Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat

Pulmonary hypertension (PH) is a progressive disorder, defined by a mean pulmonary arterial pressure ≥ 25 mmHg at rest measured by right heart catheterization, which can be severely life-limiting for patients [1]. PH is characterized by pulmonary vasoconstriction, vascular remodeling, thrombosis, and inflammation [2], and has been classified into five groups based on the cause, pathologic findings, and hemodynamic characteristics [3]. Two of these PH groups are pulmonary arterial hypertension (PAH; Group 1) and chronic thromboembolic PH (CTEPH; Group 4). Nitric oxide (NO), endothelin, and prostacyclin signaling pathways have been implicated in the pathophysiology of PAH [4]. NO plays a key role in the regulation of pulmonary vascular tone: endogenous NO binds to the enzyme soluble guanylate cyclase (sGC) in vascular smooth muscle cells, stimulating sGC to produce the secondary messenger cyclic guanosine monophosphate (cGMP), which in turn activates cGMP-dependent protein kinase to reduce the intracellular calcium concentration and prevent smooth muscle contraction [5]. Reduced levels of endogenous NO have been found in PH [6], and altered NO–sGC–cGMP signaling has been implicated in the pathophysiology of PH, including vasoconstriction, inflammation, and pulmonary vascular remodeling [5].

The various treatment options for PH have been described in detail in the 2015 European Respiratory Society/European Society of Cardiology (ERS/ESC) treatment guidelines [1]. Riociguat is an oral medication that targets the NO–sGC–cGMP pathway [7], and its benefits in the management of several PH groups have been explored [5, 8‐11]. In particular, pivotal phase III, randomized, placebo-controlled trials of riociguat—the PATENT-1 and CHEST-1 studies—were performed in patients with PAH (n = 443) and CTEPH (n = 261), respectively [12, 13]. Patients in PATENT-1 and CHEST-1 received placebo or riociguat individually dose adjusted up to 2.5 mg three times daily according to systolic blood pressure (SBP) and signs/symptoms of hypotension (Fig. S1 in the Online Resource) [12‐15]. In both studies, riociguat was generally well tolerated and significantly improved a range of clinical endpoints, including 6-min walking distance (6MWD), World Health Organization (WHO) functional class, and levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), compared with placebo [12, 13]. These improvements were maintained after 2 years of riociguat treatment in the open-label extension studies—PATENT-2 and CHEST-2—and no new safety signals were identified [16, 17].

Based on these results, riociguat has been approved in Europe and the US for the treatment of adults with PAH and adults with CTEPH that is inoperable or persistent/recurrent after surgical treatment [18, 19]. Contraindications are described in the product label [18, 19].

The role of riociguat in the management of PAH and CTEPH is addressed in PH treatment guidelines [1] and a recent review [5], while the clinical use, efficacy, and tolerability of riociguat are described elsewhere [12, 13, 15‐17, 19‐21]. In this review, we focus on the pharmacokinetic/pharmacodynamic profile of riociguat, including drug–drug interaction data, population pharmacokinetic/pharmacodynamic relationships in patients with PAH or CTEPH, and the implications of these results for clinical use.

