NONMEM population pharmacokinetic studies of cytosine arabinoside after high-dose and after loading bolus followed by continuous infusion of the drug in pediatric patients with leukemias

1996 ◽  
Vol 39 (1-2) ◽  
pp. 42-50 ◽  
Author(s):  
Antonia P. Periclou ◽  
V. I. Avramis
Keyword(s):  
Continuous Infusion ◽  
Cytosine Arabinoside ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Pharmacokinetic Studies

Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia.

1984 ◽  
Vol 2 (10) ◽  
pp. 1092-1097 ◽  
Author(s):  
J Ochs ◽  
J A Sinkule ◽  
M K Danks ◽  
A T Look ◽  
W P Bowman ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Cytosine Arabinoside ◽  
Fungal Infections ◽  
Dosage Level ◽  
High Dose ◽  
Loading Dose ◽  
Rapid Infusion ◽  
Organ Systems ◽  
State Plasma

Ten pediatric patients with refractory leukemia received continuous infusion high-dose cytosine arabinoside (ara-C) according to one of two escalating dosage schedules: (1) a 500-mg/m2 rapid infusion loading dose followed by 3.5 g/m2 per day continuous infusion daily for four consecutive days, or (2) a 600-mg/m2 rapid infusion loading dose followed by 5.0 g/m2 per day continuous infusion daily for four consecutive days. Major toxicity at the lower dosage level was grade IV hematopoietic aplasia of three weeks' duration. At the higher dosage level, there was a prohibitive toxicity in multiple organ systems including transient noncardiogenic pulmonary edema, fungal infections, peritonitis, severe diarrhea, transaminase elevations, and one treatment-related death due to acute renal failure. In contrast to other methods of administration of high-dose ara-C, no CNS toxicity occurred. Oncolytic responses were seen in all patients and two achieved brief, partial remissions. Steady-state plasma ara-C concentrations were 13 to 40 mumol/L at the 3.5-g/m2 dosage level and 10 to 225 mumol/L at the 5-g/m2 dosage level; CSF concentrations at both dosages ranged from 2 to 5 mumol/L. Intracellular levels and ratios of 1-beta-D-arabinofuranosylcytidine-5' triphosphate and endogenous deoxycytidine 5' triphosphate in marrow blasts varied widely at steady state during infusion. No positive correlation existed between steady-state plasma ara-C levels, toxicity, oncolytic effect, or intracellular nucleotide concentration.

scholarly journals Clinical Experience with High-Dose Polymyxin B against Carbapenem-Resistant Gram-Negative Bacterial Infections—A Cohort Study

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 451
Author(s):  
Yiying Cai ◽  
Hui Leck ◽  
Ray W. Tan ◽  
Jocelyn Q. Teo ◽  
Tze-Peng Lim ◽  
...  
Keyword(s):  
Cohort Study ◽  
Bacterial Infections ◽  
Kidney Injury ◽  
Polymyxin B ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Median Daily Dose

Population pharmacokinetic studies have suggested that high polymyxin B (PMB) doses (≥30,000 IU/kg/day) can improve bacterial kill in carbapenem-resistant Gram-negative bacteria (CR-GNB). We aim to describe the efficacy and nephrotoxicity of patients with CR-GNB infections prescribed high-dose PMB. A single-centre cohort study was conducted from 2013 to 2016 on septic patients with CR-GNB infection and prescribed high-dose PMB (~30,000 IU/kg/day) for ≥72 h. Study outcomes included 30-day mortality and acute kidney injury (AKI) development. Factors associated with AKI were identified using multivariable regression. Forty-three patients with 58 CR-GNB received high-dose PMB; 57/58 (98.3%) CR-GNB were susceptible to PMB. The median daily dose and duration of high-dose PMB were 32,051 IU/kg/day (IQR, 29,340–34,884 IU/kg/day) and 14 days (IQR, 7–28 days), respectively. Thirty-day mortality was observed in 7 (16.3%) patients. AKI was observed in 25 (58.1%) patients with a median onset of 8 days (IQR, 6–13 days). Higher daily PMB dose (aOR,1.01; 95% CI, 1.00–1.02) and higher number of concurrent nephrotoxins (aOR, 2.14; 95% CI; 1.03–4.45) were independently associated with AKI. We observed that a sizable proportion developed AKI in CR-GNB patients described high-dose PMB; hence, the potential benefits must be weighed against increased AKI risk. Concurrent nephrotoxins should be avoided to reduce nephrotoxicity.

Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside.

1984 ◽  
Vol 2 (5) ◽  
pp. 365-368 ◽  
Author(s):  
J Frick ◽  
P S Ritch ◽  
R M Hansen ◽  
T Anderson
Keyword(s):  
Cerebrospinal Fluid ◽  
Cytosine Arabinoside ◽  
Systemic Disease ◽  
Therapeutic Drug ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Meningeal Involvement ◽  
Drug Concentrations ◽  
High Doses ◽  
Meningeal Leukemia

Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.

