The influence of research quality on study results was also explored. The median LOE for the 74 drugs identified poor methodological quality, with a predominance of retrospective studies or case reports. Drug safety is currently inadequately reported. This is alarming as many treatments display significant safety concerns. Also, current literature displays major publication bias that probably leads to overestimation of drug efficacy in VA.

Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration-time curve from 0 to 24 h in pediatric transplant recipients treated with valganciclovir (VGCV) or GCV.Solid organ transplant or stem-cell transplant recipients who received GCV or VGCV and had available GCV concentrations per standard of care were retrospectively included in this study for pharmacokinetic modeling and development of Bayesian estimators using the iterative two-stage Bayesian method. Validation datasets included additional child recipients of a solid organ transplant or stem-cell transplant, and child recipients of a kidney or liver transplant enrolled in a previous study. Various combinations of three or two sampling times, applicable in clinical practice, were assessed based on the relative mean bias, standard deviation, and the root mean square error in a development dataset and three independent validation datasets.In the development dataset, the mean bias/standard deviation/root mean square error for the 1 h/2 h/3 h and 1 h/3 h limited sampling strategies were - 1.4%/9.3%/9.1% and - 3.5%/12.2%/12.3%, respectively for GCV, while for VGCV, the mean bias/standard deviation/root mean square error for the 1 h/2 h/6 h and 1 h/6 h limited sampling strategies were 0.7%/13.5%/13.3% and - 0.1%/12.1%/11.8%, respectively. In the independent validation datasets, seven (13%) and five (14%) children would have had misclassifications of their exposure using these Bayesian estimators and limited sampling strategies for VGCV and GCV, respectively.Three plasma samples collected at 1 h/2 h/3 h and 1 h/2 h/6 h post-dose for GCV and VGCV respectively, are sufficient to accurately determine GCV area under the concentration-time curve from 0 to 24 h for pharmacokinetic-enhanced therapeutic drug monitoring.

