Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll-like receptors 7 and 8.

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll-like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double-blind, placebo-controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single-dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple-dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo-stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open-label, one-way crossover study in the 25 mg single-dose cohort. Single- and multiple-oral doses of enpatoran up to 200 mg were well tolerated and no significant dose-limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose-proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure-dependent inhibition of ex vivo-stimulated interleukin-6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID-19 pneumonia.

Evobrutinib, a covalent Bruton's tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants.

The highly selective, covalent Bruton's tyrosine kinase inhibitor evobrutinib is under investigation for treatment of patients with multiple sclerosis (MS). Early clinical studies in healthy participants and patients with relapsing MS indicated that evobrutinib is well-tolerated and effective. We undertook a mass balance study in six men who received a single 75-mg oral dose of evobrutinib containing ~ 3.6 MBq (100 µCi) 14 C-evobrutinib, to determine the absorption, metabolic pathways, and routes of excretion of evobrutinib. The primary objectives of this phase I study (NCT03725072) were to (1) determine the rates and routes of total radioactivity excretion, including the mass balance of total drug-related radioactivity in urine and feces, (2) assess the pharmacokinetics (PKs) of total radioactivity in blood and plasma, and (3) characterize the plasma PKs of evobrutinib. Exploratory end points included identifying and quantifying evobrutinib and its metabolites in plasma and excreta (urine and feces) and exploring key biotransformation pathways and clearance mechanisms. Evobrutinib was primarily eliminated in feces (arithmetic mean percentage, SD, 71.0, 2.1) and, to a lesser extent, in urine (20.6, 2.0), with most of the total radioactivity (85.3%) excreted in the first 72 h after administration. No unchanged evobrutinib was detected in excreta. Evobrutinib was rapidly absorbed and substantially metabolized upon absorption. Only one major metabolite M463-2 (MSC2430422) was identified in plasma above the 10% of total drug exposure threshold, which classifies M463-2 (MSC2430422) as a major metabolite according to the US Food and Drug Administration (FDA; metabolites in safety testing [MIST]) and the European Medicines Agency (EMA; International Conference on Harmonization [ICH] M3). These results support further development of evobrutinib and may help inform subsequent investigations.

Elastomer coils for wearable MR detection.

PURPOSE: To explore the use of conductive elastomer for MR signal detection and the utility of this approach for wearable detector arrays. METHODS: An elastomer filled with silver microparticles was used to form stretchable radiofrequency coils for MR detection. Their electrical performance in terms of the Qunloaded and Q ratio was assessed in the relaxed state and under repeated strain up to 40%. In a phantom imaging study, the signal-to-noise ratio yield of conductive elastomer coils was compared with that of a reference copper coil. Four elastomer coils were integrated with a stretchable textile substrate to form a wearable array for knee imaging. The array was employed for multiple-angle and kinematic knee imaging in vivo. RESULTS: The elastomer coils proved highly stretchable and mechanically robust. Upon repeated stretching by 20%, a medium-sized coil element settled at Qunloaded of 42 in the relaxed state and 32 at full strain, reflecting sample-noise dominance. The signal-to-noise ratio of elastomer coils was found to be 8% to 16% lower than that achieved with a conventional copper coil. Multiple-angle and kinematic knee imaging with the wearable array yielded high-quality results indicating robustness of detection performance against stretching and warping of the array. CONCLUSION: Conductive elastomer is a viable material for MR detection. Coils made from this material reconcile high stretchability and adequate electrical performance with ease of manufacturing. Conductive elastomer also offers inherent restoring forces and is readily washable and sanitizable, making it an excellent basis of wearable detector front ends.

Publisher Correction: Detector clothes for MRI: A wearable array receiver based on liquid metal in elastic tubes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Detector clothes for MRI: A wearable array receiver based on liquid metal in elastic tubes.

In modern magnetic resonance imaging, signal detection is performed by dense arrays of radiofrequency resonators. Tight-fitting arrays boost the sensitivity and speed of imaging. However, current devices are rigid and cage-like at the expense of patient comfort. They also constrain posture, limiting the examination of joints. For better ergonomics and versatility, detectors should be flexible, adapt to individual anatomy, and follow posture. Towards this goal, the present work proposes a novel design based on resonators formed by liquid metal in polymer tubes. Textile integration creates lightweight, elastic devices that are worn like pieces of clothing. A liquid-metal array tailored to the human knee is shown to deliver competitive image quality while self-adapting to individual anatomy and adding the ability to image flexion of the joint. Relative to other options for stretchable conductors, liquid metal in elastic tubes stands out by reconciling excellent electrical and mechanical properties with ease of manufacturing.

An In-Bore Receiver for Magnetic Resonance Imaging.