Amsacrine and Continuous-Infusion High-Dose Cytosine Arabinoside as Induction Therapy for Patients with Newly-Diagnosed Acute Myelogenous Leukemia

1996 ◽  
Vol 22 (1-2) ◽  
pp. 71-76 ◽  
Author(s):  
Habib M. Ghaddar ◽  
Sherry Pierce ◽  
Hagop M. Kantarjian ◽  
Emil J. Freireich ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Induction Therapy ◽  
Cytosine Arabinoside ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Newly Diagnosed ◽  
Acute Myelogenous

Determination of the Maximum Tolerated Dose of Cyclophosphamide in Conjunction with High-Dose Etoposide and Carboplatin Followed by Autologous CD34+ Hematopoietic Rescue in Pediatric Patients with Recurrent/Refractory Solid Tumors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5462-5462
Author(s):  
Michelle P. Hudspeth ◽  
Barbara Duffy ◽  
Stephen Noga ◽  
Steven Goodman ◽  
Curt I. Civin ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Solid Tumors ◽  
Median Time ◽  
Pediatric Patients ◽  
Cardiac Toxicity ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Cyclophosphamide (Cy) is an alkylating agent utilized in almost all preparative regimens for hematopoietic stem cell transplantation, and in vitro sensitivity has been demonstrated with carboplatin and etoposide. Multiple previous studies have involved this combination of agents; however, they almost exclusively utilized a fixed dose of Cy and/or bolus administration. The potential fatal cardiac toxicity of Cy is likely related to high peak concentrations of active metabolites from bolus dosing. Additionally, some evidence exists that the increased metabolism of Cy with continuous infusion has a therapeutic benefit. The objective of this study was to determine the maximum tolerated dose (MTD) of continuous infusion Cy with fixed dose etoposide (2400 mg/m2) and carboplatin (2175 mg/m2) followed by autologous CD34+ hematopoietic rescue in pediatric patients with recurrent/refractory solid tumors. Twenty patients were enrolled, and fourteen patients completed therapy on study. The MTD of Cy was 60 mg/kg/24 hr by continuous 60 hr infusion on days -4 to -2 for a total dose of 150 mg/kg. Alopecia, stomatitis and nausea were the most common toxicities. The single episode of direct cardiac toxicity was reversible. Two Grade IV toxicities occurred, consisting of diarrhea in one patient and coma in another patient who recovered and remains a long-term survivor. All patients were evaluable for neutrophil engraftment, with a median time to ANC > 200/μl of 11 days (range 7–30 days). Thirteen of the fourteen patients were evaluable for platelet engraftment, with a median time to platelet count of 20,000/μl independent of transfusion of 21 days (range 11–72 days). Six out of the fourteen patients remain alive greater than five years after study completion. The MTD of Cy was lower than expected. These results suggest that autoinduction of Cy metabolism (repeated administration of Cy at 24 hour intervals leads to increased hepatic cytochrome enzymes) could be a primary factor in the determination of the MTD. Future studies should aim to further characterize the pharmacokinetics and effectiveness of continuous infusion Cy in pediatric patients.

Continuous and Extended Infusions of β-Lactam Antibiotics in the Pediatric Population

2012 ◽  
Vol 46 (11) ◽  
pp. 1537-1546 ◽  
Author(s):  
Mary Covington Walker ◽  
Weng Man Lam ◽  
Kalen B Manasco
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Continuous Infusion ◽  
Pediatric Patients ◽  
Case Reports ◽  
Pediatric Population ◽  
Case Series ◽  
Current Evidence ◽  
Pharmacokinetic Studies ◽  
Randomized Controlled

OBJECTIVE: To conduct a systematic review of available data on the use of extended or continuous infusion of β-lactam and monobactam therapy in the pediatric population (aged 0–18 years). DATA SOURCES: A literature search was performed using PubMed (1975-May 2012), International Pharmaceutical Abstracts (1970-May 2012), and Web of Science (1977-May 2012) to identify studies for inclusion. In addition, reference citations from identified publications were reviewed. The following search terms were used: pediatric, children, neonate, infant, adolescent, β-lactam, cephalosporin, carbapenem, penicillin, monobactam, continuous infusion, extended infusion, and/or prolonged infusion. Individual names of drugs in each class of antibiotics were also included in the search. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled clinical trials, pharmacokinetic/pharmacodynamic studies, observational studies, and case reports involving pediatric patients who received extended or continuous infusion of β-lactam or monobactam antibiotics were reviewed. Only English-language publications were included. DATA SYNTHESIS: One randomized controlled clinical trial, 5 pharmacokinetic studies, 2 pharmacodynamic studies using Monte Carlo simulation, 1 case series, and 7 case reports were included in the analysis. The cephalosporin class has been studied the most and currently represents the only clinical trial using a continuous infusion dosing strategy in pediatric patients. There is limited clinical evidence available to support the use of extended or continuous infusion of β-lactam antibiotics in the pediatric population. Pharmacodynamic studies conducted in this population mirror the current evidence in adults for cefepime and meropenem. The single prospective clinical trial using continuous infusion of ceftazidime failed to demonstrate any clinical benefit over traditional dosing; however, there was equal efficacy. CONCLUSIONS: More well-designed prospective clinical trials are required to determine the role of extended or continuous infusion of β-lactam antibiotics in treatment of pediatric patients.

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