Acute Graft versus Host Disease (aGvHD) grades 2–4 occurs in 15–60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2–4 in 60 pediatric patients. The cumulative incidence of aGvHD 2–4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2–4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3–191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2–4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06–3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This multicenter phase II included three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Primary objective is to evaluate overall response rate after daily oral trametinib administration for 18 cycles each 28 days duration. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. RESULTS As of June 1 2020, 37 patients have been enrolled (NF1: 7 patients, KIAA1549-BRAF fusion: 22, other: 8 (including 5 patients with FGFR1 alterations). Median age is 9.3 years (range 2.3–25.4). Median follow-up is 8.8 months (range 0–19.3). Twenty-eight patients are evaluable. Best response includes: 4 partial response (PR) (14%), 5 minor response (MR) (18%), 18 stable disease (64%), 1 progressive disease (3.5%). Median time to response is 2.8 months (range 2.4–11.3). Median duration of response is 8.0 months (range 0.6–16.8. Progression free survival at 12 months is 83.1% (95% CI 70.5–98.0%) and median progression free survival has not reached. Nine patients (24%) discontinued treatment: 3 for progressive disease, 4 adverse events (3 alanine aminotransferase increase, 1 paronychia), 2 for other reasons. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Background: Many medications given to children have no commercially available, age-appropriate formulations. This leads to manipulation of dosage forms designed for adults (compounding), which can result in an increased risk of dosing errors and adverse events, lack of medication adherence because of taste issues, and suboptimal dosing with therapeutic failure.Objectives: To determine which drugs required compounding for oral administration to children in a Canadian hospital and, for each compounded drug, to determine whether it was available as licensed oral pediatric formulations in the United States or the European Union.Methods: Drugs requiring compounded liquid formulations for oral administration, dispensed from January 1 to December 31, 2015, at a Canadian university-affiliated tertiary pediatric hospital, and prepared in a quantity exceeding 0.5 L per year, were retrospectively identified. The online drug databases of Health Canada, the US Food and Drug Administration, the European Medicines Agency (EMA), and the UK Medicines and Healthcare Products Regulatory Agency were searched to determine the availability of child-friendly oral formulations for these drugs. The regulatory status in each jurisdiction was also compared. For licensed formulations with potential concerns about excipient safety, EMA guidelines for sorbitol, propylene glycol, ethanol, and sodium benzoate were used to determine pediatric suitability.Results: Of the 56 compounded drugs investigated, 27 (48%) had a suitable commercialized child-friendly formulation available outside Canada. Overall, these drugs had been on the Canadian market for a median of 35 years, and almost half (27 [48%]) had a pediatric indication in Canada.Conclusions: Canada is lagging behind the United States and the European Union in ensuring availability of and access to suitable pediatric formulations. Potential explanations for this gap include small market size, regulatory uncertainties, and reimbursement shortcomings. Steps must be taken to implement pediatric-sensitive regulations and incentives, as well as reimbursement policies, to address these unmet needs.Keywords: compounding, child-friendly medicines, pediatric oral medicinesRÉSUMÉContexte : Plusieurs médicaments administrés aux enfants ne sont pas disponibles commercialement sous une forme pharmaceutique adaptée à leur âge. Ceci entraîne une manipulation des formes destinées aux adultes (préparation magistrale) et peut conduire à une augmentation du risque d’erreurs de dosage et d’effets indésirables, un manque d’observance médicamenteuse secondairement à des problèmes de goût, et un dosage sous-optimal associé à des échecs thérapeutiques.Objectifs : Définir les médicaments qui exigent une préparation magistrale pour être administrés par voie orale aux enfants dans un hôpital canadien et, pour chaque médicament faisant l’objet d’une préparation magistrale, déterminer s’il est disponible sous une forme pharmaceutique orale autorisée pour les enfants aux États-Unis ou dans l’Union européene.Méthodes : Les médicaments nécessitant des préparations magistrales liquides pour administration orale, distribués entre le 1er janvier et le 31 décembre 2015 dans un hôpital de soins pédiatriques tertiaires affilié à une université canadienne et dont la quantité préparée était supérieure à 0.5 L par an, ont été déterminés rétrospectivement. Les bases de données en ligne de médicaments de Santé Canada, de la Food and Drug Administration américaine, de l’Agence européenne des médicaments (AEM) et de la Medicines and Healthcare Products Regulatory Agency (Royaume-Uni) ont été interrogées pour déterminer la disponibilité de formes pharmaceutiques orales adaptées aux enfants pour ces médicaments. Le statut réglementaire de chaque pays a également fait l’objet d’une comparaison. Pour les formes pharmaceutiques autorisées présentant des problèmes potentiels d’innocuité des excipients, les directives de l’AEM concernant le sorbitol, le propylène glycol, l’éthanol et le benzoate de sodium ont servi à déterminer si un usage pédiatrique était acceptable.Résultats : Des 56 médicaments étudiés faisant l’objet d’une préparation magistrale, 27 (48 %) avaient une forme pharmaceutique commercialisée adaptée aux enfants en dehors du Canada. Au total, ces médicaments sont sur le marché canadien depuis une médiane de 35 ans et près de la moitié (27 [48 %]) ont une indication pédiatrique au Canada.Conclusions : Le Canada accuse un retard par rapport aux États-Unis et à l’Union européenne quant à la disponibilité et à l’accès à des formes pharmaceutiques adéquates pour les enfants. La petite taille du marché, les incertitudes en matière réglementaire et les lacunes concernant le remboursement pourraient notamment expliquer cet écart. Il est nécessaire de prendre des mesures pour mettre en place des réglementations et des incitatifs ainsi que des politiques de remboursement axés sur les enfants pour répondre à ces besoins criants.Mots-clés : préparation magistrale, médicaments adaptés aux enfants, médicaments pédiatriques pour administration orale

Background/objectives Efficacy of topical sirolimus has recently been described in lymphatic anomalies but not in other types of vascular anomalies. To our knowledge, systemic absorption of topical sirolimus in these lesions has not yet been reported. The objective was to evaluate the efficacy, tolerance, and absorption of topical sirolimus 0.1% with different types of vascular anomalies in children. Methods Sirolimus 0.1% was applied on cutaneous vascular anomalies in six children aged 2-17. These anomalies consisted of three extratruncular micro- and macrocystic lymphatic malformations and one each verrucous venous malformation, truncular lymphatic malformation with angiokeratomas, and infantile hemangioma. Sirolimus blood levels were measured after 1 week, 1 month, and 3 months. Results A rapid decrease in the size of superficial lymphatic malformations in three of six patients and a significant decrease in discharge from oozing lesions were observed. Response occurred in less than 3 months. The truncular lymphatic malformation, verrucous venous malformation, and infantile hemangioma did not respond to topical sirolimus. Sirolimus levels were undetectable. Adverse effects were limited to local irritation. Conclusions Topical sirolimus 0.1% is a useful treatment for cutaneous manifestations of extratruncular lymphatic malformations. The only adverse effect is local irritation. No systemic effects are expected, because blood levels are clinically insignificant.