In magnetic resonance imaging, the use of array detection and the number of detector elements have seen a steady increase over the past two decades. As a result, per-channel analog connection via long coaxial cable, as commonly used, poses an increasing challenge in terms of handling, safety, and coupling among cables. This situation is exacerbated when complementary recording of radiofrequency transmission or NMR-based magnetic field sensing further add to channel counts. A generic way of addressing this trend is the transition to digital signal transmission, enabled by digitization and first-level digital processing close to detector coils and sensors in the magnet bore. The foremost challenge that comes with this approach is to achieve high dynamic range, linearity, and phase stability despite interference by strong static, audiofrequency, and radiofrequency fields. The present work reports implementation of a 16-channel in-bore receiver, performing signal digitization and processing with subsequent optical transmission over fiber. Along with descriptions of the system design and construction, performance evaluation is reported. The resulting device is fully MRI compatible providing practically equal performance and signal quality compared to state-of-the-art RF digitizers operating outside the magnet. Its use is demonstrated by examples of head imaging and magnetic field recording.

On the Bending and Stretching of Liquid Metal Receive Coils for Magnetic Resonance Imaging.

The eGaIn coil on neoprene demonstrated in this paper presents a stretchable radio frequency receive coil for magnetic resonance imaging (MRI). The coil with dimensions [Formula: see text] is tuned to resonate at 128 MHz for 3 T MRI. We investigate the effect of stretching (up to 40% strain) and bending (50 mm radius of curvature) of the coil on the coil's resistance and resonance frequency. Measurements and simulations show a decrease in resonance frequency of 2.5 MHz per 10% strain. The higher resistivity of liquid metal compared to copper reduces the SNR of MRI scans by 34%; therefore, a tradeoff between flexibility and performance remains. Nevertheless, we have successfully performed MRI scans with the liquid metal coil.

Automatic Resonance Frequency Retuning of Stretchable Liquid Metal Receive Coil for Magnetic Resonance Imaging.

Stretchable magnetic resonance (MR) receive coils show shifts in their resonance frequency when stretched. An in-field receiver measures the frequency response of a stretchable coil. The receiver and coil are designed to operate at 128 MHz for a 3T MR scanner. Based on the measured frequency response, we are able to detect the changes of the resonance frequency of the coil. We show a proportional-integral-derivative controller that tracks the changes in resonance frequency and retunes the stretchable coil. The settling time of the control loop is less than 3.8ms. The retuning system reduces the loss in signal-to-noise ratio of phantom images from 1.6 dB to 0.3 dB, when the coil is stretched by 40% and the coil is retuned to 128 MHz.

Effect of multiple oral doses of linagliptin on the steady-state pharmacokinetics of a combination oral contraceptive in healthy female adults: an open-label, two-period, fixed-sequence, multiple-dose study.

BACKGROUND: Linagliptin is an oral dipeptidyl peptidase (DPP)-4 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. Microgynon® 30 is a combined oral contraceptive pill containing both ethinylestradiol 30 µg and levonorgestrel 150 µg (EE 30 µg/LNG 150 µg). OBJECTIVE: The objective of this study was to determine the effect of multiple doses of linagliptin (5 mg once daily) on the steady-state pharmacokinetics of EE and LNG following once-daily doses of EE 30 µg/LNG 150 µg. METHODS: This was an open-label, two-period, fixed-sequence, multiple-dose study, consisting of a run-in period, a 14-day reference treatment period and a 7-day test treatment period. The study recruited 18 healthy pre-menopausal female subjects aged 18-40 years with a body mass index of 18.5-27.0 kg/m2. Only women with regular menstrual cycles were included in this study. The treatment sequence was divided into three steps: an individually tailored run-in period with EE 30 µg/LNG 150 µg to synchronize the menstrual cycles of the subjects followed by a washout period of 7 days; the reference treatment period, during which EE 30 µg/LNG 150 µg alone was taken on days 1-14; and the test treatment period, during which EE 30 µg/LNG 150 µg plus linagliptin were taken on days 15-21. The pharmacokinetic parameters measured were maximum steady-state plasma concentration during a dosage interval (C(max,ss)), time to reach maximum plasma concentration following administration at steady state (t(max,ss)) and area under the plasma concentration-time curve during a dosage interval (τ) at steady state (AUC(τ,ss)). RESULTS: The AUC(τ,ss) and C(max,ss) of EE and LNG were comparable when EE 30 µg/LNG 150 µg was given alone or combined with linagliptin. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of EE following EE 30 µg/LNG 150 µg plus linagliptin versus EE 30 µg/LNG 150 µg alone were 101.4 (90% CI 97.2, 105.8) and 107.8 (90% CI 99.7, 116.6), respectively. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of LNG following EE 30 µg/LNG 150 µg plus linagliptin versus EE 30 µg/LNG 150 µg alone were 108.8 (90% CI 104.5, 113.3) and 113.5 (90% CI 106.1, 121.3), respectively. The combination was well tolerated. CONCLUSION: Linagliptin had no clinically relevant effect on the steady-state pharmacokinetics of EE and LNG in healthy female subjects, and the combination of EE 30 µg/LNG 150 µg and linagliptin was well tolerated in this study. Therefore, linagliptin has the potential to be used in the treatment of female patients with type 2 diabetes in combination with oral contraceptives containing these components, such as EE 30 µg/LNG 150 µg. TRIAL REGISTRATION: The EudraCT number for this study is 2008-000953-37.

