The Effect of Food on the Pharmacokinetics of the Potassium-Competitive Acid Blocker Vonoprazan.

Herein, we report a food-effect study of vonoprazan, an oral potassium-competitive acid blocker. In a phase 1, randomized, open-label, crossover study, healthy subjects received a single 20-mg dose of vonoprazan either following an overnight fast or 30 minutes after a high-fat breakfast. Plasma vonoprazan levels were determined at 0 hour and at 17 subsequent assessment points up to 48 hours after dosing. After a 5-day washout, subjects received a second 20-mg vonoprazan dose in the alternative fed/fasted state (identical process repeated). Twenty-four subjects completed the study. Vonoprazan exposure was not meaningfully affected by food. Geometric mean ratios for maximum concentration, area under the concentration-time curve from time 0 to 24 hours, and area under the plasma concentration-time curve extrapolated to infinity obtained under fed and fasting conditions were 1.05 (90% confidence interval, 0.98-1.12), 1.13 (1.09-1.18), and 1.15 (1.11-1.19), respectively. Four subjects experienced 6 adverse events that were all mild and considered unrelated to the study drug. Vonoprazan can be administered without regard to food intake.

Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure.

Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16-72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.

Population pharmacokinetic-pharmacodynamic modelling of the relationship between testosterone and prostate specific antigen in patients with prostate cancer during treatment with leuprorelin.

AIMS: This investigation aimed to quantitatively characterize the relationship between the gonadotropin-releasing hormone agonist leuprorelin, testosterone (T) and prostate specific antigen (PSA) concentrations over time, to aid identification of a target T concentration that optimises the balance of the benefits of T suppression whilst reducing the risk of side effects related to futile over-suppression. METHODS: Data from a single dose study to investigate the effect of leuprorelin in a 6-month depot formulation on T and PSA in prostate cancer patients were analysed using a population pharmacokinetic-pharmacodynamic modelling approach. The developed model was qualified using external data from 3 studies, in which the effect of different formulations of leuprorelin on T and PSA was evaluated in prostate cancer patients. RESULTS: The effect of leuprorelin on the relationship between T and PSA was adequately characterized by the Romero model with minor modifications, combined with a turnover model to describe the delay in response between T and PSA. The data were significantly better described when assuming a minimum PSA level that is independent on the treatment-related reduction in T, as compared to a model with a proportional reduction in PSA and T. CONCLUSIONS: The model-based analysis suggests that on a population level, reducing T concentrations below 35 ng/dL does not result in a further decrease in PSA levels (>95% of the minimal PSA level is reached). More data are required to support this relationship in the lower T and PSA range.

Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.

Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Rising TAK-438 (Vonoprazan) Doses in Healthy Male Japanese/non-Japanese Subjects.

OBJECTIVES: To evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 (vonoprazan, a potassium-competitive acid blocker) in healthy male subjects. METHODS: In two phase I, randomized, double-blind, placebo-controlled, single rising-dose studies, healthy male subjects (Japan N=84; UK N=63) received a single TAK-438 dose (1-120 mg in Japan and 1-40 mg in the UK). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (intragastric pH). RESULTS: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax up to 2 h). Estimated mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional. No clear difference in TAK-438 pharmacokinetics was observed between Japanese and non-Japanese subjects. Acid suppression was dose dependent and similar in both studies. The 24-h intragastric pH ≥4 holding time ratio with 40 mg TAK-438 was 92% in Japan and 87% in the UK. TAK-438 was well tolerated, with no adverse events reported in Japanese subjects; 10 of 63 UK subjects experienced 12 treatment-emergent adverse events (non-serious). Increases in serum gastrin and pepsinogen I and II concentrations were observed at doses ≥10 mg, but there were no changes in alanine aminotransferase concentrations. CONCLUSIONS: Single oral doses of TAK-438 20-120 mg caused rapid, profound, and 24-h suppression of gastric acid secretion in healthy male subjects, regardless of geographical region, and TAK-438 was well tolerated at all doses studied, making it a potential alternative to proton pump inhibitors for the treatment of acid-related disorders.

Acute mortality in critically ill patients undergoing echocardiography with or without an ultrasound contrast agent.

