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.

Fig. 1

Chemical structure of roxadustat

Fig. 2

Reversible effect–concentration correlation between roxadustat and EPO. When roxadustat concentrations rise, EPO levels start increasing, with a 5 h delay. When roxadustat concentrations decrease, the EPO levels decline faster here in animals than in humans [16]. EPO erythropoetin, t_max time to reach maximum concentration, C_max maximum concentration, AUC area under the concentration-time curve, t_peak time to peak concentration, AUEC area under the effect-time curve

Fig. 3

Roxadustat pharmacodynamics of the effect (E₁) on EPO. By graphical analysis, a TED₅₀ of 10 h can be seen from the published diagram [8]. The TED₅₀ corresponds to a pharmacodynamic EPO t_½ of 10 h. EPO erythropoetin, TED₅₀ effect bisection time, BIW twice weekly, t_½ elimination half-life

Fig. 4

Roxadustat multiple-dose pharmacokinetics in a semi-logarithmic diagram. With repetitive dosing, no accumulation occurs. A t_½ of 8.5 h can be estimated by graphical analysis. t_½ elimination half-life

Fig. 5

Roxadustat effect on EPO and hemoglobin concentrations (ΔHb). With repetitive dosing, roxadustat concentrations rise and fall (Fig. 4), and, subsequently, EPO concentrations rise and fall (left). In contrast to the effect (E₁) on EPO, the effect (E₂) on hemoglobin (∆Hb) steadily increases (right). The fluctuating EPO effect (E₁) is reversible and the sustained ΔHb effect (E₂) might be interpreted as an irreversible effect. EPO erythropoetin, BIW twice weekly