Background and Objectives Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease. The pharmacokinetics, metabolic profile, and pharmacodynamics of roxadustat were investigated in subjects with different degrees of kidney function. Methods This phase 1 open-label study enrolled subjects with normal and severely impaired kidney function, and end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or hemodialysis/hemodiafiltration (HD/HDF). All subjects received a single 100-mg dose of oral roxadustat. Within a single-sequence, two-treatment period design (P1/P2), subjects with ESRD on HD/HDF received roxadustat 2 h after (P1) and 2 h before (P2) a dialysis session. Area under the plasma concentration–time curve (AUC) from administration to infinity (AUC inf ), maximum concentration ( C max ), and terminal elimination half-life ( t 1/2 ) were assessed for roxadustat; AUC and C max were assessed for erythropoietin. Results Thirty-four subjects were enrolled and received roxadustat (normal kidney function, n = 12; severely impaired kidney function, n = 9; ESRD on CAPD/APD, n = 1; ESRD on HD/HDF, n = 12). The geometric least-square mean ratio of AUC inf was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; C max and t 1/2 were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUC inf and t 1/2 for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and C max of erythropoietin increased in subjects with severely impaired kidney function or ESRD on HD/HDF. Roxadustat was well tolerated. Conclusions Kidney function impairment increased the AUC of roxadustat and its metabolites. The C max and t 1/2 of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040. Electronic supplementary material The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users.

The aim of this study was to evaluate the impact of renal impairment on the pharmacokinetics (PK), safety, and tolerability of daridorexant, a dual orexin receptor antagonist (DORA) intended for the treatment of insomnia. A single-center, open-label study evaluated the PK of daridorexant in patients with severe renal function impairment (SRFI, determined by creatinine clearance using the Cockcroft-Gault equation; n=8) not on dialysis, and in matched control subjects (based on sex, age, and body weight; n=7). A single oral dose of daridorexant 25 mg was orally administered in the morning. Blood samples were collected up to 72 hours postdose for PK assessments of daridorexant. In patients with SRFI, maximum plasma concentrations (C max ; geometric mean ratio [GMR] and 90% confidence interval [CI]: 0.94 [0.60-1.46]), time to reach C max (t max ; median difference [90% CI] of -0.25 hours [-0.75 to 0.25]), and half-life (GMR [90% CI] of 0.99 [0.66-1.48]), were virtually unchanged. Exposure (area under the plasma concentration-time profile) to daridorexant was slightly higher in patients with SRFI than in control subjects with the GMR (90% CI) being 1.16 (0.63-2.12). No safety issue of concern was detected as all adverse events were transient and of mild or moderate intensity, and no treatment-related effects on vital signs, clinical laboratory, or ECG variables were observed following daridorexant administration in patients with SRFI and control subjects. Based on these observations, PK alterations of daridorexant due to renal function impairment are not considered of clinical relevance and no dose adjustment is necessary in these patients.

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Trypsin-specific and trypsin-plasmin inhibitors were isolated from seminal vesicles of guinea pigs. Two different procedures were used: 1. Inhibitor material obtained from perchloric acid extracts was purified by affinity chromatography (using water insoluble trypsin resin) and gradient elution chromatography on Sulfoethyl Sephadex. Mainly two very similar trypsin-specific inhibitors and five somewhat different trypsin-plasmin inhibitors were obtained. (The amino acid compositions are given in Table 3). 2. Also by avoiding the trypsin resin step several inhibitor fractions were obtained which were differing considerably in their amino acid compositions. Inhibitors containing a lysine residue in the reactive site are reversibly inactivated by acylation with maleic anhydride; arginine inhibitors are inactivated by reaction with a butandion-2,3 reagent. In the reactive site of the trypsin-specific inhibitor the sequence Arg-Ile is present. The modified inhibitor (Argile bond is broken) is inactivated by incubation with carboxypeptidase B or reaction with excessive maleic anhydride. The native inhibitor (Arg-Ile bond intact) is converted into the modified form both during contact with the trypsin resin and by incubation with 2.3 mole percent trypsin. From acidic extracts of boar seminal plasma a trypsinplasmin inhibitor was isolated by affinity chromato-This article contains parts of E. FINK, Dissertation,

Summary: The serum concentration of several lipids, including high-density lipoprotein-cholesterol (HDL-C) and the HDL subfractions, HDL-2-C and HDL-3-C, were measured in 44 male and 26 female survivors of myocardial infarction and compared with those of a control group matched for age, sex, and body weight. Serum concentrations of total cholesterol (TC) and low-density lipoprotein (LDL-C) were significantly increased in patients as compared to control individuals. The total HDL-C concentration was lower in patients than in controls. By differential quantitation of HDL subfractions with a new precipitation method using polyethylene glycol, it was found that HDL-3-C was not significantly different between female patients and controls. The reduction of HDL-3-C in male patients was only of borderline significance. HDL-2-C in contrast was highly significantly reduced in both male and female patients. The greatest difference between patients and controls was found in the HDL-2/HDL-3-C ratio. It is therefore concluded that HDL-2-C quantitation is a valuable risk indicator for myocardial infarction yielding a better discrimination of patients from controls than total HDL-C quantitation.