Evaluation of an individualized dosing regimen of busulfan in children undergoing allogeneic haematopoietic stem cell transplantation

OBJECTIVE To assess target attainment of busulfan exposure using a new model-based dosing regimen and therapeutic drug monitoring (TDM). Busulfan is an alkylating drug used in conditioning regimens for allogeneic haematopoietic cell transplantation (allo-HCT). Its narrow therapeutic range in combination with large interindividual variability in exposure, even after intravenous administration, necessitates dose individualization. DESIGN Prospective cohort study. METHODS All children who underwent allo-HCT in 2011 or 2012 receiving busulfan-based conditioning were included. Intravenous busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and k. For each patient a 'hypothetical' exposure (cAUC) without TDM was determined by extrapolating the AUC of day 1. The 'true' cAUC was then estimated based on pharmacokinetic data obtained on days 1-4 including TDM-based dose adjustment. Means and ranges were compared between cAUCs determined with and without TDM-based dose corrections. Also target attainment rates (cAUC 80-100 mg-h/L] were compared between 'hypothetical' and 'true' exposure. RESULTS 50 patients were included. Without TDM mean cAUC was 85.3 mg-h/L versus 96.2 mg-h/L with TDM. The range in individual cAUCs was significantly larger without TDM than with TDM IP = 0.001 ). Without TDM 34% of patients reached target cAUC and with TDM this significantly increased to 70% of patients (P = 0.0011. CONCLUSION The weight-based dosing regimen overall led to a mean busulfan exposure within the target range, yet the interindividual variation was substantial. Therefore, TDM of intravenous busulfan remains recommended and is of utmost importance to reach optimal target exposure in order to optimize HCT outcomes

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study

Aims: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC Plus nebulizer in children with cystic fibrosis. Methods: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. Results: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. Conclusions: Nebulization of 75 mg TIS with the I-neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury

Les premiers équipements sportifs à La Réunion : une politique de l'Etat (1956-1971)

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Bioavailability of cyclosphosphamide and vincristine after intraperitoneal administration in cats

Cyclophosphamide and vincristine are widely used intravenous chemotherapeutic agents in both human and veterinary oncology. Although intravenous administration of these chemotherapeutics is the gold standard in most treatment protocols, this route of administration has several disadvantages (e.g. long infusion times and risk of extravasation). Therefore, alternative routes have been explored in the past. Recently, good clinical results were achieved with intraperitoneal (i.p.) administration of cyclophosphamide and vincristine in cats. However, the bioavailability following i.p. administration of cyclophosphamide and vincristine providing proof of principle has not been investigated and is the focus of the present study. The pharmacokinetics of cyclophosphamide and vincristine after i.p. and intravenous administration was investigated in six cats in a cross-over study by analysis of plasma levels of cyclophosphamide and vincristine after simultaneously administration of 0.6 mg/m2 vincristine and 200 mg/m2 cyclophosphamide. The median bioavailability on i.p. administration was 76% for cyclophosphamide and 100% for vincristine. Median areas under the curve for i.p. and intravenous administration were 11.4 and 16.0 ng h/ml for cyclophosphamide and 16.7 and 16.5 ng h/ml for vincristine, respectively. No specific i.p. administration-related adverse events were observed after i.p. administration. The high bioavailability of both cyclophosphamide and vincristine after i.p. administration and the absence of specific i.p. administration-related side effects suggest that i.p. administration is a suitable route of systemic chemotherapy for both chemotherapeutics. These results are promising and may serve as a stepping stone for the investigation of the pharmacology, safety, and efficacy of i.p. administration of cyclophosphamide and vincristine in humans

Bioavailability of cyclosphosphamide and vincristine after intraperitoneal administration in cats

Cyclophosphamide and vincristine are widely used intravenous chemotherapeutic agents in both human and veterinary oncology. Although intravenous administration of these chemotherapeutics is the gold standard in most treatment protocols, this route of administration has several disadvantages (e.g. long infusion times and risk of extravasation). Therefore, alternative routes have been explored in the past. Recently, good clinical results were achieved with intraperitoneal (i.p.) administration of cyclophosphamide and vincristine in cats. However, the bioavailability following i.p. administration of cyclophosphamide and vincristine providing proof of principle has not been investigated and is the focus of the present study. The pharmacokinetics of cyclophosphamide and vincristine after i.p. and intravenous administration was investigated in six cats in a cross-over study by analysis of plasma levels of cyclophosphamide and vincristine after simultaneously administration of 0.6 mg/m2 vincristine and 200 mg/m2 cyclophosphamide. The median bioavailability on i.p. administration was 76% for cyclophosphamide and 100% for vincristine. Median areas under the curve for i.p. and intravenous administration were 11.4 and 16.0 ng h/ml for cyclophosphamide and 16.7 and 16.5 ng h/ml for vincristine, respectively. No specific i.p. administration-related adverse events were observed after i.p. administration. The high bioavailability of both cyclophosphamide and vincristine after i.p. administration and the absence of specific i.p. administration-related side effects suggest that i.p. administration is a suitable route of systemic chemotherapy for both chemotherapeutics. These results are promising and may serve as a stepping stone for the investigation of the pharmacology, safety, and efficacy of i.p. administration of cyclophosphamide and vincristine in humans

Nonlinear protein binding of phenytoin in clinical practice: Development and validation of a mechanistic prediction model

Item does not contain fulltextAIMS: To individualize treatment, phenytoin doses are adjusted based on free concentrations, either measured or calculated from total concentrations. As a mechanistic protein binding model may more accurately reflect the protein binding of phenytoin than the empirical Winter-Tozer equation that is routinely used for calculation of free concentrations, we aimed to develop and validate a mechanistic phenytoin protein binding model. METHODS: Data were extracted from routine clinical practice. A mechanistic drug protein binding model was developed using nonlinear mixed effects modelling in a development dataset. The predictive performance of the mechanistic model was then compared with the performance of the Winter-Tozer equation in 5 external datasets. RESULTS: We found that in the clinically relevant concentration range, phenytoin protein binding is not only affected by serum albumin concentrations and presence of severe renal dysfunction, but is also concentration dependent. Furthermore, the developed mechanistic model outperformed the Winter-Tozer equation in 4 out of 5 datasets in predicting free concentrations in various populations. CONCLUSIONS: Clinicians should be aware that the free fraction changes when phenytoin exposure changes. A mechanistic binding model may facilitate prediction of free phenytoin concentrations from total concentrations, for example for dose individualization in the clinic

Redispensing of unused HIV post-exposure prophylaxis for medical students

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Manual punch versus automated flow-through sample desorption for dried blood spot LC-MS/MS analysis of voriconazole

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