Aims The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism. Methods Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.1-20) who received intravenous busulfan during the conditioning regimen prior to stem cell transplantation. Weight, sex, baseline disease (malignant vs. non-malignant), age, conditioning regimen and GSTA1 diplotypes were evaluated as covariates of pharmacokinetic parameters by using nonlinear mixed effects analysis. The ability to achieve the target AUC24h (3600-6000 μM min-1 ) was assessed by estimating the first dose based on the present PopPK model and by comparing the results with other available models in children. Results A one-compartment model with first-order elimination best described the data. Allometric scaling of weight and a factor of busulfan metabolism maturation were included in the base model. GSTA1 diplotypes were found to be a significant covariate of busulfan clearance, which was 7% faster in rapid metabolizers and 12% slower in poor metabolizers, in comparison with normal ones. Busulfan doses calculated using the parameters of the proposed PopPK model were estimated to achieve the target AUC in 85.2% of the cases (95% CI 78.7-91.7%). Conclusion This is the first PopPK for busulfan that successfully incorporated GSTA1 genotype in a paediatric population. Its use may contribute to better prediction of busulfan exposure in children and adolescents since the first dose, by tailoring the dose according to the individual metabolic capacity.

The RASopathies are developmental syndromes caused by germline gain-of-function mutations in genes of the RAS/MAPK signaling pathway. RIT1 mutations are particularly associated with cardiovascular disease, including hypertrophic cardiomyopathy (HCM) distinct from that seen in sarcomeric mutations.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose.

Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. We hypothesize that we will observe responses in recurrent/refractory PLGG treated with trametinib. METHODS This is a multicenter phase II including three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Patients will receive daily oral trametinib for a total of 18 cycles of 28 days. A total of 104 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. RESULTS As of January 7 2020, 28 patients have been enrolled (NF1: 6 patients, KIAA1549-BRAF fusion: 17, other: 5 including 3 patients FGFR1 alteration). Median age is 8.5 years (range 2.5–25.4 years). Median follow-up is currently 4.6 months (range 0.16–14.7 months). Twenty patients are currently evaluable. Best response includes: 1 complete response (5%), 3 partial response (15%), 4 minor response (20%), 8 stable disease (40%), 4 progressive disease (20%). 8 patients (28,5%) discontinued treatment: 4 for progressive disease, 3 adverse event (alanine aminotransferase increase), 1 withdrew. CONCLUSION Trametinib is potential effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Background The emergence of coagulase-negative staphylococci with reduced vancomycin susceptibility in some neonatal intensive care units has resulted in an increase of linezolid use. Linezolid pharmacokinetics (PK) and safety in premature infants still need to be better established. Methods This was a retrospective PK study. All infants who received intravenous linezolid and had linezolid plasma concentrations per standard of care were included. Linezolid concentrations were measured by high performance liquid chromatography. A population PK model was developed using nonlinear mixed effects modeling. Optimal dosing was determined based on achievement of the surrogate pharmacodynamics target for efficacy: a ratio of the area under the concentration-time curve to minimum inhibitory concentration >80. We assessed the occurrence of thrombocytopenia and lactic acidosis in relation with drug exposure. Results A total of 78 plasma concentrations were collected from 26 infants, with a median postnatal age (PNA) of 24 days (8-88) and weight of 1423 g (810-3256). A 1-compartment model described linezolid data well. The final model included PNA and weight on clearance and weight on volume of distribution. Considering an MIC90 of 1 mg/L, all infants reached an area under the concentration-time curve/minimum inhibitory concentration > 80. Although thrombocytopenia and hyperlactatemia occurred frequently, they were not sustained and were not considered related to linezolid. Conclusion and was well tolerated in critically ill premature infants. PNA was the main determinant of clearance.

