Validated extended multiplexed LC-MS/MS assay for the quantification of adagrasib and sotorasib in human plasma, together with four additional SMIs.

Recently, two small molecular inhibitors (SMIs) -adagrasib and sotorasib- have been introduced for targeting Kirsten rat sarcoma (KRAS) p.G12C mutations in patients with non-small cell lung cancer (NSCLC). In order to support pharmacokinetic research as well as clinical decision making, we developed and validated a simple and accurate liquid chromatography-tandem mass spectrometry method for the multiplexed quantification of adagrasib and sotorasib.

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study.

Background: There is a lack of evidence on oral amoxicillin pharmacokinetics and exposure in neonates with possible serious bacterial infection (pSBI). We aimed to describe amoxicillin disposition following oral and intravenous administration and to provide dosing recommendations for preterm and term neonates treated for pSBI.

Methods: In this pooled-population pharmacokinetic study, 3 datasets were combined for nonlinear mixed-effects modeling.

Development and validation of an HPLC-MS/MS method to simultaneously quantify brigatinib, lorlatinib, pralsetinib and selpercatinib in human K2-EDTA plasma.

A liquid chromatography-tandem mass spectrometry method was developed and validated to quantify the small-molecule inhibitors (SMIs) brigatinib, lorlatinib, pralsetinib and selpercatinib, which are used in patients with oncogenic-driven non-small cell lung cancer. Chromatographic separation was performed on a HyPURITY® C analytical column with a gradient elution using ammonium acetate in water and in methanol, both acidified with formic acid 0,1%. Detection and quantification were performed using a triple quad mass spectrometer with an electrospray ionization interface.

Development and validation of an HPLC-MS/MS method to simultaneously quantify alectinib, crizotinib, erlotinib, gefitinib and osimertinib in human plasma samples, using one assay run.

A liquid chromatography-tandem mass spectrometry method was developed and validated to quantify alectinib, crizotinib, erlotinib and gefitinib. This assay can be combined with our method for osimertinib, allowing quantification of the most used ALK- and EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer with a single-assay setup. Chromatographic separation was performed on a HyPurity® C analytical column using an elution gradient of ammonium acetate in water and in methanol, both acidified with formic acid 0.

Validation of an analytical method using HPLC-MS/MS to quantify osimertinib in human plasma and supplementary stability results.

A new method for quantification of osimertinib (OSIM) in human plasma using a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated. Methanol was used for protein precipitation and pazopanib as internal standard. Separation was performed on a HyPURITY®C analytical column (50 × 2.

Official International Association for Therapeutic Drug Monitoring and Clinical Toxicology Guideline: Development and Validation of Dried Blood Spot-Based Methods for Therapeutic Drug Monitoring.

Dried blood spot (DBS) analysis has been introduced more and more into clinical practice to facilitate Therapeutic Drug Monitoring (TDM). To assure the quality of bioanalytical methods, the design, development and validation needs to fit the intended use. Current validation requirements, described in guidelines for traditional matrices (blood, plasma, serum), do not cover all necessary aspects of method development, analytical- and clinical validation of DBS assays for TDM.

Development and validation of an analytical method using UPLC-MS/MS to quantify everolimus in dried blood spots in the oncology setting.

While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated.

Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation.

Background: Particularly in the pediatric clinical pharmacology field, data-sharing offers the possibility of making the most of all available data. In this study, we utilize previously collected therapeutic drug monitoring (TDM) data of term and preterm newborns to develop a population pharmacokinetic model for phenobarbital. We externally validate the model using prospective phenobarbital data from an ongoing pharmacokinetic study in preterm neonates.

Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants.

Aim: Direct-acting oral anticoagulants (DOACs) have become available for the prevention of stroke in patients with atrial fibrillation (AF). Conflicting results have been published on the risk of acute myocardial infarction (AMI) with the use of DOACs in comparison with vitamin K antagonists (VKAs). The objective of the present study was to evaluate the risk of AMI in patients with AF who are exposed to either VKAs, DOACs or low-dose (< 325 mg) aspirin.

