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PAH: treatment

half-life of seven to nine hours.12


The findings that riociguat can cause maternal and foetal toxicity could be associated with the exaggerated pharmacological effects (vasodilation, blood pressure lowering) of the foetus, and riociguat should not be administered to pregnant women. Therefore, reliable contraception must be provided in patients receiving riociguat. The co- administration with NO-donors, nitrates, and PDE5 inhibitors is contraindicated12 as hypotension may occur. No pharmacodynamic interactions were observed between riociguat and warfarin (the single dose of warfarin led to a slight decrease (16%) in maximum concentration of riociguat in plasma, which is not likely to be clinically relevant15

) and aspirin.

with PAH. However, the treatment with PDE-5 inhibitors is not always effective in PH patients and needs to be combined with other available treatments. An alternative therapeutic strategy targets downstream components of the NO signalling pathway is the stimulation of sGC.

sGC stimulators Previous sGC stimulators, BAY 41-2272 and BAY 41-8543 (Bayer Healthcare AG, Wuppertal, Germany), demonstrated beneficial effects in experimental models of PH, but were associated with unfavourable drug metabolism and pharmacokinetic properties. The potent sGC stimulator, riociguat (BAY 63-2521, Bayer Healthcare AG, Wuppertal, Germany) was identified, exhibiting an improved profile and exerting strong effects on pulmonary haemodynamics.


The chemical name of BAY 63-2521 (riociguat) is methyl 4,6-diamino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b] pyridine-3-yl]-5-pyrimidinyl(methyl) carbamate and its chemical formula is C20

H19 FN8 O2 . The structural formula is

shown in Figure 2.12 As shown in vitro, riociguat has a dual mode of action:12

it 24

sensitises sGC to low levels of NO and directly stimulates sGC, thereby increasing cGMP levels independently of NO. In animal models of PH, riociguat improved pulmonary haemodynamics, partially reversed right ventricular

hypertrophy and muscularisation of small pulmonary arteries13

and improved right

ventricular function by suppressing pulmonary vascular remodelling.14 Because riociguat is metabolised via the cytochrome P450 (CYP) pathways, CYP1A1, CYP2C8, CYP2J2, CYP3A4 and not CYP3A5 to the metabolite M-1, the concomitant use with strong multipathway CYP and P-glycoprotein- breast cancer resistance protein (P-gp/ Bcrp) inhibitors, such as azole antimycotics (ketoconazole, itraconazole), strong P-gp inhibitors (cyclosporine A), HIV protease and CYP1A1 inhibitors (such as the tyrosine kinase inhibitor, erlotinib) is not recommended, because of the pronounced increase in riociguat exposure. Riociguat has a nearly complete absolute bioavailability following oral administration (94%), and a terminal

Clinical studies with riociguat Healthy volunteers

Riociguat demonstrated a favourable safety profile and was well tolerated in healthy white, black, Hispanic and Asian subjects with renal or hepatic impairment, confirmed in more than 30 clinical pharmacology studies.16

Riociguat showed

the expected pharmacodynamic effects with dose-dependent increases in heart rate, slight reductions in diastolic blood pressure, no clinically relevant reductions in systolic blood pressure and concurrent increase in plasma cGMP. Doses up to 2.5mg were safe and well tolerated. No serious adverse events were reported and there were no life-threatening events. BAY 63-2521 exhibited dose-proportional pharmacokinetics. Exposures observed in subjects with renal impairment were highly variable and the ranges of exposures were overlapping with those observed in healthy controls. In subjects with hepatic impairment, mean exposure to riociguat was significantly increased by at least 50% in Child Pugh B subjects compared with their matched healthy controls with the rank order of exposure Child Pugh B subjects > Child Pugh A subjects healthy controls. The pharmacodynamic and pharmacokinetic properties of BAY 63-2521 suggested that it could offer a unique mode of action in the treatment of pulmonary hypertension. In PH

Figure 2: Structural formula of riociguat (BAY 63-2521)12

in 19 subjects with PH (PAH, distal chronic thromboembolic pulmonary

A single-dose riociguat proof-of-concept study17

is mainly excreted via the biliary/faecal route, and does not possess any genotoxic, phototoxic or carcinogenic risks to humans.12

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