Population pharmacokinetics (PK) of riociguat in patients (pts) with renal and hepatic impairment

Background: Riociguat, an oral soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH. Aims: To characterize the population PK (PopPK) of riociguat in pts with renal and hepatic impairment. Methods: Plasma and urine samples were collected from pts in four Phase I studies; two renal impairment (n=64) and two hepatic impairment (n=64) studies, including smokers (n=56) and non-smokers (n=72). A single oral dose of riociguat 1.0 or 0.5 mg was administered. Nonlinear mixed-effects modeling was used to develop a PopPK model for riociguat and its metabolite M1. A combined, two-compartment model for riociguat and M1 was developed. Riociguat and M1 clearance (CL) was split into a renal part (filtration and excretion) and a non-renal part; the non-renal part for riociguat was split into its metabolism to M1 and a remaining non-renal part. Results: The PK of riociguat was described well by a two-compartment model. Total riociguat CL (1.912 L/h) was dominated by its metabolism to M1 (1.2 L/h). Renal CL (0.242 L/h) was mainly determined by filtration (0.174 L/h). Renal impairment reduced riociguat and M1 renal CL. Smoking increased riociguat metabolism to M1 by 3.5-fold. No effect of hepatic function biomarkers and Child–Pugh classification was found on riociguat or M1 CL. Conclusions: Riociguat and M1 renal CL was reduced by renal impairment. Similar values for the non-renal (non-metabolism) CL of riociguat were estimated in all groups; non-renal CL was increased in smokers.