Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed.

Methods

We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE.

Results

PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions.

Conclusions

These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies.

Trial registration

ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.

     

Impact of transducer frequency setting on speckle tracking measures

Speckle tracking echocardiography is an emerging technique, which is currently being included in clinical guidelines. We sought to investigate the impact of transducer frequency settings on speckle tracking derived measures. The study comprised of 22 subjects prospectively enrolled for a randomized controlled trial (LOOP-study, Clinicaltrials.gov:NCT02036450). Patients were above 70 years of age with increased risk of stroke, and had an echocardiogram performed, which included focused images of the left ventricle. Focused images were obtained with the transducer frequency set at both 1.7/3.3 and 1.5/3.0 MHz. The images were obtained immediately after each other at the exact same position for the two settings. Speckle tracking was performed in three apical projections, allowing for acquisition of layered global longitudinal strain (GLS) and strain rate measures. Concordance between the frequency settings was tested for endo-, mid-, and epicardial GLS and strain rates by coefficients of variation, bias coefficients and visually displayed by Bland–Altman plots. Bland–Altman plots did not reveal any significant over- or underestimation of any speckle tracking measure. Bias coefficients showed that none of the measurements differed significantly between the two settings (bias for GLS_endo?=???0.07?±?2.94, p?=?0.91; GLS_mid?=?0.02?±?2.70, p?=?0.98, GLS_epi?=?0.07?±?2.53, p?=?0.90). Coefficients of variation were as follows: GLS_endo?=?15.11%, GLS_mid?=?15.28%, GLS_epi?=?17.26%, systolic strain rate?=?15.66%, early diastolic strain rate?=?38.46%, late diastolic strain rate?=?11%. Changing between transducer frequency settings does not systematically derange speckle tracking measures. One can safely reduce the transducer frequency without compromising the validity of speckle tracking derived measures.     

Qualitative angiographic and quantitative myocardial perfusion assessment using fluorescent cardiac imaging during graded coronary artery bypass stenosis

Intraoperative graft assessment in coronary artery bypass (CAB) grafting is important to avoid early graft failure. This study aimed to evaluate the accuracy of fluorescent cardiac imaging (FCI) for intraoperative qualitative angiographic and quantitative myocardial perfusion assessment during graded CAB stenosis compared to coronary angiography (CA). After CAB grafting to the left anterior descending coronary artery, graded distal bypass stenoses were created in ten pigs by 25, 50, 75, and 100% flow reduction assessed by transit-time flow measurement (TTFM). Visual angiographic assessment was performed by FCI and CA during baseline and graded bypass stenoses. Altered myocardial perfusion was assessed by quantitative intraoperative fluorescence intensity (QIFI) derived from FCI and correlated to TTFM. Patent bypass grafts and graft occlusion were visualized successfully by FCI and CA, while discrimination between various graded bypass stenosis was possible in 73.3%. The degree of CAB stenosis was overestimated in 16.7% and underestimated in 10.0% by FCI compared to CA. Graded CAB stenosis reduced regional myocardial perfusion quantified by decreased QIFI value (p?<?0.001). Mean QIFI value was 76.8 (95% CI 67.2–86.3) during baseline, 55.6 (95% CI 45.3–65.9) during 25% flow-reduction, 30.6 (95% CI 22.3–39.0) during 50% flow-reduction, 20.3 (95% CI 15.4–25.3) during 75% flow-reduction, and 0 during CAB occlusion (p?<?0.001) with a significant correlation to TTFM (r?=?0.955; p?<?0.0001). Solely visual assessment of CAB quality using FCI is limited as compared to CA. Additional QIFI assessment identified graded CAB stenosis and occlusion with a significant correlation to TTFM.     

Imaging the myocardial ischemic cascade

Non-invasive imaging plays a growing role in the diagnosis and management of ischemic heart disease from its earliest manifestations of endothelial dysfunction to myocardial infarction along the myocardial ischemic cascade. Experts representing the North American Society for Cardiovascular Imaging and the European Society of Cardiac Radiology have worked together to organize the role of non-invasive imaging along the framework of the ischemic cascade. The current status of non-invasive imaging for ischemic heart disease is reviewed along with the role of imaging for guiding surgical planning. The issue of cost effectiveness is also considered. Preclinical disease is primarily assessed through the coronary artery calcium score and used for risk assessment. Once the patient becomes symptomatic, other imaging tests including echocardiography, CCTA, SPECT, PET and CMR may be useful. CCTA appears to be a cost-effective gatekeeper. Post infarction CMR and PET are the preferred modalities. Imaging is increasingly used for surgical planning of patients who may require coronary artery bypass.     