Evaluation of Vancomycin Prediction Methods Based on Estimated Creatinine Clearance or Trough Levels.

Background: The aim of this study was to investigate whether vancomycin clearance (CLva) can be adequately predicted with CLva prediction methods. Additionally, other covariates influencing the CLva were investigated and predictivity of monitoring of only trough levels to 24-hour area under the curve (AUC24) was evaluated.

Methods: Routine vancomycin plasma levels were measured with a fluorescence polarization immunoassay.

Vancomycin dosing in neutropenic patients.

Background: To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia.

Methods: Patients ≥18 years admitted on general wards were included. Routinely vancomycin trough and peak plasma concentrations were measured with a fluorescence polarization immunoassay.

Is the standard dose of amoxicillin-clavulanic acid sufficient?

Background: The pharmacodynamic (PD) efficacy target of amoxicillin is 40% time above the minimal inhibition concentration (40%T > MIC). Recent studies of other antibiotics have shown that PD-efficacy targets are not always reached. The aim of this study was to evaluate the percentage of hospitalised patients, using amoxicillin/clavulanic acid intravenously (iv), that reach the pharmacodynamic efficacy target 40%T > MIC.

A non-fatal intoxication with a high-dose sodium nitrate.

A 67-year-old man accidentally ingested 75 g of sodium nitrate. He had instant gastrointestinal symptoms. On physical examination, he was respiratorily and haemodynamically stable and there were no signs of central or peripheral cyanosis.

Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation.

Introduction: Tacrolimus has originally been registered as a twice-daily formulation (Prograf, Tac BID), although a once-daily formulation (Advagraf, Tac QD) is also available. A reduced intrapatient variability of Tac Cmin, a surrogate marker for 24-hour drug exposure (AUC0-24), has been suggested. The variability of AUC0-24 has never been studied prospectively yet.

Use of biguanides and the risk of colorectal cancer: a register-based cohort study.

Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma.

The ciprofloxacin target AUC : MIC ratio is not reached in hospitalized patients with the recommended dosing regimens.

Aim: The aim of this study was to determine the ciprofloxacin serum concentrations in hospitalized patients and to determine which percentage reached the efficacy target of AUC : MIC > 125. Additionally, the influence of demographic anthropomorphic and clinical parameters on the pharmacokinetics and pharmacodynamics of ciprofloxacin were investigated.

Methods: In serum of 80 hospitalized patients ciprofloxacin concentrations were measured with reverse phase high performance liquid chromatography with fluorescence detection.

Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls.

This article reviews dried blood spot (DBS) sampling in therapeutic drug monitoring. The DBS method involves applying whole blood obtained via a fingerprick to a sampling paper. After drying and transportation, the blood spot is extracted and analyzed in the laboratory.

Dried blood spot measurement: application in tacrolimus monitoring using limited sampling strategy and abbreviated AUC estimation.

Dried blood spot (DBS) sampling and high-performance liquid chromatography tandem-mass spectrometry have been developed in monitoring tacrolimus levels. Our center favors the use of limited sampling strategy and abbreviated formula to estimate the area under concentration-time curve (AUC(0-12)). However, it is inconvenient for patients because they have to wait in the center for blood sampling.

Evaluation of limited sampling strategies for tacrolimus.

Objective: In literature, a great diversity of limited sampling strategies (LSS) have been recommended for tacrolimus monitoring, however proper validation of these strategies to accurately predict the area under the time concentration curve (AUC0-12) is limited. The aim of this study was to determine whether these LSS might be useful for AUC prediction of other patient populations.

Methods: The LSS from literature studied were based on regression equations or on Bayesian fitting using MWPHARM 3.

Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms.

Tacrolimus, an immunosuppressant used after organ transplantation, has a narrow therapeutic range and its pharmacokinetic variability complicates its daily dose assessment. P-glycoprotein (P-gp), encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) and the cytochrome (CYP) 3A4 and 3A5 enzymes appears to play a role in the tacrolimus metabolism. In the present study, two different renal transplant recipient groups were used to examine the influence of ABCB1 and CYP3A polymorphisms on the daily tacrolimus dose and several pharmacokinetic parameters.