Akebia Therapeutics, Inc., Cambridge, Massachusetts, USA.
Clin Pharmacol Drug Dev. 2022 Apr;11(4):475-485. doi: 10.1002/cpdd.1033. Epub 2022 Feb 16.
Vadadustat is a hypoxia-inducible factor prolyl-hydroxylase inhibitor being developed for the treatment of anemia in patients with chronic kidney disease. Sequelae of chronic kidney disease include hyperphosphatemia and anemia, which are frequently treated with phosphate binders and iron supplements, respectively. Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. In study 1, 54 healthy women and men were administered vadadustat (300 mg) alone and 1 hour before, concurrently with, or 2 hours after a phosphate binder (sevelamer carbonate 1600 mg, calcium acetate 1334 mg, or ferric citrate 2000 mg). In study 2, 10 healthy men were administered vadadustat (450 mg) alone and concomitantly with the oral iron supplement ferrous sulfate (325 mg [equivalent to 65 mg of elemental iron]). Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, or ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve from time 0 to infinity were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders. Vadadustat was well tolerated when administered in conjunction with phosphate binders or an iron supplement.
瓦达昔他司是一种低氧诱导因子脯氨酰羟化酶抑制剂，目前正在开发用于治疗慢性肾脏病患者的贫血。慢性肾脏病的后遗症包括高磷血症和贫血，这两种情况通常分别采用磷酸盐结合剂和铁补充剂治疗。两项评估健康成年参与者单次口服瓦达昔他司与磷酸盐结合剂或铁补充剂联合用药的药代动力学、安全性和耐受性的研究正在进行中。在研究 1 中，54 名健康女性和男性分别接受了单独使用瓦达昔他司（300 毫克）以及在 1 小时前、同时或 2 小时后与磷酸盐结合剂（司维拉姆碳酸 1600 毫克、醋酸钙 1334 毫克或柠檬酸铁 2000 毫克）联合用药。在研究 2 中，10 名健康男性分别接受了单独使用瓦达昔他司（450 毫克）以及与口服铁补充剂硫酸亚铁（325 毫克[相当于 65 毫克元素铁]）同时使用。与司维拉姆碳酸、醋酸钙、柠檬酸铁或硫酸亚铁联合用药时，瓦达昔他司的暴露量减少。通过磷酸盐结合剂和硫酸亚铁，瓦达昔他司的几何均数比值（AUC0-∞）的比值减少了 37%至 55%。然而，当瓦达昔他司在磷酸盐结合剂前 1 小时给药时，瓦达昔他司暴露量的 90%置信区间在+50%至-33%的无效应边界内，表明通过在磷酸盐结合剂前 1 小时给药，可以减少药物相互作用。当与磷酸盐结合剂或铁补充剂联合使用时，瓦达昔他司的耐受性良好。
