Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01095-x.