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Adempas

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Adempas

CLINICAL PHARMACOLOGY

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.

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].

Hemodynamic parameters were assessed in CTEPH patients in CHEST-1 [see Clinical Studies]. 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 (dyn*s*cm-5) -226 23.1 -246 -303 to -190
Pulmonary Vascular Resistance Index(dyn*s*cm-5*m²) -397 48.3 -449 -554 to -344
Systemic Vascular Resistance (dyn*s*cm-5) -445 16.6 -478 -602 to -354
Systemic Vascular Resistance Index (dyn*s*cm-5*m²) -799 53.7 -914 -1141 to -687

Hemodynamic parameters were assessed in PAH patients in PATENT-1 [see Clinical Studies]. 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 (dyn*s*cm-5) -223 -8.9 -226 -281 to -170
Pulmonary Vascular Resistance Index(dyn*s*cm-5*m²) -374 -22.4 -377 -469 to -285
Systemic Vascular Resistance (dyn*s*cm-5) -448 -67.5 -395 -473 to -316
Systemic Vascular Resistance Index (dyn*s*cm-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].

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].

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.

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.

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 by metabolism by CYP1A1, CYP3A, CYP2C8 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.

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

Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics - Illustration

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

Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics - Illustration

*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, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are coadministered [see DRUG INTERACTIONS].

Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Animal Toxicology

In growing rats, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis [see Use In Specific Populations].

Clinical Studies

Chronic-Thromboembolic Pulmonary Hypertension

A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they:

  • were technically inoperable for pulmonary endarterectomy, with PVR > 300 dyn*sec*cm-5 and mean pulmonary artery pressure > 25 mmHg measured at least 90 days after the start of full anticoagulation, or
  • had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm-5 measured at least 180 days following pulmonary endarterectomy.

Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline).

The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively.

Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3.

Figure 3: CHEST-1 Mean Change from Baseline in the 6-Minute Walk Distance

Mean Change from Baseline in the 6-Minute Walk Distance - Illustration

The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used.

Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p < 0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m).

Figure 4 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving Adempas (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo.

Figure 4: CHEST-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance

Distribution of Patients by Change from Baseline in 6-Minute Walk Distance - Illustration

Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (see Figure 5).

Figure 5: Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance(meters) by Prespecified Subgroups

Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance(meters) by Prespecified Subgroups - Illustration

WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4.

Table 4: Effects of Adempas on the Change in WHO Functional Class in CHEST-1 from Baseline toWeek 16

Change in WHO Functional Class Adempas (n=173) Placebo (n=87)
Improved 57 (33%) 13 (15%)
Stable 107(62%) 68(78%)
Deteriorated 9(5%) 6(7%)
  p-value=0.0026

Long Term Treatment of CTEPH

An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 582 days (± 317). The probabilities of survival at 1 and 2 years were 97% and 94%, respectively. Without a control group, however, these data must be interpreted cautiously.

Pulmonary Arterial Hypertension

A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR > 300 dyn*sec*cm-5 and a PAP mean > 25 mmHg.

Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to Adempas were initiated at 1.0 mg three times a day. The dose of Adempas was up-titrated every 2 weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies.

The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg 3 times a day, respectively.

Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6.

Figure 6: PATENT-1 Mean Change from Baseline in the 6-Minute Walk Distance

Mean Change from Baseline in the 6-Minute Walk Distance - Illustration

The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used.

Figure 7 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving Adempas (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo.

Figure 7: PATENT-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance

Distribution of Patients by Change from Baseline in 6-Minute Walk Distance - Illustration

Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p < 0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m).There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day.

Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (see Figure 8).

Figure 8: PATENT-1 Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute WalkDistance (meter) by Prespecified Subgroups

Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute WalkDistance (meter) by Prespecified Subgroups - Illustration

WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5.

Table 5: Effects of Adempas on the Change in WHO Functional Class in PATENT-1 from Baseline to Week 12

Change in WHO Functional Class Adempas (IDT)
(n=254)
Placebo
(n=125)
Improved 53(21%) 18(14%)
Stable 192(76%) 89(71%)
Deteriorated 9(4%) 18(14%)
  p-value = 0.0033

Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO Functional Class.

Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 6.

Table 6: Effects of Adempas in PATENT-1 on Events of Clinical Worsening (ITT analysis set)

Clinical Worsening Events Adempas (IDT) (n=254) Placebo (n=126)
Patients with any clinical worsening* 3(1.2%) 8(6.3%)
  Death 2(0.8%) 3(2.4%)
  Hospitalizations due to PH 1(0.4%) 4(3.2%)
  Decrease in 6MWD due to PH 1(0.4%) 2(1.6%)
  Persistent worsening of FC due to PAH 0 1(0.8%)
  Start of new PAH treatment 1(0.4%) 5(4.0%)
* p-value=0.0285 (Mantel-Haenszel estimate)

Note: Patients may have had more than one event of clinical worsening.

Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate). The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9.

Figure 9: PATENT-1 Time (in Days) to Clinical Worsening (ITT analysis set)

Time (in Days) to Clinical Worsening - Illustration

Long Term Treatment of PAH

An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 663 days (± 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously.

Last reviewed on RxList: 5/27/2014
This monograph has been modified to include the generic and brand name in many instances.

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