Pharmacokinetics of metronomic temozolomide in cerebrospinal fluid of children with malignant central nervous system tumors.

PURPOSE: Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide. METHODS: Eleven pediatric CNS tumor patients (aged 4-14 years) treated with oral temozolomide using a metronomic schedule (24-77 mg/m2/day) were included. Temozolomide concentrations in 28 plasma samples and 64 CSF samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modeling and simulations were performed using non-linear mixed effects modeling (NONMEM 7.4.2). RESULTS: Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) µg/ml and 0.37 (0.06-1.76) µg/ml, respectively. A two-compartment model (central/plasma [1], CSF [2]) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (Vc) were 3.29 L/h (95% confidence interval (CI) 2.58-3.95) and 10.5 L (8.17-14.32), respectively. Based on simulations, we found a median area under the concentration vs. time curve ratio (AUCCSF / AUCplasma ratio) of 37%. CONCLUSION: Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults.

Clinical Pharmacokinetics and Pharmacodynamics of Cefiderocol.

Cefiderocol is a new broad-spectrum cephalosporin antibiotic with promising activity against various Gram-negative bacteria including carbapenem-resistant strains. A chlorocatechol group in the C-3 side chain provides cefiderocol with a siderophore activity, improving its stability against ß-lactamases and facilitating the transportation of cefiderocol across outer bacterial membranes. Cefiderocol shows linear pharmacokinetics over a broad range of clinically relevant doses, with unchanged renal excretion constituting the main route of elimination. Geometric means (coefficient of variation) of the volume of distribution and clearance in individuals with normal kidney function were 15.8 (15%) L and 4.70 (27%) L/h, respectively. In patients with end-stage renal disease, clearance was 1.10 (24%) L/h. Time above the minimum inhibitory concentration is the main predictor of efficacy. There is no evidence for clinically relevant interactions of cefiderocol with other drugs mediated by metabolizing enzymes or drug transporters. Simulations based on population pharmacokinetic modeling suggest that dosing regimens should be adjusted based on kidney function to optimize therapeutic exposure to cefiderocol. Clinical efficacy trials indicated that cefiderocol is non-inferior to imipenem/cilastatin in the treatment of complicated urinary tract infections and acute uncomplicated pyelonephritis, and to meropenem in the treatment of nosocomial pneumonia. In the one study currently available, cefiderocol performed similarly to the best available therapy in the treatment of severe carbapenem-resistant Gram-negative infections regarding clinical and microbiological efficacy. In summary, cefiderocol shows favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol might be a viable option to treat infections with bacteria resistant to other antibiotics.

Accuracy in diagnosing deep and pelvic vein thrombosis in primary care: an analysis of 395 cases seen by 58 primary care physicians.

BACKGROUND: Ruling out a deep vein thrombosis (DVT) is difficult in general practice because the clinical manifestations of DVT are nonspecific and more often due to other diseases. The aim of diagnostic screening in primary care must be to rule out a DVT with high accuracy in most patients, so that only those who are likely to have a DVT will undergo further testing. In this study, we tested the accuracy of exclusion of DVT by the combination of a clinical score (the Wells score) with either a bedside D-dimer test or selective compression sonography. METHOD: This cohort study included all patients who presented to the participating primary care physicians and were suspected of having a DVT on the basis of pre-defined inclusion criteria. To rule out DVT, a Wells score was determined for all patients, and all patients additionally underwent either a D-dimer test or selective compression sonography as required by the clinical algorithm. Patients were seen six weeks later in follow-up to determine whether they had actually had a DVT (gold standard). The negative predictive value (NPV) for the exclusion of DVT in this way was determined, as was the NPV of clinical judgment alone, without knowledge of Wells score or D-dimer results. RESULTS: 395 patients were evaluated by 58 primary care physicians for suspected DVT; 59 were ultimately found to have had a definite DVT, and 9 a probable DVT. Exclusion of DVT with the study protocol had an NPV of 99.0% (95% CI, 96.3 to 99.8)-i.e. only one case of DVT in 100 patients was missed (maximum: 4, minimum: 0)-while clinical judgment alone had an NPV of 95.0% (95% CI, 90.7 to 97.7). CONCLUSION: We recommend the Wells score combined with either a D-dimer test or selective compression sonography according to the algorithm used in this study for use in primary care to rule out DVT. Clinical judgment alone is less effective.