Background: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD. Methods: Retrospective review of consecutive cases treated with allopurinol. Metabolites and their ratios (6-MMP/6-TGN) were compared pre- and post-allopurinol. Clinical and endoscopic remission were assessed. Results: Allopurinol ( n = 66) reduced mean dose of AZA by 70% ( p < 0.01). Baseline levels (SD) 6-TGN, 6-MMP and 6-MMP/6-TGN were 165 (64), 9388 (5234) and 59.8 (30.3), respectively. These values improved on allopurinol to 297 (102), 896 (1031) and 3.4 (4.0), respectively ( p < 0.0001). Therapeutic 6-TGN level (>235) was achieved in 49/58 cases on allopurinol combination therapy, versus 9/58 monotherapy ( p = 0.0001). Among the thiopurine failure group (40 patients), clinical remission or response was observed in 65% and 22% of patients, respectively. In the asymptomatic group with excessive 6-MMP, 11/14 achieved sustained remission on allopurinol. Repeat colonoscopy ( n = 28) showed mostly endoscopic remission (67.9%) or improvement (17.8%). Few had unimproved lesions (14.3%). Importantly, 46% of cases had complete mucosal healing. Two patients had cancer on combination therapy (de novo pancreatic cancer and fatal recurrence of metastatic testicular cancer). Elevated transaminases were reduced on allopurinol (48.2 versus 6.9%) ( p < 0.001); no change in leukopenic or infectious events occurred. Conclusion: Allopurinol in combination with low-dose thiopurine corrected excessive 6-MMP levels, resulting in clinical remission and mucosal healing in the majority of cases. The potential cancer risk of allopurinol and thiopurine combination therapy needs further research.

// Marc Ansari 1,2 , Patricia Huezo-Diaz Curtis 1,2,* , Chakradhara Rao S. Uppugunduri 1,2,* , Mohammed Aziz Rezgui 3 , Tiago Nava 1,3,5,6 , Vid Mlakar 1,2 , Laurence Lesne 1,2 , Yves Theoret 3,4,5 , Yves Chalandon 7 , Lee L. Dupuis 8 , Tao Schechter 8 , Imke H. Bartelink 9,17 , Jaap J. Boelens 9 , Robbert Bredius 10 , Jean-Hugues Dalle 11 , Saba Azarnoush 11 , Petr Sedlacek 12 , Victor Lewis 13 , Martin Champagne 14 , Christina Peters 15 , Henrique Bittencourt 3,4,5,16 and Maja Krajinovic 3 - 5,16,18 1 Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland 2 Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland 3 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada 4 Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 5 Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada 6 Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil 7 Department of Medical Specialties, Division of Hematology, Geneva University Hospital, Geneva, Switzerland 8 Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada 9 Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands 10 Department of Pediatrics, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands 11 Pediatric Hematology Department, Robert Debre Hospital, Assistance Publique, Hopitaux de Paris, Paris, France 12 Department of Pediatric Hematology and Oncology Teaching Hospital, 2nd Medical School, Charles University, Prague, Czech Republic 13 Department of Pediatrics, Alberta Children’s Hospital, Calgary, Alberta, Canada 14 Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada 15 Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children’s Hospital, Vienna, Austria 16 Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 17 Department of Medicine, The University of California San Francisco, San Francisco, CA, USA 18 On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, Leiden, The Netherlands * These authors have contributed equally to this work Correspondence to: Patricia Huezo-Diaz Curtis, email: // Keywords : busulfan, pharmacokinetics, pharmacogenetics, toxicity, hematopoietic stem cell transplantion Received : July 18, 2017 Accepted : July 23, 2017 Published : August 27, 2017 Abstract Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 ( GSTA1 ) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p

Aims The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately. Methods Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4–18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife. Results A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h−1 and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from −2.8 to −1.9% and from 7.4 to 12.5%, respectively. Conclusions The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0–12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.

