Background:Although diuretic resistance leading to residual congestion is a known predictor of a poorer heart failure (HF) prognosis, better therapeutic strategies for effective and safe decongestion ...have not been established.Methods and Results:In this study, 81 HF patients with fluid retention (despite taking ≥40 mg/day furosemide (FUR)), with an estimated glomerular filtration rate <45 mL/min/1.73 m2, were randomized into 2 groups and administered either ≤15 mg/day additive tolvaptan (TLV) or ≤40 mg/day increased FUR for 7 days. Changes in urine volume between baseline and mean urine volume during treatment were significantly higher in the TLV than FUR group (P=0.0003). Although there was no significant decrease in body weight or improved signs and symptoms of congestion between the 2 groups, the increase in serum creatinine on Day 7 from baseline was significantly smaller in the TLV than FUR group (P=0.038). Multiple logistic regression analysis revealed that additive TLV (odds ratio 0.157, 95% confidence interval 0.043–0.605, P=0.001) was an independent clinical factor for improved renal function during treatment compared with increased FUR.Conclusions:In HF patients with residual congestion and renal dysfunction refractory to standard therapy, additive TLV increased urine volume without further renal impairment compared with patients who received an increased dose of FUR.
The relationship between drug concentration and QTc interval is typically evaluated by applying the standard analysis model proposed in a scientific whitepaper by Garnett et al. (
...https://doi.org/10.1007/s10928-017-9558-5
). The model is a mixed effects model in which a baseline QTc interval is included as a covariate. Two or more baseline QTc intervals are sometimes observed for a study participant, such as time-matched baselines on a baseline day in parallel studies, or pre-dose baselines in each period in crossover studies. In such situations, the baseline adjustments are not straightforward because these baselines correlate with not only the corresponding QTc intervals after drug administration, but also other QTc intervals at different timepoints for parallel studies, or those in different periods for crossover studies. In this study, we compared three analysis models through simulations and clinical study examples in settings in which two or more baselines were observed for a subject. We compared a model without baseline adjustment, a model with baseline adjustment, and a model in which baseline and baseline mean were included as covariates. In the simulations and clinical study examples, the model with baseline and baseline mean as covariates demonstrated higher accuracy and power than the other models. This model assumed a specific covariance structure in QTc intervals, which well approximated the correlations between QTc intervals within and between days. When there are two or more baselines in concentration-QTc analyses, the baseline mean should be included as a covariate in addition to the corresponding baseline.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Blood is a commonly used biofluid for biomarker discovery. Although blood lipid metabolites are considered to be potential biomarker candidates, their fundamental properties are not well ...characterized. We aimed to (1) investigate the matrix type (serum vs. plasma) that may be preferable for lipid biomarker exploration, (2) elucidate age- and gender-associated differences in lipid metabolite levels, and (3) examine the stability of lipid metabolites in matrix samples subjected to repeated freeze-thaw cycles. Using liquid chromatography-mass spectrometry, we performed lipidomic analyses for fasting plasma and serum samples for four groups (15 subjects/group) of young and elderly (25-34 and 55-64 years old, respectively) males and females and for an additional aliquot of samples from young males, which were subjected to repeated freeze-thaw cycles. Lysophosphatidylcholine and diacylglycerol levels were higher in serum than in plasma samples, suggesting that the clotting process influences serum lipid metabolite levels. Gender-associated differences highlighted that the levels of many sphingomyelin species were significantly higher in females than in males, irrespective of age and matrix (plasma and serum). Age-associated differences were more prominent in females than in males, and in both matrices, levels of many triacylglycerols were significantly higher in elderly females than in young females. Plasma and serum levels of most lipid metabolites were reduced by freeze-thawing. Our results indicate that plasma is an optimal matrix for exploring lipid biomarkers because it represents the original properties of an individual's blood sample. In addition, the levels of some blood lipid species of healthy adults showed gender- and age-associated differences; thus, this should be considered during biomarker exploration and its application in diagnostics. Our fundamental findings on sample selection and handling procedures for measuring blood lipid metabolites is important for ensuring the quality of biomarkers identified and its qualification process.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study was a comprehensive analysis of metabolites in plasma and urine specimens from subjects who received probenecid, a potent inhibitor of renal organic anion transporters (OATs). Taurine and ...glycochenodeoxycholate sulfate (GCDCA-S) could be identified using authentic standards. Probenecid had no effect on the area under the plasma-concentration time curves of taurine and GCDCA-S, whereas it significantly inhibited their urinary excretion in a dose-dependent manner. Probenecid at 500, 750, and 1500 mg orally decreased the renal clearance (CL
) values of taurine and GCDCA-S by 45% and 60%, 59% and 79%, and 70% and 88%, respectively. The CL
values correlated strongly (r > 0.96) between the test compounds (benzylpenicillin, 6β-hydroxycortisol, taurine, and GCDCA-S). Taurine and GCDCA-S were substrates of OAT1 and OAT3, with K
values of 379 ± 58 and 64.3 ± 3.9 μM, respectively. The K
values of probenecid for the OAT1- and OAT3-mediated uptake of taurine and GCDCA-S (9.49 ± 1.27 and 7.40 ± 0.70 μM, respectively) were similar to those of their typical substrate drugs. The magnitude of the reduction in the CL
of taurine and GCDCA-S by probenecid could be reasonably explained using the geometric mean values of unbound probenecid concentration and K
values. These results suggest that taurine and GCDCA-S can be used as probes for evaluating pharmacokinetic drug-drug interactions involving OAT1 and OAT3, respectively, in humans.
Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD.
A phase 3, multicenter, randomized, double blind, placebo-controlled study ...investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m(2)) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5-4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment.
The mean change in serum phosphate was -1.29 mg/dl (95% confidence interval, -1.63 to -0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, -0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline median, -142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo.
In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.
Aims
Elobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat ...in Japanese patients with chronic constipation.
Methods
This study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.
Results
Food consumption reduced systemic exposure by around 80% e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.
Conclusions
Elobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Concentration–QTc (C–QTc) modeling is being increasingly used in phase 1 studies. For studies without a placebo arm (single arm studies), the scientific whitepaper by Garnett et al. (
...https://doi.org/10.1007/s10928-017-9558-5
) states that time-matched baseline adjustments may minimize the effect of diurnal variation in QTc intervals, and categorical time effects are not needed in the model. However, how diurnal variations can be accounted for when only pre-dose baselines are available is unclear. This research investigates whether including categorical time effects in the model can adjust diurnal variation in single arm studies with pre-dose baselines, where QTc prolongation is evaluated at a concentration of interest based on ΔQTc at 24 h and ΔΔQTc (a model-derived difference in ΔQTc from concentration zero). To understand the operating characteristics for the models with and without categorical time effects, simulations were conducted under various scenarios considering oncology early phase studies. When the C–QTc relationship is linear, models without categorical time effects provided biased estimates for model parameters and inflated or decreased false negative rates (FNRs) depending on the pattern of diurnal variations in QTc intervals, whereas models with categorical time effects caused no biases and controlled the FNRs. For non-linear C–QTc relationships, ΔΔQTc estimations made using the model with categorical time effects were not robust. Thus, for single arm studies where only pre-dose baselines are available, we recommend collecting QTc measurements at 24 h and estimating ΔQTc at a concentration of interest at 24 h using the C–QTc model with categorical time effects.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Serum metabolites can reflect the diffusion/export of biochemicals from various organs. They can serve as biomarkers related to diseases and therapeutic efficacy/toxicity. While studies in Caucasians ...suggested that subject gender and age can affect circulating metabolite profiles, the Japanese population has not been surveyed. Our objective was to delineate gender- and age-associated differences in serum metabolite profiles among Japanese populations. Using a mass spectrometry-based global metabolomics approach, 516 endogenous metabolites were detected in sera from Japanese individuals. The principal component analysis identified gender as the primary component, followed by age, suggesting that these two criteria were key contributors to variations in the dataset. Gender-associated differences were observed in 31 and 25% of metabolites in the young (age 25–35) and old (ages 55–65) populations, respectively, in redox homeostasis, and in steroid and purine nucleotide metabolism pathways. Age-associated differences were observed in 24 and 23% of metabolites in men and women, respectively. No pathway was commonly highlighted. Thus, gender and age impact on metabolite profiles in the Japanese population. Our results provide useful information to explore biomarkers for clinical applications in the Japanese population and to assess the applicability of known biomarkers identified in other populations to the Japanese population.
Background
Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical studies indicated the ...possibility that the concomitant use of the non-steroidal anti-inflammatory drug oxaprozin affects the pharmacokinetics of dotinurad. We evaluated drug–drug interactions with respect to the pharmacokinetics and safety of dotinurad when co-administered with oxaprozin.
Methods
This was an open-label, two-period, add-on study in healthy adult males. For a single dose of 4 mg of dotinurad with and without oxaprozin, we compared its pharmacokinetic parameters and evaluated safety.
Results
This study enrolled 12 subjects, 11 of whom completed the study. The geometric mean ratio (90% confidence interval CI) of the urinary excretion rate of glucuronate conjugates of dotinurad after co-administration with oxaprozin compared to administration of dotinurad alone was 0.657 (0.624–0.692), while the geometric mean ratios (90% CIs) of the maximum plasma concentration and area under the plasma concentration–time curve from time zero to infinity (AUC
0–inf
) were 0.982 (0.945–1.021) and 1.165 (1.114–1.219), respectively. During the study, two adverse events occurred after administration of dotinurad alone and one occurred after administration of oxaprozin alone.
Conclusions
In comparison with administration of dotinurad alone, co-administration with oxaprozin was associated with a 34.3% decrease in the urinary excretion rate of the glucuronate conjugates of dotinurad, and a 16.5% increase in AUC
0–inf
of dotinurad. However, no clinically meaningful drug–drug interactions were observed. Administration of dotinurad alone was similar safety to co-administration with oxaprozin.
Clinical trial registration
ClinicalTrials.gov Identifier: NCT03350386.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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