Cardiac myxoma: a contemporary multimodality imaging review

Cardiac myxoma (CM) is by far the most common primary benign cardiac tumor, typically arising in the left atrium with an attachment point in the fossa ovalis region. Although the etiology of CM remains unclear, we know that this endocardial-based mass originates from undifferentiated mesenchymal cells. Continuous technical improvements in the field of echocardiography since the 1960s has profoundly changed the diagnostic approach by allowing a good tumor detection as well as the preoperative planning by providing crucial information concerning the attachment point location. However, echocardiography has its limitations among which lack of tissue characterization and restricted field of view can arise diagnosis difficulties in atypical presentations. With the widespread and routine use of echocardiography and chest computed tomography (CT), incidental detection of CM is not infrequent. As a consequence, it has become mandatory for cardiologists and radiologists evolving in a multimodality imaging world to be familiar with the wide range of presentations of this tumor. The authors present here a review of the common and less common aspects of CM using the main imaging modalities available: echocardiography, cardiovascular magnetic resonance imaging, CT, positron emission tomography and coronary angiography.     

The effectiveness of interventions to reduce the household economic burden of illness and injury: a systematic review

Objective

To determine the nature, scope and effectiveness of interventions to reduce the household economic burden of illness or injury.

Methods

We systematically reviewed reports published on or before 31 January 2014 that we found in the CENTRAL, CINAHL, Econlit, Embase, MEDLINE, PreMEDLINE and PsycINFO databases. We extracted data from prospective controlled trials and assessed the risk of bias. We narratively synthesized evidence.

Findings

Nine of the 4330 studies checked met our inclusion criteria – seven had evaluated changes to existing health-insurance programmes and two had evaluated different modes of delivering information. The only interventions found to reduce out-of-pocket expenditure significantly were those that eliminated or substantially reduced co-payments for a given patient population. However, the reductions only represented marginal changes in the total expenditures of patients. We found no studies that had been effective in addressing broader household economic impacts – such as catastrophic health expenditure – in the disease populations investigated.

Conclusion

In general, interventions designed to reduce the complex household economic burden of illness and injury appear to have had little impact on household economies. We only found a few relevant studies using rigorous study designs that were conducted in defined patient populations. The studies were limited in the range of interventions tested and they evaluated only a narrow range of household economic outcomes. There is a need for method development to advance the measurement of the household economic consequences of illness and injury and facilitate the development of innovative interventions to supplement the strategies based on health insurance.     

Normalizing Glutamine Concentration Causes Mitochondrial Uncoupling in an In Vitro Model of Human Skeletal Muscle

Background: Glutamine has been considered essential for rapidly dividing cells, but its effect on mitochondrial function is unknown. Materials and Methods: Human myoblasts were isolated from skeletal muscle biopsy samples (n = 9) and exposed for 20 days to 6 different glutamine concentrations (0, 100, 200, 300, 500, and 5000 µM). Cells were trypsinized and manually counted every 5 days. Seven days before the end of exposure, half of these cells were allowed to differentiate to myotubes. Afterward, energy metabolism in both myotubes and myoblasts was assessed by extracellular flux analysis (Seahorse Biosciences, Billerica, MA). The protocol for myoblasts was optimized in preliminary experiments. To account for different mitochondrial density or cell count, data were normalized to citrate synthase activity. Results: Fastest myoblast proliferation was observed at 300 µM glutamine, with a significant reduction at 0 and 100 µM. Glutamine did not influence basal oxygen consumption, anaerobic glycolysis or respiratory chain capacity. Glutamine significantly (P = .015) influenced the leak through the inner mitochondrial membrane. Efficiency of respiratory chain was highest at 200–300 µM glutamine (~90% of oxygen used for adenosine triphosphate synthesis). Increased glutamine concentration to 500 or 5000 µM caused mitochondrial uncoupling in myoblasts and myotubes, decreasing the efficiency of the respiratory chain to ~70%. Conclusion: Glutamine concentrations, consistent with moderate clinical hypoglutaminemia (300 µM), bring about an optimal condition of myoblast proliferation and for efficiency of aerobic phosphorylation in an in vitro model of human skeletal muscle. These data support the hypothesis of hypoglutaminemia as an adaptive phenomenon in conditions leading to bioenergetic failure (eg, critical illness).