Effect of midostaurin on the pharmacokinetics of P-gp, BCRP, and CYP2D6 substrates: assessing potential drug-drug interactions in healthy participants : Brief title: Drug-drug interaction of midostaurin.

Purpose: Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults.

Landing force reveals new form of motion-induced sound camouflage in a wild predator.

Predator-prey arms races have led to the evolution of finely tuned disguise strategies. While the theoretical benefits of predator camouflage are well established, no study has yet been able to quantify its consequences for hunting success in natural conditions. We used high-resolution movement data to quantify how barn owls () conceal their approach when using a sit-and-wait strategy.

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

Purpose: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants.

Methods: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2.

Prospecting movements link phenotypic traits to female annual potential fitness in a nocturnal predator.

Recent biologging technology reveals hidden life and breeding strategies of nocturnal animals. Combining animal movement patterns with individual characteristics and landscape features can uncover meaningful behaviours that directly influence fitness. Consequently, defining the proximate mechanisms and adaptive value of the identified behaviours is of paramount importance.

Influence of prey availability on habitat selection during the non-breeding period in a resident bird of prey.

Background: For resident birds of prey in the temperate zone, the cold non-breeding period can have strong impacts on survival and reproduction with implications for population dynamics. Therefore, the non-breeding period should receive the same attention as other parts of the annual life cycle. Birds of prey in intensively managed agricultural areas are repeatedly confronted with unpredictable, rapid changes in their habitat due to agricultural practices such as mowing, harvesting, and ploughing.

What evidence exists on the effect of the main European lowland crop and grassland management practices on biodiversity indicator species groups? A systematic map protocol.

Background: The intensification of the agricultural practices in Europe over the last decades has drastically transformed the agroecosystems. The simplification of the landscape, the loss of semi-natural habitats and the application of chemicals on crops are known to have led to biodiversity decline in agricultural landscapes, raising substantial concerns about the loss of essential ecosystem services, such as pollination or pest control. Depending on the location, the scale and the regional context, different indicator species groups (ISGs) are often surveyed to assess the state and trend of biodiversity changes in agroecosystems.

Evaluation of drug-drug interactions between midostaurin and strong CYP3A4 inhibitors in patients with FLT-3-mutated acute myeloid leukemia (AML).

Purpose: Midostaurin, approved for the treatment of newly diagnosed, FLT3-mutated acute myeloid leukemia (AML), is metabolized by cytochrome P450 3A4 (CYP3A4). Midostaurin with concomitant strong CYP3A4 inhibitors use (e.g.

Home range size and habitat quality affect breeding success but not parental investment in barn owl males.

Life-history theory predicts that parents should balance their limited resources to maximize lifetime fitness, limiting their investment in current reproduction when the fitness value of current progeny is lower than that gained by producing offspring in the future. Here, we examined whether male barn owls (Tyto alba) breeding in low-quality habitats increased their parental effort to successfully complete offspring rearing or limited their investment by paying a fitness cost while saving energy for the future. We equipped 128 males with GPS devices between 2016 and 2020 to collect information on home range size, habitat composition, food provisioning rate to the brood and nightly distances covered.

Phase II, Randomized Study of Spartalizumab (PDR001), an Anti-PD-1 Antibody, versus Chemotherapy in Patients with Recurrent/Metastatic Nasopharyngeal Cancer.

Purpose: No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC.

Patients And Methods: Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled.

Behaviour-specific habitat selection patterns of breeding barn owls.

Background: The intensification of agricultural practices over the twentieth century led to a cascade of detrimental effects on ecosystems. In Europe, agri-environment schemes (AES) have since been adopted to counter the decrease in farmland biodiversity, with the promotion of extensive habitats such as wildflower strips and extensive meadows. Despite having beneficial effects documented for multiple taxa, their profitability for top farmland predators, like raptors, is still debated.

Differential fitness effects of moonlight on plumage colour morphs in barn owls.

The Moon cycle exposes nocturnal life to variation in environmental light. However, whether moonlight shapes the fitness of nocturnal species with distinct colour variants remains unknown. Combining data from long-term monitoring, high-resolution global positioning system tracking and experiments using prey, we show that barn owls (Tyto alba) with distinct plumage colourations are differently affected by moonlight.

Pharmacokinetics and safety of indacaterol and glycopyrronium (IND/GLY) following repeated once daily inhalation from a fixed-dose combination in healthy Chinese subjects .

Objective: Indacaterol/glycopyrronium (IND/GLY) is a once-daily fixed-dose combination of two long-acting bronchodilators: indacaterol 110 µg (long-acting β-adrenergic agonist, LABA) and glycopyrronium 50 µg (long-acting muscarinic antagonist, LAMA). This study assessed the pharmacokinetics of IND/GLY 110/50 µg following multiple once-daily inhaled administrations in healthy Chinese subjects.

Methods: This was a single-centre, open-label, multiple-dose study of inhaled IND/GLY delivered via the Breezhaler device.

Population pharmacokinetics of IND/GLY (indacaterol/glycopyrronium) in COPD patients.

Objective: Indacaterol/glycopyrronium (IND/GLY) is a fixed-dose combination (FDC) of indacaterol, an inhaled long-acting β2-agonist (LABA), and glycopyrronium, an inhaled long-acting muscarinic antagonist (LAMA), developed as a maintenance bronchodilator treatment for patients with chronic obstructive pulmonary disease (COPD). A population pharmacokinetic (PK) analysis was performed to describe the PK profiles of indacaterol and glycopyrronium following the twice daily (b.i.

Social huddling and physiological thermoregulation are related to melanism in the nocturnal barn owl.

Endothermic animals vary in their physiological ability to maintain a constant body temperature. Since melanin-based coloration is related to thermoregulation and energy homeostasis, we predict that dark and pale melanic individuals adopt different behaviours to regulate their body temperature. Young animals are particularly sensitive to a decrease in ambient temperature because their physiological system is not yet mature and growth may be traded-off against thermoregulation.

Pharmacokinetics of Glycopyrronium Following Repeated Once-Daily Inhalation in Healthy Chinese Subjects.

Background And Objectives: Glycopyrronium is a once-daily long-acting muscarinic antagonist for the maintenance treatment of patients with chronic obstructive pulmonary disease. This study assessed the pharmacokinetics of inhaled glycopyrronium 50 µg once-daily for 14 days in healthy Chinese subjects.

Methods: In this open-label study, 12 Chinese healthy subjects (six males and six females; mean age 23.

Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study.

Objective: Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects.

Methods: This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 µg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability.

Effect of dual bronchodilation with QVA149 on cardiac safety in healthy volunteers.

Objectives: QVA149 is a dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium, for the treatment of chronic obstructive pulmonary disease (COPD). Here we assess the potential of QVA149 (440/200 μg) at 4-fold the therapeutic dose for causing cardiac pharmacodynamic (PD) effects.

Methods: This double-blind, randomized study estimated the time-matched largest heart rate (HR) change and average HR change (over 24 hours) from baseline for QVA149 vs.

Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium.

Objective: Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor.

Methods: In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments.

Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach.

Aims: Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease. In this study, we used population pharmacokinetic (PK) modelling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and, in turn, to understand the impact of lung bioavailability and residence time on the choice of dosage regimen.

Methods: We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers.

Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects.

Background: Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).

Methods: Study 1 was performed in 48 healthy schoolchildren in Tanzania.

Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state.

Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state.