Case Report: Torsade de Pointes Induced by the Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Osimertinib Combined With Litsea Cubeba.

Torsades de Pointes (TdP) occurred in a 68-year-old female with epidermal growth factor receptor (EGFR) mutant lung cancer administered osimertinib, the third-generation EGFR tyrosine kinase inhibitor (TKI). Electrocardiogram (ECG) recorded at Tdp showed QT prolongation (QTc = 515 ms), to which a Traditional Chinese Medicine (TCM) named "Litsea Cubeba" may have contributed. After discontinuation of osimertinib and Litsea Cubeba, magnesium supplementation, potassium supplementation, lidocaine infusion, and the pacemaker frequency adjustment, Tdp terminated. However, QT prolongation sustained at discharge (QTc = 528 ms), partly because of the emergency use of amiodarone. Osimertinib may prolong the QT interval leading to TdP, especially when multiple risk factors to lengthen QT interval are incidentally overlapped. Thus, regular monitoring of ECG and appropriate management of concomitant drugs are highly recommended.

Pharmacokinetics of Esomeprazole in Critically Ill Patients.

BACKGROUND: Esomeprazole, a potent proton pump inhibitor (PPI), is widely used for the prevention of stress ulcers in intensive care unit (ICU) patients. OBJECTIVE: This study investigates the pharmacokinetics (PK) of esomeprazole in critically ill patients. METHODS: The study included eligible adult ICU patients who received endotracheal intubation assisted mechanical ventilation for more than 48 h and had at least an extra risk factor for stress ulcers. All enrolled patients received once-daily intravenous (IV) esomeprazole 40 mg. After the first dose of esomeprazole was administrated, serial blood samples were collected at 3, 5, 15, 30 min and 1, 2, 4, 6, 8, and 10 h. The total sample concentrations of esomeprazole were measured by UPLC-MS/MS. Esomeprazole PK parameters were analyzed using noncompartmental analysis. RESULTS: A total of 30 patients were evaluable. Mean age and body mass index (BMI) were 61.97 years and 23.14. PK sampling on the first dose resulted in the following median (IQR) parameters: AUC0-∞ 8.06 (6.65-9.47) mg·h/L; MRT0-∞ 4.70 (3.89-5.51) h; t1/2 3.29 (2.7-3.87) h; V 24.89 (22.09-27.69) L; CL 6.13 (5.01-7.26) L/h; and Cmax 2.56 (2.30-2.82) mg/L. CONCLUSIONS: According to the label of esomeprazole, our study showed different esomeprazole PK parameters in ICU patients compared with healthy volunteers. Esomeprazole has unique pharmacokinetic parameters in critically ill patients.

Effects of Plasma Albumin on the Pharmacokinetics of Esomeprazole in ICU Patients.

OBJECTIVES: To evaluate the effects of plasma albumin on pharmacokinetics of esomeprazole in ICU patients. METHODS: This study was performed in 32 consecutive intensive care unit (ICU) patients. They were divided into two groups according to the plasma albumin levels. Nineteen patients with low plasma albumin levels (<30 g/L; male/female, 12/7) were assigned to low plasma albumin group (LPAG). Thirteen patients with plasma albumin levels >30 g/L (male/female, 9/4) were assigned to high plasma albumin group (HPAG). All patients were received intravenous (IV) of 40 mg esomeprazole in 5 min. Blood samples were collected via basilic vein at different time points and concentrations of esomeprazole were determined by UPLC-MS/MS. RESULTS: MRT(0-∞), t1/2, V, CL, and Cmax between two groups were significantly difference (P<0.05). Compared with HPAG, MRT(0-∞), t1/2, and V of esomeprazole in LPAG were increased by 1.42-fold, 1.49-fold, and 1.24-fold, respectively; the maximum drug concentration of esomeprazole in LPAG was decreased to 82.5%. AUC(0-∞) of LPAG was 1.23 times than that of group B. CL in LPAG was 80% of HPAG. There was no statistical difference between the two groups of AUC(0-∞) and CL. CONCLUSIONS: Some pharmacokinetic parameters of esomeprazole may be changed in ICU patients with low plasma albumin.

Determination of xanthotoxin using a liquid chromatography-mass spectrometry and its application to pharmacokinetics and tissue distribution model in rat.

A simple and selective liquid chromatography mass spectrometry method for determination of xanthotoxin in rat plasma and various tissues for pharmacokinetic was developed. Chromatographic separation was achieved on a C18 (2.1 mm × 150 mm, 5 µm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 217 for xanthotoxin and m/z 326 for the internal standard. The resulting calibration curves offered satisfactory linearity (R(2) > 0.99) within the test range. Mean recoveries of xanthotoxin in rat plasma were in the range of 79.9%-84.6%. RSD of intra-day and inter-day precision were both < 14%. The accuracy of the method ranged from 87.5% to 109.8%. The assay was successfully applied to the pharmacokinetics and tissue distribution model studies of xanthotoxin in rats. The oral bioavailability of xanthotoxin was 73.2% in rats.

Tissue distribution model and pharmacokinetics of nuciferine based on UPLC-MS/MS and BP-ANN.

Nuciferine has shown remarkable biological activities and been considered as a promising drug. In this study, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of nuciferine in tissue and plasma. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 296.0→265.1 for nuciferine, and m/z 322.0→307.0 for berberrubine internal standard (IS). Based on the UPLC-MS/MS method, the tissue distribution profile of nuciferine in mice and plasma pharmacokinetics in rat were studied. The results showed nuciferine was absorbed through intestinal tract and distributed into tissues rapidly. The bioavailability of nuciferine was identified at 17.9%. It can across through blood brain barrier, the concentrations in liver and kidney are highest, then followed by spleen, lung heart and brain. Nuciferine is eliminated quickly in the tissues and plasma, the t1/2 within 5 hour. The concentrations in these tissues are correlated to each other, and can be predicted by a back-propagation artificial neural network model.