Extracellular Vesicles as Surrogates for the Regulation of the Drug Transporters ABCC2 (MRP2) and ABCG2 (BCRP).

Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity.

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.

Differential Effect of a Continental Breakfast on Tacrolimus Formulations With Different Release Characteristics.

Food reduces tacrolimus bioavailability after immediate-release tacrolimus (IR-Tac) and after a new prolonged-release tacrolimus formulation (PR-Tac), when using a high-fat breakfast, but the effects of a continental breakfast on PR-Tac are unknown. In an open-label, 4-phase, randomized, 2-sequence, crossover pharmacokinetic trial, 36 healthy volunteers (18 females) received single 5-mg tacrolimus doses as PR-Tac and as IR-Tac fasted or with a standardized continental breakfast. Tacrolimus pharmacokinetics were analyzed using noncompartmental methods and mixed-model analysis of variance.

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways.

Background: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making.

Prolonged-Release Tacrolimus Is Less Susceptible to Interaction With the Strong CYP3A Inhibitor Voriconazole in Healthy Volunteers.

The nature and extent of drug-drug interactions between oral drugs is affected by numerous modulators. The effect of the formulation (prolonged release (PR) vs. immediate release (IR)) of a victim drug during treatment with a CYP3A (cytochrome P450 enzyme 3A4) inhibitor is unknown but expected to be smaller with PR.

Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided.

Aims: We assessed the potential mutual interaction of oral macitentan (cytochrome P450 (CYP) 3A4 substrate) at steady-state with single-dose oral rivaroxaban (CYP3A4 and P-glycoprotein substrate) and evaluated the effect of the CYP3A and P-glycoprotein inducer St John's wort (SJW) on the pharmacokinetics of these drugs in healthy volunteers.

Methods: Twelve healthy volunteers completed this open-label, monocentre, two-period, one-sequence phase I clinical trial. The pharmacokinetics of macitentan (10 mg) was assessed on study days 3 (single dose), 15 (steady-state), 16 (impact of rivaroxaban) and 29 (after induction by oral SJW), and of rivaroxaban on days 2 (single dose), 16 (impact of macitentan at steady-state) and 29 (after induction by SJW).

Dried-Blood-Spot Technique to Monitor Direct Oral Anticoagulants: Clinical Validation of a UPLC-MS/MS-Based Assay.

Plasma concentrations of direct oral anticoagulants (DOACs) vary largely between individuals, and they correlate well with desired and adverse outcomes. Although regular concentration monitoring of DOACs is not recommended, information on DOAC exposure could be useful in situations when multiple DOAC-clearance pathways are impaired or nonadherence is suspected. Self-sampling techniques, like the use of dried-blood spots (DBSs), would be particularly useful because they enable the collection of information in ambulatory patients at relevant points in time of the dosing interval (e.

Simultaneous quantification of direct oral anticoagulants currently used in anticoagulation therapy.

Direct oral anticoagulants (DOACs) are among the most effective options to prevent serious thromboembolic events in patients with atrial fibrillation. Coagulation assays are used to assess DOAC activity, but lack the possibility to quantify drugs with concurrent pharmacodynamic effect. We developed a selective multi-drug assay to analyze apixaban, betrixaban, dabigatran, edoxaban, edoxaban M4, and rivaroxaban with ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) in plasma fulfilling all requirements of the FDA und EMA guidelines for bioanalytical method validation.

Pharmacokinetics and Clinical Outcomes of Generic Tacrolimus (Hexal) Versus Branded Tacrolimus in De Novo Kidney Transplant Patients: A Multicenter, Randomized Trial.

Background: Scrupulous comparison of the pharmacokinetic and clinical characteristics of generic tacrolimus formulations versus the reference drug (Prograf) is essential. The pharmacokinetics of the Tacrolimus Hexal (TacHexal) formulation is similar to Prograf in stable renal transplant patients, but data in de novo patients are lacking.

Methods: De novo kidney transplant patients were randomized to generic tacrolimus (TacHexal) or Prograf in a 6-month open-label study.

Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment.

Background: Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH).

Objective: The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments.

Methods: PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations.

Urinary Calprotectin Differentiates Between Prerenal and Intrinsic Acute Renal Allograft Failure.

Background: Urinary calprotectin has recently been identified as a promising biomarker for the differentiation between prerenal and intrinsic acute kidney injury (AKI) in the nontransplant population. The present study investigates whether calprotectin is able to differentiate between these 2 entities in transplant recipients as well.

Methods: Urinary calprotectin was assessed by enzyme-linked immunosorbent assay in 328 subjects including 125 cases of intrinsic acute allograft failure, 27 prerenal graft failures, 118 patients with stable graft function, and 58 healthy controls.

Impact of de novo donor-specific HLA antibodies detected by Luminex solid-phase assay after transplantation in a group of 88 consecutive living-donor renal transplantations.

De novo donor-specific HLA antibodies (DSA) after renal transplantation are known to be correlated with poor graft outcome and the development of acute and chronic rejection. Currently, data for the influence of de novo DSA in patient cohorts including only living-donor renal transplantations (LDRT) are limited. A consecutive cohort of 88 LDRT was tested for the occurrence of de novo DSA by utilizing the highly sensitive Luminex solid-phase assay for antibody detection.

Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-β.

Purpose: In glioma-in contrast to various other cancers-the impact of T-lymphocytes on clinical outcome is not clear. We investigated the clinical relevance and regulation of T-cell infiltration in glioma.

Experimental Design: T-cell subpopulations from entire sections of 93 WHO°II-IV gliomas were computationally identified using markers CD3, CD8, and Foxp3; survival analysis was then done on primary glioblastomas (pGBM).