Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat

Abstract

Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)-sGC-cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food and as crushed or whole tablets. Riociguat exposure shows pronounced interindividual (60%) and low intraindividual (30%) variability in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), and is therefore administered using an individual dose-adjustment scheme at treatment initiation. The half-life of riociguat is approximately 12 h in patients and approximately 7 h in healthy individuals. Riociguat and its metabolites are excreted via both renal (33-45%) and biliary routes (48-59%), and dose adjustment should be performed with particular care in patients with moderate hepatic impairment or mild to severe renal impairment (no data exist for patients with severe hepatic impairment). The pharmacodynamic effects of riociguat reflect the action of a vasodilatory agent, and the hemodynamic response to riociguat correlated with riociguat exposure in patients with PAH or CTEPH in phase III population pharmacokinetic/pharmacodynamic analyses. Riociguat has a low risk of clinically relevant drug interactions due to its clearance by multiple cytochrome P450 (CYP) enzymes and its lack of effect on major CYP isoforms and transporter proteins at therapeutic levels. Riociguat has been approved for the treatment of PAH and CTEPH that is inoperable or persistent/recurrent after surgical treatment.

Fig. 1

Chemical structure of riociguat (methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate)

Fig. 2

Summary of riociguat mass-balance, excretion-pattern, distribution, and clearance properties in humans. All numbers are approximate; sum of percentages is 90–95%, which is the recovery of radiolabel in the human mass-balance study (n = 4). Percentages separated by dashes indicate minimum–maximum observed values in the mass-balance study. Ae _ur amount excreted into urine, Ae _fec amount excreted into bile/feces, CL _sys systemic (plasma) clearance, CL _R renal clearance (via glomerular filtration), CYP cytochrome P450, F _abs absolute bioavailability, M1, M3, and M4 metabolites M1 (BAY 60-4552), M3, and M4, V _ss volume of distribution at steady state

Fig. 3

Relationship between riociguat plasma concentration and heart rate over 1 min, described using a sigmoid E _max model. Relative change in heart rate = 1 + [(0.47 × Cp)/(82.3 + Cp)]. The shaded area represents the effective concentrations as characterized using the sigmoid E _max model. Cp riociguat plasma concentration, EC ₅₀ half maximal effective concentration, E ₅₀ half of E_max, E _max estimated maximal effect. Reproduced from Frey R, et al. J Clin Pharmacol. 2008;48(8):926–34, with permission. Copyright © 2008 John Wiley & Sons, Inc.