Clinical Implications of Riociguat Pharmacokinetics and Pharmacodynamics: Introduction to the Riociguat Clinical Pharmacology Supplement

Riociguat (BAY 63-2521) is a novel oral soluble guanylate cyclase (sGC) stimulator developed for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). ¹ It targets the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) pathway and, via a dual mode of action, both stimulates sGC directly, independently of NO, and sensitizes sGC to endogenous NO by stabilizing NO-sGC binding. As a result, riociguat restores the NO-sGC-cGMP pathway, increasing intracellular levels of cGMP,^1–3 thereby addressing the imbalance of vasoconstriction over vasodilation that is present in the lung vasculature of patients with pulmonary hypertension (PH). ⁴

Riociguat has been evaluated in a rigorous clinical trial program, including two large randomized, double-blind, placebo-controlled phase 3 studies, PATENT-1 and CHEST-1, and their respective long-term extension studies, PATENT-2 and CHEST-2. These studies have shown that riociguat can improve exercise capacity, hemodynamic function, and quality-of-life parameters in patients with PAH or CTEPH.^5–8 Data from the clinical trial program have also shown riociguat to be well tolerated and to have a favorable safety profile that was sustained over long-term treatment. Most of the observed side effects are consistent with the vasodilatory effects of the drug, such as headache, dizziness, and hypotension, and adverse events were evenly matched between riociguat and placebo treatment groups. Syncope was an adverse event of special interest, but in the two pivotal trials the incidences of serious syncope events were higher in the placebo groups than in the riociguat groups. Few patients discontinued treatment as a result of adverse events.^5–10

On the basis of these studies, riociguat was the first therapy to be approved for the treatment of two indications: PAH, as demonstrated in patients with etiologies of idiopathic or heritable PAH or PAH associated with connective-tissue disease, and inoperable or persistent/recurrent CTEPH.^9,10 Patients with congenital heart disease were also included in the PATENT studies. ¹¹ Riociguat is now licensed in more than 50 countries worldwide, including European countries, the United States, Canada, and Japan. Additional clinical trials are ongoing to investigate the efficacy and tolerability of riociguat in other indications, including PH associated with idiopathic interstitial pneumonia (ClinicalTrials.gov identifier: NCT02138825).

In addition to the phase 3 studies, riociguat has a comprehensive clinical pharmacology portfolio based on a series of pharmacokinetic (PK) and pharmacodynamic (PD) studies. The choice of clinical pharmacology studies conducted with riociguat was guided by the PK (e.g., drug-drug interactions based on known metabolism) and PD (e.g., known hemodynamic/vasoactive activity) properties of riociguat, in addition to the typical characteristics of the PH patient population (e.g., patient covariates, such as renal/hepatic function, and potential concomitant medication use, such as warfarin). PK profiling of riociguat was of particular interest because of the observed direct link between riociguat exposure and its hemodynamic activity, as demonstrated in initial clinical pharmacology and proof-of-concept studies^12,13 and later supported by a population PK and PD analysis from the phase 3 studies. ¹⁴ Evidence from these studies facilitates the safe and effective use of riociguat, as reflected in the US prescribing information ¹⁰ and the European summary of product characteristics, ⁹ and helps to inform physicians making treatment decisions.

This supplement includes a collection of the PK and PD studies conducted with riociguat, to provide a complete clinical pharmacology profile of the drug in both healthy volunteers and patients with PAH and CTEPH.

CLINICAL IMPLICATIONS

Riociguat bioavailability

Riociguat is readily absorbed, with an elimination half-life of between 5 and 10 hours in healthy subjects and approximately 12 hours in patients with PH.^12,13 It is mainly cleared by cytochrome P450 (CYP) metabolism (CYP1A1, CYP3A4, and CYP2J2) to its main metabolite, M1.^9,10

The bioavailability of riociguat has been examined in healthy volunteers in three open-label, randomized crossover studies. ¹⁵ Riociguat showed complete oral absorption, with no clinically meaningful effects when taken with or without food. Additional studies demonstrated that the bioavailability of riociguat was similar between oral suspensions and the whole immediate-release (IR) tablet and between the whole IR tablet and a crushed IR tablet suspended in applesauce or water. ¹⁶ This suggests that riociguat could potentially be given as an oral suspension or a crushed-tablet preparation in patients struggling to swallow whole tablets, such as children or elderly individuals.

