Academic literature on the topic '134th Infantry Regiment'

Abstract Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants. Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfan Patients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts < 9 kg and 171 pts < 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg]. PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1st(D1), 9th (D9) and 13th (D13) dose in 150 patients, D1 and D9 in 40 patients, D1 and D13 in 46 patients while 62 patients were monitored on D1 only (684 PK datasets). PK analysis was performed using Non linear Mixed Effect Modelling. A one-compartment PK model suitably fitted the concentrations vs time data. Median follow up is 27 months (0.33 to 96 months post BMT). Results: At D1, 67% of patients were within the therapeutic window (TW) [900-1500 µM.min] and 66% of patients reached the cumulative TW [14400-24000 µM.min]. Incidence of VOD and niPD were respectively 35% and 14%. Both toxicities correlated with type of CR and age <1 year at transplantation. Incidence of aGVH was 33%. However, these incidences were very different according to the CR. BuFlu showed the lowest incidence compared to other combinations of drugs (p < 0.001 and =0.022 for VOD and niPD, respectively). When using a second alkylating agent, incidence of VOD reached 41% (vs 19% in BuFlu, p<0.001) and niPD 17% (vs 8% in BuFlu, p<0.040). Toxicities were also related to BW, with 48% vs 30% (p<0.013) for VOD below or above 9 kg, and respectively, 28% vs 9% (p<0.0002) for niPD. This tendency was also found with a 15 kg cut-off for aGVH. No correlation was found with Bu AUC. However, there was a trend for lower OS (HR 1.60 [1.00-2.58], p=0.051) in patients with AUC D1 <900 µM.min compared to patients with AUC D1 > 900 µM.min. OS was 69.1% at last follow up and was not significantly associated with CR and age at transplantation. Conclusion: In this large series of pediatric BMT recipients, we found that toxicities as VOD and niPD correlated with type of CR and age at transplantation in univariate analysis. Combination of 2 alkylating agents with Bu or BuFlu and transplantation < 1 year of age were associated with the highest incidence of toxicites. The TW targeting performance was improved in this cohort compared to previous reported data (Paci et al. TDM 2012). Specific TW for each group of pathologies will be proposed. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1811 Background: Busulfan (Bu) is a standard component of HSCT regimens and shows a narrow therapeutic range. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Intravenous (IV) Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the IV Bu dosage in children [Vassal G. et al., CCP 2006]. Search for additional relevant covariates is still a topical question to further explain the variability in young children (Pts) and infants. Objective: to screen for the effect of heterogeneous patient characteristics on IV Bu PK disposition, and to evaluate the consistency of weight-based dosing strategy (as recommended in the European SmPC) in a large cohort of children, especially in patients with rare diseases and a BW less than 9 kg. Patients and Method: The prospective observational study included 115 patients (pts), mostly infants (median age: 13 months [0.3-148], median BW: 9 kg [3.5-58]). Main diagnoses were immunodeficiency (n=71, mainly SCID and lymphohistiocytosis) and inherited metabolic disorders (n=15). Additional data (90 pts, mostly malignant diseases) from two prospective clinical trials previously described [Nguyen L. et al., BMT 2004] [Vassal G. et al., CCP 2006] were pooled with the observational dataset. Altogether, 205 children aged from 10 days to 15 years (median of 30 months) and weighed from 3.5 to 62.5 kg (median of 11.0 kg) were analysed. IV Bu (Busilvex®) was given over 2 h q6h × 16 doses. For most of the pts (88%), the starting doses were given according to the European SmPC: 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg and 0.8 mg/kg for pts <9 kg, 9 – <16 kg, 16–23 kg, >23–34 kg, and >34 kg BW, respectively. PK was assessed on plasma samples from the 1st, 9th and 13th dose (536 PK datasets). PK analysis was performed using Non Linear Mixed Effect modelling with the NONMEM program. Results: A one-compartment PK model suitably fitted the concentrations vs time data. BW remained the main determinant of IV Bu PK disposition. Increase of IV Bu clearance with child's growth was observed to be faster in younger than in older children. For children < 9 kg, a doubling in BW is associated with a 2.4-fold increase in Bu clearance while a 1.7-fold increase in Bu clearance is observed in pts ≥ 9 kg for the same BW growth. To take into account this difference, the relationships between Clearance (CL) and BW was modelled using a different allometric exponent for children with a BW of < 9 kg and ≥ 9 kg. The predictive equations were: CL (L/h) = 2.18 × (BW/9)1.25 and CL(L/h) = 2.18 × (BW/9)0.76 in pts < 9 kg and ≥ 9 kg, respectively. The inter-individual variability decreased from 64% (covariate-free model) to 23% for Bu CL. No further significant impact was identified even when considering large fluctuations of the following covariates: creatinine clearance (up to 11 × Upper Normal Limit), bilirubin (up to 4 × UNL), ferritine (up to 43 × UNL), hepatic transaminases (up to 39 × UNL), alkaline phosphatases (up to 4 × UNL), gGT (up to 86 × UNL), total protein (0.5 to 1.4 × UNL) and lactate deshydrogenase (up to 3 × UNL). No PK difference was observed between patients under Benzodiazepine and those under Phenytoin prophylaxis, neither when comparing different groups of diagnoses. Similar performances for targeting an AUC range of 900 – 1500 μM.min were achieved when comparing Bu dosing either adjusted according to the model predictive equation or with the use of the European SmPC recommendations. The success rates were about 60% and 80% in pts < 9 kg and ≥ 9 kg respectively. Conclusion: BW is confirmed to be the only relevant predictor to optimally define the IV Bu dosing in children. The population PK model has established a higher allometric exponent for younger children (< 9kg) in order to take into account the faster maturation of clearance in this weight group. This model is consistent with the dosing strategy recommended in the EMA registration. Disclosures: Daher Abdi: Pierre Fabre Médicament: Employment. Pétain:Pierre Fabre Médicament: Employment. Nguyen:Pierre Fabre Médicament: Employment.

Abstract Sand deposition and transportation in pipelines has become one of the major concerns for flow assurance in petroleum industry. However, research in this field is still in its infancy. This study describes the current development of sand deposition and sand transport in pipeline. The mechanism of particles deposition is described. The effects of particle properties, fluid properties and pipeline structure on the carrying capacity of single-phase and multiphase flow carrying sand are introduced, with emphasis on factors such as particle size, liquid viscosity, flow regime and pipeline inclination. As for modeling studies, the sand transport models can be classified to three categories based on the approach used to develop them: empirical, mechanistic, and semi-mechanistic. The methods for developing and extending models are illustrated in this study. Based on the experimental data, the prediction accuracy of four multiphase models for critical velocity in stratified flow is verified. Further researches should focus on the mechanisms and the establishment of the accurate model for sand flow pattern transformation boundary.