Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

Abstract

The pharmacokinetics of roxadustat are well characterized, with an apparent volume of distribution after oral administration of 22-57 L, apparent clearance of 1.2-2.65 L/h, and renal clearance of 0.030-0.026 L/h in healthy volunteers; the elimination half-life is 9.6-16 h. Plasma binding is 99% and the fraction eliminated by hemodialysis is 2.34%. As an interpretation of the pharmacodynamics of roxadustat, we proposed a concept with a hypothetical cascade of two subsequent effects, first on erythropoetin (EPO) and second on hemoglobin (delta Hb). The primary effect on EPO is observed within a few hours after roxadustat administration and can be modeled using the sigmoidal Hill equation. The concentration at half-maximum effect can be inferred at 10-36 µg/mL, the Hill coefficient at 3.3, and the effect bisection time at 10-17 h, corresponding to EPO half-life. The subsequent effect on hemoglobin (delta Hb) is observed after several weeks and can be interpreted as an irreversible, dose proportional, unsaturable effect, continuing in agreement with the lifespan of red blood cells of 63-112 days.

Effects of Roxadustat on Erythropoietin Production in the Rat Body

“…Deglycosylation-coupled Western blot analysis was performed as described previously [ 26 , 31 , 32 ]. For the Western blot of plasma Epo, 10 μL of plasma was subjected to deglycosylation with and without PNGase as described below.…”

“…The hematopoietic effects of PHD inhibitors on renal anemia in chronic kidney disease (CKD) patents have been established [ 9 , 26 , 27 ]. Whether PHD inhibitors stimulate Epo production in the liver or not is the major question.…”

Roxadustat: Not just for anemia

“…Roxadustat is an oral, potent, and reversible small molecule HIF-PHI whose molecular weight is 352.34 g/mol and chemical formula is C 19 H 16 N 2 O 5 ( Czock and Keller, 2022 ). It is a second-generation HIF-PHI that was synthesized by adding a phenoxy group to carbon-7 of the quinoline core of its precursor, FG-2261 ( Del Vecchio and Locatelli, 2018 ).…”

“…After oral administration, it usually reaches a maximum blood concentration in about 2 h ( Groenendaal-van de Meent et al, 2016a ). The absorption of roxadustat is independent of food ( Shibata et al, 2019 ), and body weight, age, gender, race, and drug dose have no significant effects on its pharmacokinetics ( Czock and Keller, 2022 ). After oral absorption, roxadustat is transported to the liver mainly via phase I oxidation by cytochrome P450 2C8 and phase II glucuronidation by uridine diphosphate glucuronyltransferase (UGT1A9) ( Groenendaal-van de Meent et al, 2021a ).…”

“…After oral absorption, roxadustat is transported to the liver mainly via phase I oxidation by cytochrome P450 2C8 and phase II glucuronidation by uridine diphosphate glucuronyltransferase (UGT1A9) ( Groenendaal-van de Meent et al, 2021a ). Its elimination half-life is approximately 9.6–16 h in healthy volunteers and approximately 18 h in patients with impaired renal function ( Rekić et al, 2021 ; Czock and Keller, 2022 ). Roxadustat is a lipophilic acid, and is therefore tightly bound (approximately 99%) to plasma proteins, and cannot be significantly removed by dialysis ( Provenzano et al, 2020 ).…”