There were no clinically meaningful effects of age, sex, weight, or race/ethnicity on the PK properties of riociguat in healthy volunteers, and no dose adjustments were needed.^14,17 However, riociguat exposure tended to be higher in elderly healthy volunteers than in young healthy volunteers, partly because of reduced renal clearance and differences in body weight, although riociguat was well tolerated, with a comparable safety profile across all subgroups. Consequently, particular care is recommended during individual dose adjustment in elderly patients.

Riociguat in patients with hepatic or renal impairment

Riociguat is partly metabolized by the liver, and data from two randomized, nonblinded studies demonstrated that in patients with mild hepatic impairment, no clinically meaningful increase of riociguat exposure was observed, whereas moderate hepatic impairment (Child-Pugh B) was associated with increased riociguat exposure compared with sex-matched healthy control subjects. ¹⁸ Particular care should therefore be taken during individual dose adjustment of riociguat in patients with moderate hepatic impairment. There are currently no data available for patients with severe hepatic impairment (Child-Pugh C), and riociguat is not recommended in these patients.^9,10

Renal impairment is associated with reduced riociguat clearance, although interindividual variation in riociguat exposure was high and overlapped that observed in healthy control subjects. ¹⁹ In the phase 3 study program, approximately 49% of patients had a reduced creatinine clearance, and some had a clearance below 30 mL/min. In these patients, riociguat exposure was increased by approximately 100%, ¹⁹ although exposure levels still overlapped those observed in healthy control subjects, and the increase in exposure was not associated with an increase in treatment-related adverse events.^5,6,14 Because riociguat exposure is increased in patients with renal impairment, care should be taken during individual dose adjustment of riociguat in these patients. Currently, there are few data available for patients with severe renal impairment (creatinine clearance < 30 mL/min), and riociguat is not recommended in these patients in Europe. ⁹ In the United States, riociguat is not recommended in patients with creatinine clearance < 15 mL/min, because of a lack of safety and efficacy data in these patients. ¹⁰

Results from a population PK analysis model using data from patients in the four phase 1 studies who had renal or hepatic impairment supported the findings from the individual PK studies. ²⁰ The analyses confirmed that renal impairment could be expected to have a modest effect on riociguat exposure and that hepatic impairment appeared to have little effect on riociguat clearance.

Riociguat in smokers

As smoking is known to induce the CYP monooxygenase CYP1A1,^21,22 which has a major role in the metabolic clearance of riociguat, exposure was expected to be lower in smokers than in nonsmokers. Indeed, clinical studies confirmed that riociguat exposure was reduced in smokers compared with that in the overall population (smokers and nonsmokers combined), irrespective of renal or hepatic function.^18–20

The impact of smoking was further illustrated in the population PK analyses using data from patients in the PATENT-1 and CHEST-1 studies who had PAH and CTEPH, respectively. ¹⁴ These analyses confirmed that, under therapeutic conditions, smoking increased the metabolism of riociguat.

As a result of the impact of smoking on riociguat metabolism, current smokers should be advised to stop smoking because of a risk of a lower response, or clinicians should consider prescribing a riociguat dose toward the higher end of the recommended range (up to 2.5 mg 3 times daily) in patients who smoke. Similarly, the riociguat dose may have to be reduced in patients who stop smoking during treatment.^9,10

Interactions between riociguat and other medicinal products

A series of randomized, open-label crossover studies in healthy volunteers assessed the PK and PD interactions between riociguat and a range of drugs.^23–27 Importantly, they showed that riociguat does not interfere with the action of several drugs that are commonly required in patients receiving riociguat. In addition, riociguat has no effect on platelet aggregation and demonstrated no clinically relevant PK or PD interactions when administered to healthy men in combination with aspirin. ²³ Coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug. Similarly, there are no PK or PD interactions between riociguat and warfarin, and no dose adjustment is required. ²⁴ Furthermore, because it is a requirement for women of child-bearing potential to take effective contraception while receiving riociguat,^9,10 it has been confirmed that there are no clinically meaningful effects on exposure and no PK interactions between riociguat and the oral contraceptives levonorgestrel and ethinylestradiol. ²⁵

