Quantification of levetiracetam in plasma and urine and its application to a pharmacokinetic study of traumatic brain injury patients.

Background: Levetiracetam is an antiepileptic drug used to prevent or treat seizure in patients with severe traumatic brain injury. This study aimed to develop and validate methodology suitable for measuring levetiracetam concentrations in human plasma and urine. Methods: Plasma or urine (10 µl) samples were spiked with [2H6]-levetiracetam and processed using an acetonitrile precipitation. ESI-LC-MS/MS was employed for analyte detection. Results: The levetiracetam calibration was linear from 0.1 to 50 mg/l in a combined matrix of plasma and urine. Intra- and inter-assay imprecision and accuracy in plasma were <7.7 and 109%, and in urine were <7.9 and 108%, respectively. Conclusion: The validated method was applied to a pharmacokinetic study of levetiracetam in critically ill patients with severe traumatic brain injury.

Levetiracetam is a drug that is used for the prevention or treatment of seizure. This study aimed to design a method that would be suitable for measuring levetiracetam in human plasma and urine. The method was subsequently applied to a clinical study of patients with severe traumatic brain injury.

Wastewater analysis for psychoactive substances at music festivals across New South Wales, Australia in 2019-2020.

INTRODUCTION: Implementation of wastewater surveillance at music festivals has been limited to date. We aimed to use wastewater analysis and a self-report survey to determine the range of psychoactive substances being used during a music festival season in New South Wales, Australia. METHODS: We sampled six single-day music festivals requiring a music festival license in New South Wales from March 2019 to March 2020; between 15% and 100% of portaloos (temporary, un-fixed toilet facilities) were sampled at each festival. Samples were screened for 98 psychoactive substances and/or their metabolites with results qualitatively expressed as detection frequencies for each substance at each festival and across all festivals. We compared these data with the results of surveys of self-reported drug use at four of the six festivals. RESULTS: Festival attendance ranged from 6200 to 14,975 people. Amphetamine, cocaine, ketamine, methylone, MDMA, MDA, alprazolam, diazepam, etizolam, oxazepam and temazepam were found in almost all samples from all festivals. Ethylone, mephedrone and methcathinone were also found in over 50% of festivals. A norfentanyl (a fentanyl metabolite) and n-ethylpentylone were found at 2/6 and 1/6 festivals. No festival survey participant reported intentionally taking cathinones. DISCUSSION: The detection frequency for cathinones was higher than expected relative to recent other data sources and this may represent adulteration or substitution. Similarly, the appearance of etizolam may be related to the use of counterfeit alprazolam. The detection of highly toxic substances such as N-ethylpentylone and norfentanyl may warrant public health alerts. CONCLUSION: If provided close to real time, wastewater analysis at festivals could be complemented with information sources such as drug checking, on-site surveys, medical presentations and intelligence from peer networks to feed into early warning systems, public health alerts and peer-based harm reduction education during the festival season.

Pharmacodynamic Evaluation of a Single Dose versus a 24-Hour Course of Multiple Doses of Cefazolin for Surgical Prophylaxis.

The optimal perioperative duration for the administration of cefazolin and other prophylactic antibiotics remains unclear. This study aimed to describe the pharmacodynamics of cefazolin for a single 2 g dose versus a 24 h course of a 2 g single dose plus a 1 g eight-hourly regimen against methicillin-susceptible Staphylococcus aureus. Static concentration time-kill assay and a dynamic in vitro hollow-fibre infection model simulating humanised plasma and interstitial fluid exposures of cefazolin were used to characterise the pharmacodynamics of prophylactic cefazolin regimens against methicillin-sensitive Staphylococcus aureus clinical isolates. The initial inoculum was 1 × 105 CFU/mL to mimic a high skin flora inoculum. The static time-kill study showed that increasing the cefazolin concentration above 1 mg/L (the MIC) did not increase the rate or the extent of bacterial killing. In the dynamic hollow-fibre model, both dosing regimens achieved similar bacterial killing (~3-log CFU/mL within 24 h). A single 2 g dose may be adequate when low bacterial burdens (~104 CFU/mL) are anticipated in an immunocompetent patient with normal pharmacokinetics.

Population Pharmacokinetics of Levetiracetam in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage Exhibiting Augmented Renal Clearance.

BACKGROUND AND OBJECTIVE: Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens. METHODS: This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations. RESULTS: A two-compartment model best described the concentration-time data from 30 patients. The mean ± standard deviation parameter estimates were bioavailability (F) of 0.8 ± 0.2, absorption rate constant of 2.4 ± 2 h-1, clearance 2.5 ± 1.1 L/h, central volume of distribution 8.9 ± 3.0 L/h, and transfer rate constraints of 1.8 ± 1.1 h-1 from central to peripheral compartments and 0.7 ± 0.3 h-1 from peripheral to central compartments. For the simulated intermittent dosing regimens, on average, the median trough concentration reduced by 50% for every 40-mL/min/1.73 m2 increase in urinary creatinine clearance. Simulated doses of at least 6 g/day were required for some levels of augmented renal clearance. CONCLUSIONS: Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.

Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy.

Pharmacokinetic alterations of medications administered during surgeries involving cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been reported. The impact of CPB on the cytochrome P450 (CYP) enzymes' activity is the key factor. The metabolic rates of caffeine, dextromethorphan, midazolam, omeprazole, and Losartan to the CYP-specific metabolites are validated measures of in vivo CYP 1A2, 2D6, 3A4, 2C19, and 2C9 activities, respectively. The study aim is to assess the activities of major CYPs in patients on extracorporeal circulation (EC). This is a pilot, prospective, open-label, observational study in patients undergoing surgery using EC and patients undergoing laparoscopic cholecystectomy as a control group. CYP activities will be measured on the day, and 1-2 days pre-surgery/3-4 days post-surgery (cardiac surgery and Laparoscopic cholecystectomy) and 1-2 days after starting ECMO, 1-2 weeks after starting ECMO, and 1-2 days after discontinuation from ECMO. Aforementioned CYP substrates will be administered to the patient and blood samples will be collected at 0, 1, 2, 4, and 6 h post-dose. Major CYP enzymes' activities will be compared in each participant on the day, and before/after surgery. The CYP activities will be compared in three study groups to investigate the impact of CYPs on EC.

An improved LC-MS/MS method for simultaneous evaluation of CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activity.

AIM: To develop an LC-MS/MS assay to quantitate well-tolerated substrates; midazolam (CYP3A), omeprazole (CYP2C19), dextromethorphan (CYP2D6), losartan (CYP2C9) and their respective metabolites' concentrations in plasma samples. PATIENTS & METHODS: A solid-phase extraction method was optimized to extract analytes of interest simultaneously from human plasma samples. The assay analyzed plasma samples collected from patients who received equal or lower than therapeutic doses of CYP substrates. RESULTS: This assay was validated based on the European Medicines Agency guideline for bioanalytical method validation and was sensitive, linear, accurate and precise with acceptable recovery and matrix effects. CONCLUSION: Small sample volume and dose of cytochrome P450 substrates, short-run time, using stable isotope internal standards and being cost effective are the major advantages of the assay.

Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy.

For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug-drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population.