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Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose ( 18F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm 2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. F Hoffmann-La Roche Ltd.

Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (C ) and areas under plasma concentration-time curves were calculated. Comparing generics against each other, the differences in point estimates of the geometric mean ratios of C of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.

Purpose Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBP and down-regulates ABCA1 and ABCG1 expression. Methods We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level. Results In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1 μM atorvastatin increased miR33 by 33 % ( P  < 0.05), and decreased ABCA1 messenger RNA (mRNA) and ABCG1 mRNA by 47 % ( P  < 0.05) and 27 % (NS), respectively. In J774A.1 mouse macrophage, labelled with 3H-cholesterol, ABCA1 mRNA and ABCA1-mediated cholesterol efflux were decreased by 1 μM statin: simvastatin > pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and dalcetrapib. When HDL was incubated with rhCETP, addition of dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1 μM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by dalcetrapib. Conclusions In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.

Taspoglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist that has >90% homology with the endogenous GLP-1 while retaining equivalent potency. Once-weekly subcutaneous injections with taspoglutide demonstrated meaningful antihyperglycemic and weight loss effects in patients with type 2 diabetes. The present study was performed to compare the relative bioavailability of taspoglutide injected subcutaneously in the abdomen, upper arm, and thigh. Healthy overweight/obese subjects were randomized in an open-label, 3-way crossover study. A single 20-mg dose of taspoglutide was injected subcutaneously on 3 occasions in the abdomen, upper arm, or thigh. Each injection was separated by a 12-week washout period. Blood was sampled up to 12 weeks for the pharmacokinetic evaluation of taspoglutide. Sixty subjects were randomized into the study (mean age, 45.5 years; body weight, 97.6 kg; and body mass index, 31.4 kg/m2). AUClast values (geometric mean) for subcutaneous injections in the abdomen, upper arm, and thigh were 44.2, 61.2, and 50.0 ng·h/mL, respectively. The geometric mean ratio (relative bioavailability) for the upper arm versus the abdomen was 1.41 (90% CI: 1.22–1.62) and for the thigh versus the abdomen was 1.13 (90% CI: 0.98–1.31). Corresponding Cmax values for subcutaneous injections in the abdomen, upper arm, and thigh were 0.268, 0.382, and 0.341 ng/mL, respectively, and the geometric mean ratio for the upper arm versus the abdomen was 1.43 (90% CI: 1.24–1.64) and for the thigh versus the abdomen was 1.27 (90% CI: 1.10–1.46). Decreases in taspoglutide exposure were observed with each subsequent period. AUClast values (geometric mean across injections sites) for periods 1, 2, and 3 were 97.2, 42.6, and 31.5 ng·h/mL, respectively. The geometric mean ratio for period 2 versus 1 was 0.44 (90% CI: 0.38–0.50) and for period 3 versus 1 was 0.32 (90% CI: 0.27–0.37). Analysis of pharmacokinetic data after first injection only (period 1) showed comparable AUClast across the 3 injection sites and lower initial Cmax after injection into the abdomen compared with the other 2 injection sites. Overall, taspoglutide was well tolerated by most subjects in all 3 injection sites, with a lower incidence of nausea and vomiting when injected in the abdomen. Regardless of a pronounced period effect, relative bioavailability of taspoglutide was different across injection sites, with the lowest exposure and incidence of nausea and vomiting seen after administration in the abdomen. In the absence of comparable bioavailability, taspoglutide was recommended to be injected into the abdomen.

Preclinical studies have reported that the relative bioavailability of dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ∼60% higher when administered in the fed state compared with the fasting state. This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of dalcetrapib in healthy male subjects. Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC 0–36 or AUC 0–∞, C max) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG. Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m 2). Dalcetrapib exposure was increased by 64% (AUC 0–36) and 126% (C max) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m 2). When dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean dalcetrapib AUC 0–∞ (7400 and 7860 ng · h/mL, respectively) and C max (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC 0–∞ (14.3%–14.7%) and C max (25.5%–35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m 2). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC 0–∞ (34.9%) and C max (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated. Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated.

Fenofibrate and extended-release (ER) niacin similarly raise high-density lipoprotein cholesterol (HDL-C) concentration but their effects on levels of potent plasma antioxidant xanthophylls (lutein and zeaxanthin) and phytosterols obtained from dietary sources, and any relationship with plasma lipoproteins and pre-β1-HDL levels, have not been investigated. We studied these parameters in 66 dyslipidemic patients treated for 6 week with fenofibrate (160 mg/day) or ER-niacin (0.5 g/day for 3 week, then 1 g/day) in a cross-over study. Both treatments increased HDL-C (16 %) and apolipoprotein (apo) A-I (7 %) but only fenofibrate increased apoA-II (28 %). Lutein and zeaxanthin levels were unaffected by fenofibrate but inversely correlated with percentage change in apoB and low-density lipoprotein cholesterol and positively correlated with end of treatment apoA-II. ApoA-II in isolated HDL in vitro bound more lutein than apoA-I. Xanthophylls were increased by ER-niacin (each ~30 %) without any correlation to lipoprotein or apo levels. Only fenofibrate markedly decreased plasma markers of cholesterol absorption; pre-β1-HDL was significantly decreased by fenofibrate (−19 %, p  < 0.0001), with little change (3.4 %) for ER-niacin. Although fenofibrate and ER-niacin similarly increased plasma HDL-C and apoA-I, effects on plasma xanthophylls, phytosterols and pre-β1-HDL differed markedly, suggesting differences in intestinal lipidation of HDL. In addition, the in vitro investigations suggest an important role of plasma apoA-II in xanthophyll metabolism.