OBJECTIVES: The objective of this observational study was to compare 48-h all-cause mortality (as well as hospital stay mortality) among critically ill patients who underwent echocardiography either with or without an ultrasound contrast agent (UCA). BACKGROUND: The safety of perflutren-based UCAs has been questioned by the U.S. Food and Drug Administration (particularly when administered to critically ill patients) following rare reports of deaths or life-threatening adverse reactions that occurred in close temporal relationship to UCA administration. METHODS: This was a retrospective observational outcome study conducted in critically ill patients to compare all-cause 48-h and hospital stay mortality subsequent to echocardiography procedures performed either with or without a UCA. The study utilized discharge data from a database maintained by Premier, Inc. (Charlotte, North Carolina). Premier's database is the largest U.S. hospital-based, service-level comparative database for quality and outcomes research, and provides detailed resource utilization data along with patients' primary and secondary diagnoses and procedure billing codes. A propensity score-matching algorithm between UCA-enhanced echocardiography patients and non-contrast-enhanced echocardiography patients was utilized to reduce the potential for imbalance in covariates of selected patients in the comparison of mortality between groups. RESULTS: Patients undergoing echocardiography with a UCA had lower mortality at 48 h compared with patients undergoing non-contrast-enhanced echocardiography (1.70% vs. 2.50%), with an odds ratio = 0.66 (95% confidence interval [CI]: 0.54 to 0.80). Patients undergoing echocardiography with a UCA had lower hospital stay mortality compared with patients undergoing noncontrast echocardiography (14.85% vs. 15.66%), with an odds ratio = 0.89 (95% CI: 0.84 to 0.96). CONCLUSIONS: In critically ill, propensity-matched hospitalized patients undergoing echocardiography, use of a UCA is associated with a 28% lower mortality at 48 h in comparison with patients undergoing non-contrast-enhanced echocardiography. These results are reassuring, given previous reports suggesting an association between UCAs and increased mortality in critically ill patients.

CaRES (Contrast Echocardiography Registry for Safety Surveillance): a prospective multicenter study to evaluate the safety of the ultrasound contrast agent definity in clinical practice.

BACKGROUND: Definity (perflutren lipid microsphere) is an ultrasound contrast agent approved for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. This prospective, open-label, nonrandomized, multicenter, phase 4 surveillance registry study was conducted at 15 clinical sites in the United States and was designed to assess the risk for adverse cardiopulmonary events occurring during or within the initial 30 min after Definity administration in routine clinical practice. METHODS: Patients with suboptimal baseline images were consecutively approached regarding study participation. Safety monitoring including vital sign measurements, continuous electrocardiographic monitoring, and continuous oxygen saturation was initiated at baseline before Definity administration and then at regular intervals for 30 min after Definity injection. Patients were assessed for adverse events at 30 min after Definity administration and then contacted by telephone at 24 ± 4 hours to record any subsequent adverse events. RESULTS: A total of 1,060 patients were enrolled at 15 clinical sites. Of these, 1,053 (99.3%) received at least one dose of Definity and completed the study. No deaths, serious adverse events, or other significant adverse events occurred during this study. The overall adverse event rate was 10.8% (4.5% in patients undergoing rest echocardiography, 13% in patients undergoing rest and exercise stress echocardiography, and 27.7% in patients undergoing rest and pharmacologic stress echocardiography). The overall drug-related adverse event rate (patients with at least one adverse event reported by the principal investigator as related to Definity) was only 3.5%, and most of these (110 of 114 [96.5%]) were reported by the investigator as mild or moderate in intensity. CONCLUSIONS: Definity is well tolerated in routine clinical practice in patients with a high prevalence of cardiopulmonary disease.

Effect of caldaret on the incidence of severe left ventricular dysfunction in patients with ST-elevation myocardial infarction undergoing primary coronary intervention.

Primary percutaneous coronary intervention (PCI) decreases myocardial damage in patients with ST-elevation myocardial infarction (STEMI). Cellular reperfusion injury associated with calcium overload may limit myocardial salvage. We previously showed (CASTEMI trial) that caldaret (MCC-135), which modulates myocardial calcium handling when administered before PCI in patients with STEMI, did not change residual left ventricular (LV) function. The aim of this subanalysis was to examine whether caldaret decreases the incidence of LV dysfunction (LV ejection fraction

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients).

