Pharmacokinetics of levetiracetam in neurosurgical ICU patients.

BACKGROUND/OBJECTIVES: The pharmacokinetics (PK) of drugs is dramatically altered in critical illness. Augmented renal clearance (ARC), a phenomenon characterized by creatinine clearance (CrCl) greater than 130 ml/min/1.73m2, is commonly described in critically ill patients. Levetiracetam, an antiepileptic drug commonly prescribed for seizure prophylaxis in the neurosurgical ICU, undergoes predominant elimination via the kidneys. Hence, we hypothesize that current dosing practice of intravenous (IV) levetiracetam 500 mg twice daily is inadequate for critically ill patients due to enhanced drug elimination. The objectives of our study were to describe the population PK of levetiractam using a nonparametric approach to design an optimal dosing regimen for critically ill neurosurgical patients. METHODS: This was a prospective, observational, population PK study. Serial blood samples were obtained from neurosurgical ICU patients who received at least one dose of IV levetiracetam. We used uHPLC to analyze these samples and Pmetrics™ software to perform PK analysis. RESULTS: Twenty subjects were included, with a median age of 54 years and CrCl of 104 ml/min. A two-compartmental model with linear elimination adequately described the profile of levetiracetam. Mean clearance (CL) was 3.55 L/h and volume of distribution (V) was 18.8 L. No covariates were included in the final model. Monte Carlo simulations showed a low probability of target attainment (PTA, trough at steady state of ≥6 mg/L) with a standard dose of 500 mg twice daily. A dose of at least 1000 mg twice daily was required to achieve 80% PTA. Two subjects, both with subtherapeutic trough levels, developed early onset seizures. CONCLUSION: Our study examined the population PK of levetiracetam in a critically ill neurosurgical population. We found that this population displayed higher clearance and required higher doses to achieve target levels.

Breakthrough febrile neutropenia and associated complications in Non-Hodgkin's lymphoma patients receiving pegfilgrastim.

BACKGROUND: Febrile neutropenia (FN) is a dose-limiting complication of chemotherapy. Judicious usage of prophylactic granulocyte-colony-stimulating factors, such as pegfilgrastim, can prevent the occurrence of FN. Although studies have been conducted to evaluate the effectiveness of pegfilgrastim to prevent FN in lymphoma patients receiving myelosuppressive chemotherapy, limited data is available to identify patients who are at risk of developing FN despite primary prophylaxis with pegfilgrastim (breakthrough FN). OBJECTIVES: The aim of this study is to: (1) identify clinical characteristics of patients who develop breakthrough FN, and (2) provide descriptive data on the incidence of breakthrough FN among lymphoma patients. METHODS: This is a single-centre, retrospective cohort study. Non-Hodgkin's lymphoma patients who received CHOP-based chemotherapy with pegfilgrastim between January 2007 and May 2009 were identified through the Singapore Lymphoma Registry. Patient demographics, past and present medical history, cancer treatment history and laboratory parameters were collected from electronic databases and medical records. In this study, patients did not receive oral antibiotic prophylaxis along with chemotherapy. RESULTS: A total of 132 patients were included in the final analysis. Median age of patients was 55 years. The incidence of breakthrough FN among patients in cycle 1 and across all cycles was 4.5% and 13.6%, respectively (n = 132). 3.3% (n = 60) of the patients receiving dose-dense chemotherapy had breakthrough FN, and this was 22.2% (n = 72) in patients receiving standard dose chemotherapy. Administration of chemotherapy every 21 days (adjusted OR = 12.1, p = 0.009) and patients with positive blood cultures (adjusted OR = 18.1, p = 0.001) were strongly associated with the occurrence of breakthrough FN. CONCLUSION: Despite routine administration of pegfilgrastim with CHOP chemotherapy, a high proportion of patients experienced FN after chemotherapy. Identifying patients at risk for breakthrough FN events may allow the optimization of myeloid growth factor usage among lymphoma patients receiving chemotherapy.