BackgroundBusulfan (Bu) is widely used as a component of myeloablative conditioning regimen before hematopoietic stem cell transplantation (HSCT) in children. Obtaining the ratio of Bu to its metabolite sulfolane i.e. metabolic ratio (MR) may serve as an indicator of Bu GSH conjugating capacity of an individual.ObjectiveTo evaluate the utility of Bu MR to predict EFS in children undergoing allogeneic HSCT.MethodsTwo different cohorts with children receiving Bu in four times daily (QID, n=44) and once daily doses (QD, n=13) at St. Justine’s Hospital, Montreal were studied. Bu and Su levels were measured on day 3 of the conditioning regimen at the end of infusion (dose 9 in QID or dose 3 in QD dosing). EFS was defined from the time of transplant until death, relapse, or rejection, whichever occurred first. A receiver-operator characteristic curve (ROC) of Bu MRs was analyzed in relation to EFS. Cutoff values were defined based on the Youden´s J statistic.ResultsTwenty-two males and 22 females aged from 0.1 to 19.9 years (mean±SD: 7.2 ± 5.7) from Bu QID cohort had the mean MR of 5.9 (SD: 3.2). A cut off value of 4.9 in MR was chosen in ROC analysis in this cohort, with better sensitivity (71%) and specificity (70%) for EFS prediction (p=0.01, AUC= 0.7 (95% CI= 0.6–0.8). In QD cohort nine females, and four males aged between 0.4 and 15.8 years (6.7±5.1) had the mean MR of 29.3 (SD: 16.6). In ROC analysis, a cut off value of 25.06 was chosen with better sensitivity (100%) and specificity (100%) for EFS prediction (p=0.003; AUC=1.0).ConclusionThe Bu MR on day 3 above 4.973 and 25.06 were associated with worse EFS in children undergoing HSCT and received Bu in QID and QD dosing schedules, respectively.Disclosure(s)Nothing to disclose

BackgroundHaematopoietic stem cell transplantation (HSCT) is the only current curative treatment for Sickle Cell Disease (SCD), with potential life-threatening consequences. Busulfan is an alkylating agent used in HSCT conditioning regimen. Because of its narrow therapeutic window, determining the optimal first dose a priori remains a challenge.Busulfan is metabolized in the liver by conjugation with glutathione, which is catalyzed by Glutathione-S-Transferases (GSTs). GSTA1 is a known determinant of Busulfan clearance1 2 (just like age and weight) suggesting that those characteristics should be known a priori to adjust the first dose of Busulfan.Haemoglobinopathies (SCD and thalassemia) are not associated with changes in Busulfan clearance in a recent study.3 However, SCD is known to alter pharmacokinetics of other drugs.4 5 As it leads namely to liver dysfunction6 it may affect busulfan pharmacokinetics independently from genetic or anthropometric factors.Our aim is to compare the clearance of the first dose of Bu between patients with and without SCD, considering other constitutional factors.MethodsPatients with SCD were paired to patients without SCD on known Busulfan clearance’s covariates including GSTA1 group, age and frequency of administration.Data were collected retrospectively from the HSCT Unit database at Sainte-Justine Hospital and also used in previous studies.1 2 Weight adjusted clearance was compared between the two paired groups using a mixed procedure on SAS software.ResultsAmong the 129 patients included, 16 had SCD. Each patient was matched with up to 4 controls (total of 50 controls). Mean weight adjusted clearance was 3.04 ml/min/kg [SD:0,18] in patients with SCD versus 3.11 ml/min/kg [SD:0,14] in controls (difference 0.07 ml/min/kg F=0,14 p>F=0.714).ConclusionsThe diagnosis of SCD did not reveal to influence independently the clearance of the first dose of Bu. Consequently, no dose tailoring is needed in those patients only by the fact of being affected by SCD.ReferencesAnsari M, Curtis PH-D, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget 2017 Oct 31;8(53).Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Curtis PH-D, Duval M, et al. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. British Journal of Clinical Pharmacology. 84(7):1494–504.McCune JS, Baker KS, Blough DK, Gamis A, Bemer MJ, Kelton-Rehkopf MC, et al. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. Journal of Clinical Pharmacology. 2013 Mar;53(3):264–75.Maksoud E, Koehl B, Kaguelidou F, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother 2018 Apr;62(4).Dampier CD, Setty BN, Logan J, Ioli JG, Dean R. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995 Mar;126(3):461–7.Gremse DA, Fillingim E, Hoff CJ, Wells DJ, Boerth RC. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998 Jun;132(6):989–93.Disclosure(s)Nothing to disclose

