Guidance of adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial.

BACKGROUND: In intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients. METHODS: Patients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy. DISCUSSION: The aim of this trial is to use drug screens in PDO to precise treatment selection for adjuvant instillation therapies in patients with intermediate-risk NMIBC. The ultimate goal of this trial is to reduce the risk of cancer recurrence. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care. Trial registration NCT05024734.

Polypharmacy and drug-drug interactions among older and younger male prisoners in Switzerland.

PURPOSE: The purpose of this paper is to determine the prevalence of polypharmacy and drug-drug interactions (DDIs) in older and younger prisoners, and compared if age group is associated with risks of polypharmacy and DDIs. DESIGN/METHODOLOGY/APPROACH: For 380 prisoners from Switzerland (190 were 49 years and younger; 190 were 50 years and older), data concerning their medication use were gathered. MediQ identified if interactions of two or more substances could lead to potentially adverse DDI. Data were analysed using descriptive statistics and generalised linear mixed models. FINDINGS: On average, older prisoners took 3.8 medications, while younger prisoners took 2.1 medications. Number of medications taken on one reference day was higher by a factor of 2.4 for older prisoners when compared to younger prisoners (p = 0.002). The odds of polypharmacy was significantly higher for older than for younger prisoners (>=5 medications: odds ratio = 5.52, p = 0.035). Age group analysis indicated that for potentially adverse DDI there was no significant difference (odds ratio = 0.94; p = 0.879). However, when controlling for the number of medication, the risk of adverse DDI was higher in younger than older prisoners, but the result was not significant. ORIGINALITY/VALUE: Older prisoners are at a higher risk of polypharmacy but their risk for potentially adverse DDI is not significantly different from that of younger prisoners. Special clinical attention must be given to older prisoners who are at risk for polypharmacy. Careful medication management is also important for younger prisoners who are at risk of very complex drug therapies.

Development and Validation of an LC-MS/MS Method and Comparison with a GC-MS Method to Measure Phenytoin in Human Brain Dialysate, Blood, and Saliva.

Phenytoin (PHT) is one of the most often used critical dose drugs, where insufficient or excessive dosing can have severe consequences such as seizures or toxicity. Thus, the monitoring and precise measuring of PHT concentrations in patients is crucial. This study develops and validates an LC-MS/MS method for the measurement of phenytoin concentrations in different body compartments (i.e., human brain dialysate, blood, and saliva) and compares it with a formerly developed GC-MS method that measures PHT in the same biological matrices. The two methods are evaluated and compared based on their analytical performance, appropriateness to analyze human biological samples, including corresponding extraction and cleanup procedures, and their validation according to ISO 17025/FDA Guidance for Industry. The LC-MS/MS method showed a higher performance compared with the GC-MS method. The LC-MS/MS was more sensitive, needed a smaller sample volume (25 µL) and less chemicals, was less time consuming (cleaning up, sample preparation, and analysis), and resulted in a better LOD (<1 ng/mL)/LOQ (10 ng/mL). The calibration curve of the LC-MS/MS method (10-2000 ng/mL) showed linearity over a larger range with correlation coefficients r2 > 0.995 for all tested matrices (blood, saliva, and dialysate). For larger sample numbers as in pharmacokinetic/pharmacodynamic studies and for bedside as well as routine analyses, the LC-MS/MS method offers significant advantages over the GC-MS method.

Free phenytoin assessment in patients: measured versus calculated blood serum levels.

BACKGROUND: Total serum drug levels are routinely determined for the therapeutic drug monitoring of selected, difficult-to-dose drugs. For some of these drugs, however, knowledge of the free fraction is necessary to adapt correct dosing. Phenytoin, with its non-linear pharmacokinetics, >90 % albumin binding and slow elimination rate, is such a drug requiring individualization in patients, especially if rapid intravenous loading and subsequent dose adaptation is needed. In a prior long-term investigation, we showed the excellent performance of pharmacy-assisted Bayesian forecasting support for optimal dosing in hospitalized patients treated with phenytoin. In a subgroup analysis, we evaluated the suitability of the Sheiner-Tozer algorithm to calculate the free phenytoin fraction in hypoalbuminemic patients. OBJECTIVE: To test the usefulness of the Sheiner-Tozer algorithm for the correct estimation of the free phenytoin concentrations in hospitalized patients. SETTING: A Swiss tertiary care hospital. METHOD: Free phenytoin plasma concentration was calculated from total phenytoin concentration in hypoalbuminemic patients and compared with the measured free phenytoin. The patients were separated into a low (35 ≤ albumin ≥ 25 g/L) and a very low group (albumin <25 g/L) for comparing and statistically analyzing the calculated and the measured free phenytoin concentration. MAIN OUTCOME MEASURES: Calculated and the measured free phenytoin concentration. RESULTS: The calculated (1.2 mg/L (SD = 0.7) and the measured (1.1 mg/L (SD = 0.5) free phenytoin concentration correlated. The mean difference in the low and the very low albumin group was: 0.10 mg/L (SD = 1.4) (n = 11) and 0.13 mg/L (SD = 0.24) (n = 12), respectively. Although the variability of the data could be a bias, no statistically significant difference between the groups was found: t test (p = 0.78), the Passing-Bablok regression, the Spearman's rank correlation coefficient of r = 0.907 and p = 0.00. The Bland-Altman plot including the regression analysis revealed no systematic differences between the calculated and the measured value [M = 0.11 (SD = 0.28)]. CONCLUSION: In absence of a free phenytoin plasma concentration measurement also in hypoalbuminemic patients, the Sheiner-Tozer algorithm represents a useful tool to assist therapeutic monitoring to calculate or control free phenytoin by using total phenytoin and the albumin concentration.

A quantitative phenytoin GC-MS method and its validation for samples from human ex situ brain microdialysis, blood and saliva using solid-phase extraction.

This study describes the development and validation of a gas chromatography-mass spectrometry (GC-MS) method to identify and quantitate phenytoin in brain microdialysate, saliva and blood from human samples. A solid-phase extraction (SPE) was performed with a nonpolar C8-SCX column. The eluate was evaporated with nitrogen (50°C) and derivatized with trimethylsulfonium hydroxide before GC-MS analysis. As the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin was used. The MS was run in scan mode and the identification was made with three ion fragment masses. All peaks were identified with MassLib. Spiked phenytoin samples showed recovery after SPE of ≥94%. The calibration curve (phenytoin 50 to 1,200 ng/mL, n = 6, at six concentration levels) showed good linearity and correlation (r² > 0.998). The limit of detection was 15 ng/mL; the limit of quantification was 50 ng/mL. Dried extracted samples were stable within a 15% deviation range for ≥4 weeks at room temperature. The method met International Organization for Standardization standards and was able to detect and quantify phenytoin in different biological matrices and patient samples. The GC-MS method with SPE is specific, sensitive, robust and well reproducible, and is therefore an appropriate candidate for the pharmacokinetic assessment of phenytoin concentrations in different human biological samples.