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Zinpentraxin alfa is a recombinant form of the human pentraxin‐2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd‐generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st‐ and 2nd‐generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double‐blind, 2‐sequence crossover, sequential 2‐stage study (ISRCTN59409907), single intravenous (IV) doses of 1st‐ and 2nd‐generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd‐ compared to the 1st‐generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st‐ and 2nd‐generation drug products, and antidrug antibody (ADA) was not observed in this study. [ABSTRACT FROM AUTHOR]

Increased blood pressure (BP) is observed in patients with impaired baroreflexes after water drinking. The stimulus for this effect is low blood osmolality, and it has been termed the osmopressor response (OPR). The BP increase is associated with activation of the sympathetic nervous system and a requirement for transient receptor potential vanilloid 4 (TRPV4) channels. However, the mechanisms underlying the OPR are poorly understood. We tested the hypothesis that hypotonicity is sensed in the portal area to initiate the OPR. Sino-aortic denervated mice were used and BP was monitored for 30 min after fluid infusion while mice were under anesthesia. Infusion of hypotonic fluid (0.45% saline), but not of isotonic 0.9% saline, directly into the portal vein, produced an immediate OPR (increase in BP with saline 0.45%: 15 ± 13 vs. 0.9%: − 7 ± 2 mm Hg, p = 0.003; AUC: 0.45%: 150 ± 99, n = 7 vs. 0.9%: − 74 ± 60 mm Hg·min, n = 5, p = 0.003). However, 0.45% saline was not able to trigger a similar response in TRPV4 −/− mice (ΔBP TRPV4 : − 2 ± 5 mm Hg, n = 8, p = 0.009). Hypotonic saline did not raise BP when infused at the same speed and volume into the jugular vein (jugular: − 5 ± 6 mm Hg, p = 0.002, compared to portal). Denervation of the splanchnic nerve by celiac ganglionectomy (CGX) did not abolish the OPR (CGX: 15 ± 11 vs. Sham: 16 ± 6 mm Hg, p = 0.34). Renal denervation diminished the OPR elicited by duodenal water infusion (denervation: 9 ± 4 vs. sham: 31 ± 15 mm Hg, p = 0.016). Therefore, hypotonicity in the portal circulation, probably sensed by TRPV4 channels, triggers the OPR and intact renal nerves are needed for the full response. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52‐week, placebo‐controlled TULIP‐1 and TULIP‐2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21‐gene type I interferon gene signature (21‐IFNGS) in patients with high IFNGS. The pharmacokinetic/pharmacodynamic relationship was analyzed graphically and modeled with a nonlinear mixed‐effects model. British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response rates were compared across 21‐IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 were IFNGS high. Over 52 weeks, higher average anifrolumab serum concentrations were associated with increased median 21‐IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12‐52), lower and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with week 24 anifrolumab trough concentration exceeding the IC80 (3.88 μg/mL) was greater with anifrolumab 300 mg vs anifrolumab 150 mg (≈83% vs ≈27%), owing to the higher estimated median trough concentration (15.6 vs 0.2 μg/mL). BICLA response rates increased with 21‐IFNGS neutralization; more patients had a BICLA response in the highest vs lowest neutralization quartiles at week 52 (58.1% vs 37.6%). In conclusion, anifrolumab 300 mg every 4 weeks rapidly, substantially, and sustainably neutralized the 21‐IFNGS and was associated with clinical efficacy, supporting this dosing regimen in patients with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]