BackgroundChildren with sickle cell disease (SCD) are at high risk of intractable pain and severe infections despite early and aggressive drug treatment. SCD is a multisystemic disease potentially leading to liver and renal dysfunction. Altogether, those may lead to pharmacokinetic (PK) alterations, which may contribute to therapeutic failure or drug toxicity. We performed a systematic literature review to describe the current evidence on the effect of SCD on drug disposition in children.MethodsA systematic literature search was conducted by a librarian on 5 databases until 08.2018 and independently assessed by two reviewers. All full-text articles, containing PK data in children, were included. The reported differences in PK parameters between SCD and non-SCD children were examined.ResultsAmong 4213 retrieved abstracts, 50 full-text articles were assessed and 27 studies were included (13 exclusively children). Data on 15 drugs was available from which 5 were exclusively developed for SCD (impeding any comparison). From the remaining 10 drugs, a comparison of PK parameters was available in 8. Six were investigated in adults and children. Three (37.5%) showed significant PK alterations (morphine, cefotaxime,lidocaine) while 5 did not (hydroxyurea, sulfadoxine-pyrimethamine, methadone, rofecoxib,arginine butyrate). In children with SCD, clearance was higher by 42–61% for IV morphine, and by 24–62% for cefotaxime, compared with non-SCD controls. This difference led to a new dosing recommendation only for cefotaxime (400 mg/kg/day). Hepatic drug metabolism assessed by lidocaine was impaired in children with SCD compared to healthy controls.ConclusionSCD alters drug disposition of commonly used drugs but data is scarce. A significant increase in clearance of morphine and cefotaxime, two commonly used drugs in patients with SCD, suggests that recommended doses may not be sufficient to provide adequate analgesia and antimicrobial control. PK data is urgently needed to ensure adequate drug efficacy and safety in this high-risk population.ReferencesDong M, McGann PT, Mizuno T, et al. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Brit J Clin Pharmacol. 2016;81:742–52.Gremse DA, et al. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998;132:989–93.Dampier CD, et al. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995;126:461–7.Kopecky EA, et al. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther 2004;75:140–6.Maksoud E, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother. 2018;62: e00637–1.Disclosure(s)Nothing to disclose

BACKGROUND L-asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemia (ALL). However, immune reaction to the drug may increase the clearance or impair the function of L-asparaginase and reduces its therapeutic efficacy. The objective of this study was to identify potential plasma proteins that could be used as proxies for L-asparaginase activity. METHODS Fibrinogen, von Willebrand factor antigen (VWF:Ag), total protein, and albumin levels as well as antithrombin (AT) and L-asparaginase activities were measured in 97 children with ALL treated for prolonged period of time with L-asparaginase. Binary logistic regression and a receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive value of plasma proteins for L-asparaginase activity. RESULTS Median E. coli L-asparaginase activity was 220 IU/L (range, 0-1308) throughout the treatment period. L-asparaginase activity was below 100 IU/L in 23% of measured samples. L-asparaginase activity was inversely associated with AT activity, fibrinogen, total protein, and albumin levels (r = -0.63, -0.62, -0.57, and -0.45, respectively; P

Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection.Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L.Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (TMIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively.Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.

BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (P ≤ 0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (P ≤ 0.03). Gene-dosage effect was also observed (P ≤ 0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P=0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P=0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P=0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.

Plasma posaconazole exposure was assessed in 13 children who underwent a hematopoietic stem cell transplant. The median dosage was 12.5 mg/kg per day, divided into 3 doses. Of these 13 patients, 46.2% (6) and 30.8% (4) achieved concentrations higher than 0.7 and 1.25 mg/L, respectively. In children at high risk, a higher dosage might be needed to achieve target concentrations.

Busulfan (Bu) is an important component of the myeloablative conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) especially in children. Intravenously administered Bu exhibits a therapeutic window phenomenon requiring therapeutic drug monitoring. Analytical methods developed for Bu routine monitoring were aimed at using low volumes of biological fluids and development of simple procedures to facilitate the dosage adjustment. In this report, we describe a simple, rapid method for Bu measurement using dried blood spots (DBS) from only 5 μL of whole blood.