We sought to define acute mortality in a large multicenter cohort of hospitalized patients undergoing clinically indicated echocardiography with and without use of an ultrasound contrast agent. Although the United States Food and Drug Administration recently relaxed the issued warnings for perflutren-containing ultrasound contrast agents on May 13, 2008, concerns still exist regarding the safety of these compounds, particularly in critically ill patients. A retrospective analysis was performed using the Premier Perspective Database. Patients undergoing echocardiography during hospitalization were separated into those performed without contrast enhancement and those performed with perflutren lipid microsphere (PLM) injectable suspension contrast agent (Definity, Lantheus Medical Imaging, North Billerica, Massachusetts). Vital status within 1 day of the echocardiogram was available for all patients using hospital billing data. Between January 1, 2002 and October 31, 2007, 4,300,966 patients underwent transthoracic echocardiography at rest during hospitalization (unenhanced studies n = 4,242,712 and contrast-enhanced studies n = 58,254). Multivariate logistic regression analysis was used to compare 24-hour mortality, controlling for case mix and clinical covariates; 1-day mortality rates were 1.08% (n = 45,789 deaths) for patients undergoing noncontrast studies and 1.06% (n = 616 deaths) for patients undergoing contrast-enhanced examinations (p = 0.613). Multivariate logistic regression analysis revealed that, in patients undergoing an echocardiogram, patients receiving PLM injectable suspension contrast agent were 24% less likely to die within 1-day than patients not receiving a contrast agent (adjusted odds ratio = 0.76, 95% confidence interval 0.70 to 0.82). In conclusion, acute crude mortality was not increased in patients receiving PLM injectable suspension contrast agent. Multivariate logistic regression analysis revealed that, compared with patients not receiving a contrast agent, administration of PLM injectable suspension contrast agent during echocardiography was associated with a 24% decreased risk of mortality.

A randomized, double-blind, placebo-controlled study of the safety and efficacy of intravenous MCC-135 as an adjunct to primary percutaneous coronary intervention in patients with acute myocardial infarction: Evaluation of MCC-135 for left ventricular salvage in acute myocardial infarction (EVOLVE).

OBJECTIVES: The objective of the study was to test the hypothesis that intracellular calcium modulation by 5-methyl-2-[piperazin-1-yl] benzene sulfonic acid monohydrate (MCC-135 [Caldaret]; Mitsubishi Pharma Corporation, Osaka, Japan) would preserve left ventricular function and reduce infarct size in patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). BACKGROUND: Calcium overload inside myocytes during ischemia and reperfusion not only affects myocardial function but also may be related to myocyte necrosis. MCC-135 is the first in a new class of agents that modulate intracellular calcium overload. METHODS: Patients with acute STEMI undergoing primary PCI were randomized into placebo, low-dose, and high-dose MCC-135 groups. The predefined target population was those with anterior myocardial infarction and pre-PCI TIMI grade flow 0 or 1. Left ventricular ejection fraction (LVEF) on Day 5 was the primary end point. Secondary end points included infarct size measured by single photon emission computed tomography and by serum cardiac markers. Patients were followed up to 30 days for clinical outcome. RESULTS: Among 500 patients enrolled, 141 qualified as the target population. In this target population, there was no difference in the LVEF between 3 groups (placebo: 47.0% +/- 1.7% [mean +/- SEM], the low dose: 47.4% +/- 1.7%, the high dose: 45.1% +/- 2.0%). The infarct size on day 5 was not significantly different between the groups. The composite clinical outcome occurred in 25.5% in the placebo group, in 19.2% in the low-dose group, and in 34.2% in the high-dose group during a 30-day follow-up period (P = nonsignificant). MCC-135 appeared to be safe and well tolerated. CONCLUSION: There were no significant benefits of MCC-135 on preservation of LVEF and reduction of infarct size on day 5 in patients with STEMI undergoing primary PCI.

Relation between number of component views and accuracy of left ventricular mass determined by three-dimensional echocardiography.