However, dose adjustments may be needed in patients requiring concomitant use of riociguat with strong multipathway cytochrome inhibitors and inhibitors of key transport proteins. ²⁶ Such drugs, which include ketoconazole and ritonavir, increase exposure to riociguat. Patients receiving drugs such as ketoconazole or ritonavir may therefore require a reduced dose when commencing riociguat treatment, as recommended in the United States. ¹⁰ In Europe, however, concomitant use of riociguat with strong multipathway CYP and P-gp/BCRP (P-glycoprotein/breast cancer resistance protein) inhibitors, such as azole antimycotics (e.g., ketoconazole and itraco-nazole), or HIV protease inhibitors (e.g., ritonavir) is not recommended.9 In contrast, pure CYP3A4 inhibitors, such as clarithromycin, require no dose adaption. ²⁶

Riociguat also showed indirect interactions with antacids, ²⁷ which decreased riociguat absorption. Therefore, antacids should be taken at least 1 hour before or after taking riociguat. Proton pump inhibitors have a low impact on riociguat bioavailability, ²⁷ and no dose adjustments or special precautions are required.

Combination treatment with riociguat and other PAH-specific drugs has also been investigated. It has been shown that riociguat has no interactions with, or effects on, the exposure of endothelin receptor antagonists or nonintravenous prostanoids that merit dose adjustment.^9,10 Similarly, although concomitant administration of bosentan reduced riociguat plasma concentrations, no dose adjustment of riociguat is necessary because of the individual dose adjustment regimen of riociguat.^9,10 By contrast, concomitant use of riociguat with phosphodiesterase type 5 inhibitors (PDE5i's) is contraindicated,^9,10 as PD interactions between riociguat and PDE5i's cause an additive effect, leading to an increase in hypotensive events, as observed during long-term coadministration of sildenafil and riociguat. ²⁸ Similarly, concomitant use of riociguat with nitrates is contraindicated.^9,10

STRENGTHS AND LIMITATIONS OF PK/PD STUDIES

All riociguat PK/PD studies were conducted according to current guidance published by the European Medicines Agency and the US Food and Drug Administration. It is an accepted procedure that study cohorts for PK/PD studies are restricted to healthy adults, and these data are important to enable mechanistic investigations that will increase the knowledge base for a potential new drug. However, safety and tolerability assessments from healthy individuals that are directly transferable to the patient situation are limited. Furthermore, data from healthy volunteers do not allow any effects of the disease or concomitant medication to be taken into account.

Population PK/PD studies included in the riociguat phase 3 program investigated such interactions and support the application of findings in healthy adults to patients with PH. In particular, the effect of bosentan on riociguat was assessed in patients with PH. ¹⁴ Although riociguat clearance was higher among patients receiving concomitant bosentan than in patients who were not (riociguat exposure was decreased by 27%), the effect did not necessitate a dose adjustment. Further population PK/PD and exposure/response analyses are currently underway.

Many PK studies also restrict the study population by including only male or white individuals. However, in the case of riociguat, any effects of sex or race are likely to be minor, since previous studies have shown no clinically relevant effects of sex, age, or weight on riociguat metabolism.^14,17

Another common limitation of PK/PD studies is that they are often short-term trials conducted in small patient cohorts. Conclusions are therefore based on a small number of doses of study drug, which may not accurately reflect the situation in patients receiving chronic treatment.

The safety and efficacy of riociguat in patients aged less than 18 years have not yet been established;^9,10 consequently, riociguat PK/PD studies were conducted exclusively in adults. To address this limitation, a phase 3 study is currently underway in children aged 6–17 years (as CYP activity is known to increase up to the age of 6 years ²⁹ ), using body-weight-adjusted individual dose titration regimens and age-appropriate drug formulations to investigate the safety, pharmacokinetics, and pharmacodynamics of riociguat in this population (ClinicalTrials.gov identifier: NCT02562235). However, the use of riociguat in pediatric patients is not recommended until further research has been conducted in this patient population.^9,10

SUMMARY

In summary, this supplement provides a comprehensive overview of the PK and PD profiles of riociguat. It will be useful for physicians when considering the treatment of patients with PH.