The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.

AIM: To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QT(c) interval in healthy subjects. METHODS: The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QT(c) I) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. RESULTS: Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QT(c) I, at any time point. The placebo-corrected MCfB of QT(c) I was -1.1 (90% CI -2.7, 0.5) ms and -2.5 (-4.1, -0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QT(c) I with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS: Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation.

Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects.

OBJECTIVE: The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration. METHODS: In this randomized, two-period crossover study 11 evaluable healthy subjects received single doses of fingolimod 1.25 mg orally and 1 mg intravenously infused over 2 h. The pharmacokinetics of fingolimod, blood lymphocyte counts and heart rate were characterized for 28 days after each dose. RESULTS: After oral administration, Cmax was 1.1+/-0.2 ng/ml occurring at 12 h postdose and the AUC was 201+/-31 ng.h/ml. After intravenous infusion, Cmax was 4.9+/-0.8 ng/ml, AUC was 175+/-50 ng. h/ml, clearance was 6.3+/-2.3 l/h and distribution volume was 1199+/-260 l. The oral/intravenous ratio of dose-normalized AUCs was 0.94 (95%CI: 0.78-1.12). The pharmacologically active metabolite fingolimod-phosphate was quantifiable near its peak after oral administration but not after intravenous administration. The mean lymphocyte nadir occurred on day 1 and was 35% lower after oral (0.74x10(9)/l) than after intravenous (1.15x10(9)/l) administration. Lymphocytes recovered to the normal range by day 15 for both treatments. The mean heart rate nadir occurred 3-4 h postdose and was 11% lower after oral administration (47 bpm) versus intravenous administration (53 bpm). CONCLUSIONS: Average systemic exposure to fingolimod was similar after oral and intravenous administration. However, the acute decrease in lymphocyte counts was weaker after intravenous administration, likely because of lower blood levels of the active metabolite fingolimod-phosphate compared with oral administration.

Pharmacokinetic evaluation of three different intramuscular doses of nandrolone decanoate: analysis of serum and urine samples in healthy men.

The pharmacokinetics of nandrolone in serum and urine were investigated in healthy young men after a single im injection of 50 mg (n = 20), 100 mg (n = 17), or 150 mg (n = 17) nandrolone decanoate. Blood samples were collected before treatment and for up to 32 d after dosing. In addition, in the 50- and 150-mg groups, 24-h urine samples were collected before treatment and on d 1, 7, and 33 after treatment; in the 150-mg group, additional samples were collected after 3 and 6 months. Serum concentrations and the area under the curve of nandrolone increased proportionally with the dose administered. The peak serum concentration ranged from 2.14 ng/ml in the 50-mg group to 4.26 ng/ml in the 100-mg group and 5.16 ng/ml in the 150-mg group. The peak serum concentration was reached after 30 h (50 and 100 mg) and 72 h (150 mg), whereas the terminal half-life was 7-12 d. In urine, pretreatment concentrations of 19-norandrosterone (19-NA) and/or 19-noretiocholanolone (19-NE) were detected in five of 37 subjects (14%). In the 50-mg group, 19-NA and/or 19-NE could be detected at least until 33 d after injection in 16 of 17 subjects (94%). In the 150-mg group, who were presumed to have not previously used nandrolone, nandrolone metabolites could be detected for up to 6 months in eight of 12 subjects (67%) for 19-NE and in 10 of 12 subjects (83%) for 19-NA.

Effect of rifampin on apparent clearance of everolimus.

OBJECTIVE: To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration. METHODS: In this open-label, single-sequence, crossover study, 12 healthy subjects received a single oral 4-mg dose of everolimus alone and again after an 8-day pretreatment with rifampin 600 mg/d. Urinary excretion of 6beta-hydroxycortisol was measured at various time points during rifampin treatment as a marker of CYP3A4 induction. RESULTS: Urine excretion of 6beta-hydroxycortisol was significantly elevated during treatment with rifampin compared with prestudy, indicating enzyme induction. When everolimus was coadministered during rifampin treatment, the apparent clearance of everolimus was significantly increased, on average by 172%. This was manifested as a decrease in maximum concentration in all subjects, on average by 58% (range 14-73%). The AUC remained unaffected in 1 subject (although 6beta-hydroxycortisol indicated enzyme induction) and decreased in the other 11 subjects. The average decrease in AUC in the full study population was 63% (range 0-82%). Everolimus half-life was reduced significantly, from an average of 32 hours to 24 hours. CONCLUSIONS: In everolimus-treated patients for whom rifampin is indicated, alternative agents with less enzyme induction potential than rifampin could be considered. Alternatively, the dose of everolimus could be individually titrated based on everolimus therapeutic drug monitoring during rifampin therapy.