Three-dimensional echocardiography (3DE) allows the accurate determination of left ventricular (LV) mass, but the optimal number of component or extracted 2-dimensional (2D) image planes that should be used to calculate LV mass is not known. This study was performed to determine the relation between the number of 2D image planes used for 3DE and the accuracy of LV mass, using cardiovascular magnetic resonance (CMR) imaging as the reference standard. Three-dimensional echocardiography data sets were analyzed using 4, 6, 8, 10 and 20 component 2D planes as well as biplane 2D echocardiography and CMR in 25 subjects with a variety of LV pathologies. Repeated-measures analysis of variance and the Bland-Altman method were used to compare measures of LV mass. To further assess the potential clinical impact of reducing the number of component image planes used for 3DE, the number of discrepancies between CMR and each of the 3DE estimates of LV mass at prespecified levels (i.e., > or =5%, > or =10%, and > or =20% difference from CMR LV mass) was tabulated. The mean LV mass by magnetic resonance imaging was 177 +/- 56 g (range 91 to 316). Biplane 2-dimensional echocardiography significantly underestimated CMR LV mass (p <0.05), but LV mass by 3DE was not statistically different from that by CMR regardless of the number of planes used. However, error variability and Bland-Altman 95% confidence intervals decreased with the use of additional image planes. In conclusion, transthoracic 3DE measures LV mass more accurately than biplane 2-dimensional echocardiography when > or =6 component 2D image planes are used. The use of >6 planes further increases the accuracy of 3DE, but at the cost of greater analysis time and potentially increased scanning times.

Results of the first clinical study of adjunctive CAldaret (MCC-135) in patients undergoing primary percutaneous coronary intervention for ST-Elevation Myocardial Infarction: the randomized multicentre CASTEMI study.

AIMS: To examine the safety and efficacy of intravenous caldaret in patients with large acute ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: STEMI patients (n=387) with > or =10 mm summed ST-deviation on electrocardiogram were randomized to receive a 48 h infusion of caldaret 57.5 mg [lower dose (LD)], caldaret 172.5 mg [higher dose (HD)], or placebo, starting before PCI. Both HD and LD were well tolerated. In 247 patients with pre-PCI TIMI 0/1, there was no effect of HD or LD on single photon emission computed tomography infarct size or ejection fraction assessed at Day 7 and Day 30. Subgroup analyses suggest that future work in patients with anterior MI might be warranted. CONCLUSION: This first human experience with caldaret prior to direct PCI for large STEMI shows a good safety profile. No evidence of efficacy was discerned. Subgroup analyses in anterior MI patients showed some effects in endpoints studied, however, these findings require confirmation in a further study if a drug effect is to be established.

A randomized, double-blind, placebo-controlled study of the safety and efficacy of intravenous MCC-135 as an adjunct to primary percutaneous coronary intervention in patients with acute myocardial infarction: rationale and design of the evaluation of MCC-135 for left ventricular salvage in acute MI (EVOLVE) study.

As a consequence of acute ischemia and reperfusion in patients with acute ST elevation myocardial infarction, calcium overload inside myocytes not only affects myocardial contraction, relaxation, and myocyte recovery following reperfusion, but also may be related to myocyte necrosis and fatal arrhythmia. MCC-135 is the first in a new class of agents that reduce intracellular calcium overload. Pre-clinical and early clinical studies yielded promising results for patients with ST elevation myocardial infarction. The Evaluation of MCC-135 for Left Ventricular Salvage in Acute MI (EVOLVE) study is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled clinical trial of 2 new doses of MCC-135 (4.5 mg/kg/48 hours and 9.0 mg/kg/48 hours) as adjunct therapy for preservation of left ventricular function and reduction of infarct size in patients undergoing primary percutaneous coronary intervention (PCI) for electrocardiographically moderate-large ST elevation myocardial infarction. The primary endpoint will be left ventricular ejection fraction on Day 5 post myocardial infarction as determined by single photon emission computed tomography (SPECT). Secondary endpoints will include SPECT and echocardiographic assessments, serum cardiac markers, clinical outcomes, and safety measures at specific time points through Day 30 post myocardial infarction. Follow-up clinical and safety assessments will be continued until Day 180. The rationale, design, and methods of the EVOLVE study are described in this paper, along with 2 sub-studies, involving a comparison of pre- and post-PCI measurements with either SPECT or echocardiography, to examine myocardial salvage and the time course of changes in myocardial infarction size and left ventricular function. MINIABSTRACT: The Evaluation of MCC-135 for Left Ventricular Salvage in Acute MI (EVOLVE) study is a Phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial of two doses of MCC-135, first in a new class of agents that reduce intracellular calcium overload, as adjunct therapy for preservation of left ventricular function and reduction of infarct size in patients with moderate-large STEMI undergoing primary PCI. The rationale, design, and methods of the EVOLVE study, along with two sub-studies, are described in this paper.