Objectives/Hypothesis: There is no approved agent to prevent cisplatin-induced ototoxicity. Our objectives were to: 1) identify and compare the effect of intratympanic injections of lactate or N-acetylcysteine (NAC) in the prevention of cisplatin-induced ototoxicity, 2) investigate inner ear protection using a scanning electron microscope, and 3) study systemic diffusion of intratympanic NAC. Study Design: Prospective animal study. Methods: Sixteen guinea pigs formed two groups, and respectively received intratympanic lactate and 20% NAC in one ear. The contralateral ears received a control saline solution. After 30 minutes, an intraperitoneal cisplatin injection of 3 mg/kg was performed and repeated eight times, once a week, to achieve 24 mg/kg. Auditory brainstem responses (ABRs) were recorded before any injection, after 9 mg/kg and after 24 mg/kg of cisplatin for the frequencies 2, 4, 6 and 8 kHz. Cochleas were analyzed under scanning electron microscope. Systemic diffusion of NAC was studied using high-performance liquid chromatography. Results: For the control ears, ABR thresholds increased uniformly and averaged 28.4 dB. The lactate group showed a lower threshold increase and averaged 17.0 dB. The NAC showed an important threshold increase of 89.0 dB. Lactate showed a significant hearing protection at 2000 Hz (P < .01). Electron microscopy revealed partial preservation of outer hair cell stereocilia for the ears treated with lactate and severe disruption for NAC group. No systemic diffusion of NAC was observed with chromatography. Conclusions: Intratympanic lactate offers significant partial protection against cisplatin-induced ototoxicity at midfrequencies. High-concentration NAC does not seem a viable solution as it causes a considerable inflammatory reaction. NAC does not diffuse systemically.

Purpose The goals of this study are to evaluate the efficacy and tolerability of levetiracetam (LEV) as add-on therapy in children with refractory epilepsies and to determine the value of LEV blood level monitoring in this population. Methods Sixty-nine children (39 males and 30 females) treated with LEV between 2006 and 2007 were selected. Their medical files were reviewed for LEV efficacy and tolerability. In a subgroup of children currently taking LEV, plasma concentrations were determined by high performance liquid chromatography by ultraviolet detection (HPLC-UV) method and correlated with the given dose per kilo as well as clinical response. Results Fifty-one patients (74%) had a more than 50% reduction in seizure frequency with 16 patients (23%) becoming seizure free on LEV. Eighteen (26%) patients had a less than 50% reduction in seizure frequency. Adverse events due to LEV ranged from mild to moderate in only 18 patients (26%). The most frequently observed were drowsiness, behavioral difficulties, increase in seizure frequency and headaches. The majority (60.5%) of the responders received doses between 10 and 50mg/kg/day and had a plasma concentration (PC) between 5 and 40μg/ml. However, we found no clear correlation between PC and efficacy. Conclusion Levetiracetam given twice a day in children with refractory epilepsy reduces seizure frequency in all types of epilepsy. In children, LEV is a broad spectrum anticonvulsant with a favourable safety profile.

An improved analytical assay was developed and validated for the quantification of milrinone concentrations in patients undergoing cardiac surgery. A solid-phase extraction was optimized to isolate milrinone from a plasma matrix followed by HPLC using UV detection. Plasma samples (1 ml) were extracted using a C(18) solid-phase cartridge. Milrinone was separated on a strong cation exchange analytical column maintained at 23.4 degrees C. The mobile phase consisted of a gradient (10:90 to 45:55), 0.05 M phosphate buffer (pH 3):acetonitrile. Calibration curves were linear in the concentration range of 1.25-320 ng/ml. Mean drug recovery and accuracy were respectively > or =96% and > or =92%. Intra- and inter-day precisions (CV%) were < or =6.7% and < or =7.9%, respectively. This method proved to be reliable, specific and accurate. Using different types of column for extraction and separation of milrinone proved to be necessary to achieve the sensitivity and specificity required when milrinone is given by inhalation.

Background and Aims.Thiopurines are used in the treatment of Crohn’s disease (CD) and thiopurine S-methyltransferase (TPMT) activity can guide thiopurine dosing to avoid adverse events. This retrospective study evaluated the safety and efficacy of starting thiopurines at low dose versus full dose in patients with CD and normal TPMT.Methods.This was a single center retrospective study including adult CD patients with normal TPMT levels (≥25 nmol/hr/g Hgb) who were followed for 1 year. Patients started at full dose of azathioprine (2–2.5 mg/kg) or 6-mercaptopurine (1–1.5 mg/kg) were compared to patients started at low dose. Harvey-Bradshaw index, treatment failure, and drug-related adverse events were recorded.Results.Our study included 134 patients. Both groups had similar incidences of drug-related adverse events and discontinuation of therapy due to side effects. Fifty-six percent of all adverse events occurred within 31 days and 92% occurred within 3 months of therapy. Clinical response favored the full-dose group at 6 months (69% versus 27%,p=0.0542).Conclusions.Our study indicates that it is safe to start patients on full-dose thiopurine when they have a normal TPMT given its very similar toxicity profile to patients started on low dose. This may also positively impact efficacy.

