Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100-mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug-drug interaction study received a single dose of 100-mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real-world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94. 44 (89.93-99.18) and 79.88 (72.09-88.52), respectively. In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions. Keywords drug-drug interaction, food-drug interaction, pharmacokinetics, roxadustat, spherical carbon adsorbent Chronic kidney disease (CKD) is a condition characterized by long-term decline in renal function that typically requires dialysis treatment in later stages and is often associated with other comorbidities such as hypertension, diabetes, and cardiovascular disease. 1,2Anemia is a complication that often accompanies CKD, and is characterized by reduced hemoglobin levels, resulting, in part, from the inability of the failing kidneys to produce sufficient erythropoietin. The incidence of anemia among subjects with CKD increases with the severity of disease 3 and is associated with an impaired quality of life. Roxadustat (ASP1517, FG-4592, AZD9941) is an orally active, hypoxia-inducible factor prolyl hydroxylase inhibitor 5 that promotes erythropoiesis by increasing endogenous erythropoietin. Roxadustat has demonstrated safety and efficacy in phase 2 studies by increasing hemoglobin levels in subjects with 1 Clinical Pharmacology, Development, Astellas Pharma Inc., Tokyo, Japan 2 Research Program Management, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan 3 Clinical ...
extended from the distal arch to the proximal anastomosis of the abdominal aorta. The patient was discharged from our hospital on the twentieth postoperative day.Acute aortic dissection (AAD) during surgery is initially suspected if there is a sudden onset of hypotension or volume loss with unknown cause. Although these signs of dissection were not likely to have been missed, lowered blood pressure, caused by unclamping and subsequent bleeding, may have obscured these signs in our patient. Early detection of intraoperative dissection is important because malperfusion of visceral or cervical branches, extension of the dissection to the ascending aorta, and periaortic hematoma often need additional operation. In AAD type B, medical treatment is currently the preferred method of treatment for patients without complications, and it has a very low mortality rate, of around 1% [3]. However, these patients still have a possibility of developing complications such as those described above. The results of surgery remain suboptimal in the current era, with a reported in-hospital mortality rate of 29.3%. Postoperative complications include cerebrovascular accident, paraplegia, visceral ischemia, acute renal failure, and hypovolemic shock [4]. Tools for diagnosing aortic dissection in the operating room are limited: the visual appearance of the aortic wall, aortography (if fl uoroscopy is available), and echography including TEE. To evaluate aortic dissection, TEE is regarded as a useful tool [5]. We detected, by using TEE, that the proximal extension of the dissection stopped at the distal arch and that the branches of the arch were not involved. The information for diagnosis provided by TEE was not less than that provided by postoperative CT scans. Although we used TEE in this patient for the purposes of another study, the application of TEE to noncardiac surgery is controversial [6,7]. Nevertheless, it is important for anesthesiologists not to miss the signs of this rare complication; sudden onset of hypotension or volume loss with unknown cause. Once AAD is suspected, TEE examination should be undertaken immediately, because AAD tends to have a lethal outcome, such as cardiac tamponade and shock, without early diagnosis. References 1. Strichartz SD, Gelabert HA, Moore WS (1990) Retrograde aortic dissection with bilateral renal artery occlusion after repair of infrarenal aortic aneurysm. J Vasc Surg 12:56-59 2. Fukui D, Urayama H, Kitahara H, Takano T, Kawano T, Sakaguchi M, Amano J (2003) Retrograde aortic dissection as a complication of abdominal aortic aneurysm surgery (in Japanese). Jpn J Cardiovasc Surg 32 (Suppl):416 3. Metha RH, To the editor: Acute aortic dissection (AAD) is a rare complication that occurs during open abdominal aortic aneurysm (AAA) repair [1,2]. We report a case of intraoperative retrograde aortic dissection that occurred during elective abdominal aortic aneurysmectomy. Detection of AAD by transesophageal echocardiography (TEE) led to rapid initiation of treatment.A 73-year-old man was operated f...
Background and Objective Upacicalcet sodium hydrate is a novel small-molecule calcimimetic and has potential as a therapeutic agent for secondary hyperparathyroidism. We assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of a single intravenous dose of upacicalcet in Japanese healthy adults. Method This was a single-center, double-blinded, randomized, placebo-controlled, dose-escalation study. For each cohort, eight subjects were randomly assigned at a ratio of 3:1 to receive a single injection of placebo or upacicalcet 0.01, 0.1, 1.0, or 2.5 mg. Result The plasma concentration of upacicalcet increased in a dose-dependent manner. Upacicalcet rapidly disappeared from plasma after administration. The half-life of upacicalcet was approximately 1–2 h. The major excretion route of upacicalcet was via urine. Serum intact parathyroid hormone decreased in accordance with the upacicalcet dose, from the lowest dose of 0.01 mg. Gastrointestinal disorders occurred in one patient in the 1.0 mg group and in five patients in the 2.5 mg group. All adverse events were nonserious, and no symptomatic hypocalcemia occurred. Conclusion This study showed that upacicalcet acted as a calcimimetic and was excreted in the urine unchanged with little metabolism. Moreover, upacicalcet is a small molecule and has a small volume of distribution. In addition, less than 50% of upacicalcet binds to human plasma proteins. These findings suggest that upacicalcet administered to patients undergoing hemodialysis might be expected to have a long excretion period and sustained pharmacological effect.
Background FKB327 has been developed as a biosimilar of the adalimumab reference product (RP). We compared the pharmacokinetics (PK), safety, and immunogenicity of FKB327 with those of the adalimumab RP after a single dose by subcutaneous (SC) injection in Japanese male participants. Methods Two randomized, single-blind, single-dose studies were conducted in healthy Japanese male participants to compare PK characteristics between FKB327 and the RP. Study 1 included 130 participants who were randomized in a 1:1 ratio to receive a subcutaneous injection of 40 mg of either FKB327 or the RP into the abdomen. In Study 2, another 130 subjects were randomized in a 1:1 ratio to receive either drug as in Study 1, but the drug administration site was changed to the thigh. The primary PK endpoints of both studies were area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) and maximum serum concentration; area under the concentration-time curve from time zero to 360 h was also evaluated as one of the primary endpoints in Study 1. Biosimilarity in terms of pharmacokinetics was determined if the 90% confidence interval of the mean difference in geometric mean ratio of all primary PK parameters was within the prespecified equivalence criteria (0.80–1.25). Immunogenicity and safety were also evaluated as secondary endpoints. Results The serum concentration-time profiles were comparable between the FKB327 and the RP treatment groups in both studies. Primary PK parameters were within the prespecified bioequivalence range in Study 2, although AUC0-t was slightly outside the upper side of the range in Study 1. No differences in safety profile were observed in these studies. The incidence of anti-drug antibodies (ADAs) and impact of ADAs on PK profile were similar among the treatment groups in both studies. Conclusion Biosimilarity between FKB327 and the RP after a single 40-mg SC injection was confirmed in healthy Japanese male participants by modifying the study design. Trial registration jRCT2071200058 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200058, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200058) and jRCT2071200057 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200057, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200057). Retrospectively registered 25/11/2020.
The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.
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