Therapeutic drug monitoring of osimertinib in non-small cell lung cancer and short bowel syndrome: A case report.

Short bowel syndrome (SBS) following extensive intestinal resection is often characterized by impaired absorption of orally administered drugs, including tyrosine kinase inhibitors (TKI). We report the case of a patient with EGFR-mutated non-small cell lung carcinoma treated with 80 mg/day of the TKI osimertinib who achieved partial response of the tumour, but was subsequently subjected to a double-barrelled jejunostomy due to ileus. Due to the development of SBS after the bypass surgery, plasma concentrations of osimertinib were monitored using mass spectrometry.

CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.

Background And Objective: Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL).

Methods: At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL).

Time course of CYP3A activity during and after metamizole (dipyrone) in healthy volunteers.

Aims: In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated.

Methods: Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4 h: AUC and estimated partial metabolic clearance: eCl ) before, at steady-state, and after discontinuation of 3 × 1000 mg metamizole/day orally for 8 days.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach.

Purpose: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose.

Methods: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated.

Frailty as a Marker for the Plasma Concentrations of Direct Oral Anticoagulants in Older Patients: Results of an Exploratory Study.

Background: Frailty makes older adults vulnerable to adverse health outcomes and can modify pharmacokinetics and drug exposure.

Objective: We aimed to explore the relationship between different frailty assessments and trough plasma concentrations of direct oral anticoagulants in older patients.

Methods: The frailty status of adults aged ≥ 70 years receiving regular direct oral anticoagulant medication was assessed by four different instruments: Fried physical phenotype, Rockwood frailty index, Short Physical Performance Battery, and FRAIL scale.

Oral bioavailability of microdoses and therapeutic doses of midazolam as a 2-dimensionally printed orodispersible film in healthy volunteers.

Purpose: The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF.

Methods: Midazolam doses of 0.

The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.

Background: Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors.

Methods: We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG.

Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue.

Atrial fibrillation (AF) is an arrhythmia associated with an increased stroke risk and mortality rate. Current treatment options leave unmet needs in AF therapy. Recently, doxapram has been introduced as a possible new option for AF treatment in a porcine animal model.

Oral Drugs Against COVID-19.

Background: Five-day oral therapies against early COVID-19 infection have recently been conditionally approved in Europe. In the drug combination nirmatrelvir + ritonavir (nirmatrelvir/r), the active agent, nirmatrelvir, is made bioavailable in clinically adequate amounts by the additional administration of a potent inhibitor of its first-pass metabolism by way of cytochrome P450 [CYP] 3A in the gut and liver. In view of the central role of CYP3A in the clearance of many different kinds of drugs, and the fact that many patients with COVID-19 are taking multiple drugs to treat other conditions, it is important to assess the potential for drug interactions when nirmatrelvir/r is given, and to minimize the risks associated with such interactions.

Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans.

Purpose: To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine.

Methods: An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction).

Low Exposure to Direct Oral Anticoagulants Is Associated with Ischemic Stroke and Its Severity.

Background And Purpose: In acute stroke patients, plasma concentrations of direct oral anticoagulants (DOAC) at hospital admission only poorly mirror DOAC exposure or the coagulation status at the time of the event. Here, we evaluated whether DOAC exposure and DOAC plasma concentration at the time of transient ischemic attacks (TIA) and ischemic strokes correlate with their likelihood of occurrence.

Methods: Prospectively, consecutive DOAC patients with acute ischemic stroke or TIA were included.

Does the circulating ketoconazole metabolite N-deacetyl ketoconazole contribute to the drug-drug interaction potential of the parent compound?

Ketoconazole is a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and of P-glycoprotein (P-gp) and is often used as an index inhibitor especially for CYP3A4-mediated drug metabolism. A preliminary physiologically based pharmacokinetic (PBPK) model for drug-drug interactions indicated possible involvement of a metabolite to the perpetrator potential of ketoconazole. Still unknown for humans, in rodents, N-deacetyl ketoconazole (DAK) has been identified as the major ketoconazole metabolite.

Treatment with Edoxaban Attenuates Acute Stroke Severity in Mice by Reducing Blood-Brain Barrier Damage and Inflammation.

Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury.

Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral Factor Xa Inhibitors Administered as a Microdosed Cocktail.

Background: Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly.

Methods: In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban.

Effect of Pantoprazole on the Absorption of Hydroxychloroquinea A Randomized Drug-Drug Interaction Trial in Healthy Adults.

Hydroxychloroquine as a weak basic compound with two amines is strongly enriched in cell compartments with low pH, suggesting that modification of gastric pH by coadministered proton pump inhibitors might reduce its solubility and absorption and thus its efficacy in patients. We addressed this question in a single-center, open-label, randomized, parallel drug-drug interaction trial in healthy adults (EudraCT No. 2020-001470-30).

Bioanalysis of selinexor in mouse plasma micro-samples utilizing UPLC-MS/MS.

Selinexor, a first-in-class inhibitor of the nuclear export protein Exportin-1 (XPO1), was recently approved for the treatment of multiple myeloma in combination with dexamethasone, and as monotherapy for diffuse large B-cell lymphoma. To enable investigations of selinexor in mice, we established and validated an ultrahigh-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) assay in the plasma concentration range of 1-1000 ng/mL using plasma microsamples of 5 µL. Protein depletion with acetonitrile was used for efficient isolation of selinexor which was followed by a dilution step, resulting in a scalable sample processing.

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.

Aims: TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening.

The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model.

Background: Upregulation of the two-pore-domain potassium channel TASK-1 (hK 3.1) was recently described in patients suffering from atrial fibrillation (AF) and resulted in shortening of the atrial action potential. In the human heart, TASK-1 channels facilitate repolarization and are specifically expressed in the atria.

Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity.

Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has nonlinear pharmacokinetics (PK) after oral administration (autoinhibition of metabolism), the true impact of coadministered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose linearity of an intravenous omeprazole microdose of 100 µg and compared it with a 20-mg dose in 4 healthy poor metabolizers (PMs) and 6 extensive metabolizers (EMs) of CYP2C19 in the presence and absence of a strong inhibitor (voriconazole).

Correction to: Drug-Drug Interactions with Direct Oral Anticoagulants.

The article Drug-Drug Interactions with Direct Oral Anticoagulants, written by Kathrin I. Foerster · Simon Hermann · Gerd Mikus · Walter E. Haefeli was published under the incorrect Creative Commons (CC) license (CC-BY).

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes.

Rapid and Sensitive Quantification of Osimertinib in Human Plasma Using a Fully Validated MALDI-IM-MS/MS Assay.

The third-generation tyrosine kinase inhibitor (TKI), osimertinib, has revolutionized the treatment of patients with non-small cell lung carcinoma with epidermal growth factor receptor (EGFR)-activating mutation, and resistant to first- and second-generation TKIs. Osimertinib is now also proposed as a first-line therapy, thus extending the scope of applications in lung oncology. Personalized medicine approaches are still necessary to monitor if patients are exposed to adequate concentrations of osimertinib during their treatment.

Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): A structured summary of a study protocol for a randomised controlled trial.

Objectives: Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ). Secondary objectives: • Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells - peripheral blood mononuclear cells (PBMCs). • Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes).

A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML.