12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO).

When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation.

Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway.

Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO.

Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.

The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

12.2 Pharmacodynamics

There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output [see Clinical Studies (14)].

Hemodynamic parameters were assessed in CTEPH patients in CHEST-1 [see Clinical Studies (14.1)]. Right heart catheterization was performed at the beginning and the end of the study period in 233 patients. A statistically significant reduction of PVR (-246 dyn*s*cm-5) was shown in the Adempas group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below.

Table 2: CHEST-1, Change In Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus placebo)
Parameter (unit)	Mean change		LS mean difference	95% CI
	Adempas	Placebo
Pulmonary Capillary Wedge Pressure (mmHg)	0.59	0.18	0.58	–0.36 to 1.53
Right Atrial Pressure (mmHg)	–1.04	–0.55	–0.55	–1.72 to 0.62
Pulmonary Arterial Pressure Systolic (mmHg)	–6.84	0.95	–7.52	–10.88 to –4.16
Pulmonary Arterial Pressure Diastolic (mmHg)	–3.05	0.67	–3.62	–5.30 to –1.95
Pulmonary Arterial Pressure Mean (mmHg)	–4.31	0.76	–4.96	–6.75 to –3.16
Mean Arterial Pressure (mmHg)	–9.27	–0.29	–9.15	–11.83 to –6.46
Mixed Venous Oxygen Saturation (%)	2.95	–0.44	3.85	1.46 to 6.25
Cardiac Output (L/min)	0.81	–0.03	0.86	0.59 to 1.12
Cardiac Index (L/min/m2)	0.45	–0.01	0.47	0.33 to 0.62
Pulmonary Vascular Resistance (dynscm-5)	–226	23.1	–246	–303 to –190
Pulmonary Vascular Resistance Index (dynscm-5*m2)	–397	48.3	–449	–554 to –344
Systemic Vascular Resistance (dynscm-5)	–445	16.6	–478	–602 to –354
Systemic Vascular Resistance Index (dynscm-5*m2)	–799	53.7	–914	–1141 to –687

Hemodynamic parameters were assessed in PAH patients in PATENT-1 [see Clinical Studies (14.2)]. Right heart catheterization was performed at the beginning and the end of the study period in 339 patients.

A statistically significant reduction of PVR (-226 dyn*sec*cm-5) was shown in the Adempas individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3.

Table 3: PATENT-1, Change in Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus Placebo)
Parameter (unit)	Mean change		LS mean difference	95% CI
	Adempas	Placebo
Pulmonary Capillary Wedge Pressure (mmHg)	1.08	0.46	0.41	–0.36 to 1.18
Right Atrial Pressure (mmHg)	–0.20	0.97	–1.01	–2.15 to 0.13
Pulmonary Arterial Pressure Systolic (mmHg)	–5.39	0.78	–6.73	–9.43 to –4.04
Pulmonary Arterial Pressure Diastolic (mmHg)	–3.19	–1.12	–2.41	–4.15 to –0.68
Pulmonary Arterial Pressure mean (mmHg)	–3.93	–0.5	–3.83	–5.61 to –2.06
Mean Arterial Pressure (mmHg)	–8.54	–1.4	–7.25	–9.6 to –4.90
Mixed Venous Oxygen Saturation (%)	3.15	–2.33	5.02	3.2 to 6.84
Cardiac Output (L/min)	0.93	–0.01	0.93	0.7 to 1.15
Cardiac Index (L/min/m2)	0.54	–0.02	0.56	0.44 to 0.69
Pulmonary Vascular Resistance (dynscm-5)	–223	–8.9	–226	–281 to –170
Pulmonary Vascular Resistance Index (dynscm-5*m2)	–374	–22.4	–377	–469 to –285
Systemic Vascular Resistance (dynscm-5)	–448	–67.5	–395	–473 to –316
Systemic Vascular Resistance Index (dynscm-5*m2)	–753	–130	–675	–801 to –550

Biomarkers

In the CHEST-1 study, Adempas significantly reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP), placebo-corrected mean change from baseline -444 ng/L, 95% CI -843 to -45. In the PATENT-1 study Adempas demonstrated a statistically significant reduction of NT-proBNP, placebo‑corrected mean change from baseline: -432 ng/L, 95% CI –782 to –82.

Pharmacodynamic interactions

Nitrates: Riociguat 2.5 mg tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after riociguat. Syncope was reported in some patients [see Contraindications (4.2)].

Phosphodiesterase-5 inhibitors: In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three times a day), single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive hemodynamic effects.

Among patients with PAH on stable sildenafil treatment (20 mg, three times a day) and riociguat (1 to 2.5 mg, three times a day) there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension [see Contraindications (4.3)].

Warfarin: Concomitant administration of riociguat and warfarin did not alter prothrombin time.

Acetylsalicylic Acid: Concomitant use of riociguat and aspirin did not affect bleeding time or platelet aggregation.

12.3 Pharmacokinetics

Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%.

Absorption and distribution

The absolute bioavailability of riociguat is about 94%. Peak plasma riociguat concentrations were observed within 1.5 hours after tablet intake. Food does not affect the bioavailability of riociguat.

Bioavailability (AUC and Cmax) of riociguat administered orally as a crushed tablet suspended in applesauce or in water is similar to that of a whole tablet.

The volume of distribution at steady state is approximately 30 L. Plasma protein binding in humans is approximately 95%, with serum albumin and α1–acidic glycoprotein being the main binding components.

Riociguat is a substrate of P-gp and BCRP.

Metabolism and excretion

Riociguat is mainly cleared through metabolism by CYP1A1, CYP3A4, CYP3A5, and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with PAH are about half those for riociguat.

Following oral administration of radiolabeled riociguat in healthy individuals, about 40 and 53% of the total radioactivity was recovered in urine and feces, respectively. There appears to be considerable variability in the proportion of metabolites and unchanged riociguat excreted, but metabolites were the major components of the dose excreted in most individuals.

Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects. The terminal elimination half-life is about 12 hours in patients and 7 hours in healthy subjects.

Specific Populations: The effect of intrinsic factors on riociguat and M1 are shown below in Figure 1. There are no clinically relevant effects of age, sex, weight, or race/ethnicity on the pharmacokinetics of riociguat or M1. No dose adjustment is warranted.

Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics

Figure 1: Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics

Drug interactions: The effect of extrinsic factors on riociguat and M1 were studied in healthy subjects and are shown in Figure 2

Figure 2: Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics

Figure 2: Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics

*HIV protease inhibitors are strong CYP3A inhibitors and may increase riociguat plasma concentrations to levels similar to those seen with ketoconazole. ** AUC only, estimated using population pharmacokinetics methods *** AUC only for metabolite, estimated using population pharmacokinetics methods. **** Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.3) and Drug Interactions (7.2)].

Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered [see Drug Interactions (7.2)].

Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil [see Contraindications (4.3) and Clinical Pharmacology (12.2)].

Riociguat (2.5 mg three times per day) did not affect the systemic exposure of combined oral contraceptives containing levonorgestrel and ethinyl estradiol when concomitantly administered to healthy female subjects.