Dalcetrapib, an inhibitor of cholesteryl ester transfer protein, raises HDL cholesterol levels. In this clinical trial involving patients with an acute coronary syndrome, dalcetrapib had no beneficial effect on clinical outcomes, despite raising HDL cholesterol levels. High-density lipoproteins (HDLs) participate in the process of cellular cholesterol efflux and may have additional protective effects against atherothrombosis. 1 An inverse association between levels of HDL cholesterol and incident events of coronary heart disease has been shown in observational studies 2 , 3 and persists in most post hoc analyses and meta-analyses of trials of statin therapy for patients with cardiovascular risk factors, chronic cardiovascular disease, or recent acute coronary syndrome. 4 – 10 However, it remains uncertain whether pharmacologic intervention that raises HDL cholesterol levels results in decreased cardiovascular risk. 11 – 16 Moreover, changes in HDL cholesterol levels may not reflect changes in the . . .

The standard combination of intravenous fluorouracil plus leucovorin for adjuvant treatment of colon cancer was compared with the oral fluoropyrimidine capecitabine in almost 2000 patients with resected colon cancer. With disease-free survival as the primary end point, capecitabine was at least as effective as fluorouracil plus leucovorin. The oral drug had fewer side effects than the intravenous combination. With disease-free survival as the primary end point, capecitabine was at least as effective as fluorouracil plus leucovorin. The oral drug had fewer side effects than the intravenous combination. Almost 1 million patients receive a diagnosis of colorectal cancer yearly, and half a million deaths from this neoplasm occur annually worldwide. 1 Each year, approximately 230,000 patients with colon cancer are eligible for adjuvant chemotherapy. 1 – 3 The benefits of fluorouracil-based adjuvant chemotherapy in reducing the risk of relapse and prolonging survival in patients with resected colon cancer are well established, particularly in stage III disease. 4 – 6 Survival advantages were demonstrated with bolus intravenous fluorouracil plus leucovorin administered according to the Mayo Clinic regimen (five days, monthly, for six months) or the Roswell Park regimen (weekly bolus, six of every eight . . .

Purpose Alectinib, a central nervous system (CNS)-active ALK inhibitor, has demonstrated efficacy and safety in ALK + non-small-cell lung cancer that has progressed following crizotinib treatment. Other ALK inhibitors have shown concentration-dependent QTc prolongation and treatment-related bradycardia. Therefore, this analysis evaluated alectinib safety in terms of electrophysiologic parameters. Methods Intensive triplicate centrally read electrocardiogram (ECG) and matched pharmacokinetic data were collected across two alectinib single-arm trials. Analysis of QTcF included central tendency analysis [mean changes from baseline with one-sided upper 95% confidence intervals (CIs)], categorical analyses, and relationship between change in QTcF and alectinib plasma concentrations. Alectinib effects on other ECG parameters (heart rate, PR interval and QRS duration) were also evaluated. Results Alectinib did not cause a clinically relevant change in QTcF. The maximum mean QTcF change from baseline was 5.3 ms observed pre-dose at week 2. The upper one-sided 95% CI was <10 ms at all time points. There was no relevant relationship between change in QTcF and alectinib plasma concentrations. Alectinib treatment resulted in a generally asymptomatic exposure-dependent decrease in mean heart rate of ~11 to 13 beats per minute at week 2. No clinically relevant effects were seen on other ECG parameters. Approximately 5% of patients reported cardiac adverse events of bradycardia or sinus bradycardia; however, these were all grade 1–2. Conclusions Alectinib does not prolong the QTc interval or cause changes in cardiac function to a clinically relevant extent, with the exception of a decrease in heart rate which was generally asymptomatic.

Cardiovascular outcome trials (CVOTs) have been employed in multiple therapeutic areas to explore whether a noncardiovascular drug increases the risk for cardiovascular events. These studies are now a central part of drug development programs for antihyperglycemic drugs. These programs are expected to demonstrate that new antihyperglycemic drugs for patients with Type 2 diabetes do not have unacceptable cardiovascular risk. The hazard ratio, which is usually provided as evidence that patients receiving the investigational treatment are not at statistically significantly greater cardiovascular risk than patients on the control treatment, can be difficult to interpret for various reasons. Therefore, an alternative approach known as the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. Additionally, detailed considerations are given on how to design a non-inferiority CVOT using the RMST approach. The RMST methodology is shown to be a practical alternative to the hazard ratio methodology for designing a non-inferiority CVOT.