Background Venous blood is the usual sample for measuring various biomarkers, including 25-hydroxyvitamin D (25OHD). However, it can prove challenging in infants and young children. Hence the finger-prick capillary collection is an alternative, being a relatively simple procedure perceived to be less invasive. We elected to validate the use of capillary blood sampling for 25OHD quantification by liquid chromatography tandem-mass spectrometry (LC/MS–MS). Methods Venous and capillary blood samples were simultaneously collected from 15 preschool-aged children with asthma 10 days after receiving 100,000 IU of vitamin-D3 or placebo and 20 apparently healthy adult volunteers. 25OHD was measured by an in-house LC/MS–MS method. Results The venous 25OHD values varied between 23 and 255 nmol/l. The venous and capillary blood total 25OHD concentrations highly correlated (r2 = 0.9963). The mean difference (bias) of capillary blood 25OHD compared to venous blood was 2.0 (95% CI: − 7.5, 11.5) nmol/l. Conclusion Our study demonstrates excellent agreement with no evidence of a clinically important bias between venous and capillary serum 25OHD concentrations measured by LC/MS–MS over a wide range of values. Under those conditions, capillary blood is therefore adequate for the measurement of 25OHD.

Background and Objectives The use of complementary and alternative medicines (CAM) is becoming increasingly popular. Although considered beneficial by users, the potential for interaction or substitution with conventional treatment should not be overlooked by health care professionals. It is therefore important to gain insight into the prevalence and the factors related to the use of CAM. To establish the prevalence of use of CAM among children with cancer treated in a large pediatric hospital, describe the profile of use and factors related with use. As a secondary objective we aimed at measuring quality of life of the children aged 5 or more and compare the scores between users and non-users. Methods The study is a cross-sectional survey of parents whose child was treated at the oncology clinic or ward of Sainte-Justine Hospital, a large pediatric hospital in Montreal. Data on socio-demographic variables, the use of CAM and the quality of life was collected through a self-administered questionnaire. Quality of life was measured with the Child Health Questionnaire CHQ-PF50, while clinical data was collected from medical records. Results A total of 115 patients were recruited and 92 parents completed and returned the questionnaire, resulting in a 80% response rate. According to this survey, 49% of the children used at least one type of CAM and 20% used herbal remedies/homeopathy/vitamins in the 2 months preceding the survey. Most popular CAM were spiritual/mental and physical strategies used by 35 and 33% of children under study, respectively. Only one parent reported having delayed a conventional treatment because of CAM. Although quality of life results must be interpreted with caution, they tend to favor non-users. Conclusions CAM is likely to be used by a wide variety of people. In our study, we found that about half of the children with cancer has used CAM in the 2 preceding months. No specific profile of CAM users emerged from this study. The high prevalence of CAM warrants further studies to better understand the reasons and consequences of CAM use particularly on quality of life. Pediatr Blood Cancer 2005;44:660–668. © 2005 Wiley-Liss, Inc.

The purpose of this study was to evaluate the effect of basic fibroblastic growth factor (bFGF) on the growth of human UM-MB1 medulloblastoma xenografts injected intracranially in nude mice. Under general anesthesia, a homogenous suspension of UM-MB1 cells (10(5)/10 microl) were injected in the caudoputamen nuclei of the right cerebral hemisphere using a stereotaxic apparatus. The treatment group (n = 9) received 10 microl of a bFGF solution (20 microg/ml) at 3 and 6 days following the inoculation of the cells at the injection site using the same stereotaxic coordinates. The control group (n = 9) were injected intracranially with a phosphate-buffered saline vehicle using a similar protocol. Mice were sacrificed 3 weeks following the xenograft surgery and the brains were prepared for histological observations as well as tumor volume evaluations. The mean volume of bFGF-treated tumors (mean volume +/- SD = 50.0 +/- 32.9 +/- mm3) was significantly smaller than for the non-treated xenografts (mean volume +/- SD = 199.0 +/- 42.1 mm3) (t-test, p0.001). Compared to non-treated tumor cells, bFGF-treated medulloblastoma cells had a greater cytoplasm volume and their nuclei contained more euchromatin suggesting that bFGF may initiate differentiation. In conclusion, our results suggest that bFGF may offer a new chemotherapeutic modality for the treatment of medulloblastoma.