Key assessments of riociguat pharmacokinetics were performed in patients with PAH or CTEPH in a phase II, proof-of-concept, single-dose study [35], a phase II, open-label, multiple-dose study (ClinicalTrials.gov identifier: NCT00454558) [15], and a population pharmacokinetic analysis of patients in the PATENT and CHEST studies [36]. As in healthy individuals, riociguat is rapidly absorbed in patients with PAH or CTEPH (time to reach C _max after a single dose 0.25–1.5 h) [35]. Riociguat exposure is dose proportional, with pronounced interindividual variability (60%) but low intraindividual variability (35%) [15]. The half-life of riociguat is approximately 12 h in patients compared with approximately 7 h in healthy individuals [18, 19]. The resulting exposure is approximately two- to threefold higher at steady state compared with healthy subjects [13]. Mean AUC_∞ after single doses of 1 and 2.5 mg in the proof-of-concept study was 602 and 1411 µg·h/L, respectively [35]. Mean AUC under steady-state conditions following multiple doses of riociguat 0.5–2.5 mg three times daily in the pivotal phase III trials was 1174 µg·h/L in patients with PAH and 1433 µg·h/L in patients with CTEPH (Table 3) [15]. Based on investigations early in the clinical trial program, riociguat accumulation up to steady state is anticipated within the first few days of administration (unpublished data). No undue accumulation beyond steady state was observed; exposure in the phase III trials remained stable from day 14 to day 168 [37]. In the phase III trials, riociguat/M1 plasma concentrations were well described by a linear one-compartment model, with no evidence for time- or dose-dependent alterations [36]. The absorption rate constant, clearance, and volume of distribution for riociguat were estimated to be 2.17/h, 1.81 L/h, and 32.3 L, respectively [36]. Covariate effects in the model included smoking status, comedication with the endothelin receptor antagonist bosentan, bilirubin concentration, and baseline CrCl. Smokers had higher riociguat clearance than non-smokers; in patients not receiving bosentan, taking into account other covariate effects (bilirubin concentration and CrCl), median riociguat clearance was 1.8 L/h in non-smokers and 4.2 L/h in smokers in the PATENT studies, and 1.6 L/h in non-smokers and 4.2 L/h in smokers in the CHEST studies. The final pharmacokinetic model in patients indicated that smoking was associated with a 120% increase in riociguat clearance [37]. Bosentan comedication was associated with a slight increase in riociguat clearance in the PATENT studies (described further in Sect. 7.1) [36]. Consistent with findings in healthy individuals, riociguat exposure showed a modest increase with age in patients with PAH or CTEPH in PATENT-1 and CHEST-1, respectively [32]. Riociguat AUC was approximately 10% higher in women than in men [32], and this modest difference may be partly due to differences in body weight between women and men.

The pharmacokinetic and pharmacodynamic data for riociguat have been used to guide its clinical use in patients with PAH and CTEPH. The pharmacokinetics of riociguat have been extensively characterized in phase I and II studies and in population pharmacokinetic modeling analyses. Based on data from pharmacokinetic studies, riociguat shows complete oral absorption with dose-proportional exposure over the therapeutic dose range (0.5–2.5 mg) and can be taken with or without food [18, 19, 28, 30]. Crushed tablets and oral suspensions of riociguat are interchangeable with whole tablets [30]. This may be useful in populations who have difficulty swallowing whole tablets.

Population pharmacokinetic analyses confirm that riociguat pharmacokinetics are described by a one-compartment model in patients with PAH or CTEPH and are similar in the two conditions, but exposure is increased compared with healthy individuals [32, 33]. While some of the expected intrinsic factors, such as age (with reductions in renal excretion and/or hepatobiliary clearance), may contribute in part to this increase in exposure, the underlying disease per se alters renal and/or hepatobiliary elimination of drugs owing to various factors, including reduced cardiac output, liver shunts, and worsening renal function [50‐54]. Accordingly, patient covariates such as renal function and bilirubin reduced unexplained interindividual variability of systemic clearance in patients with PAH or CTEPH described via population pharmacokinetic approaches [34, 37]. In the population pharmacokinetic analyses, only renal function appeared to be a significant covariate affecting exposure [37]. Of note, median CrCl levels at baseline in the PATENT and CHEST studies were 86.6 and 72.8 mL/min, respectively, suggesting a degree of renal impairment [37]. Mean cardiac index at baseline in the CHEST study population was 2.2–2.3 L/min/m², suggesting impaired cardiac function [38].

Differences in riociguat exposure due to age or sex are not clinically relevant and do not warrant further dose adjustment beyond the approved individual dose-adjustment scheme [30, 32, 40]. However, particular care should be exercised during individual dose adjustment in elderly patients because riociguat exposure tends to be somewhat higher in older versus younger individuals, partly due to differences in body weight and renal clearance [19, 32].

Renal impairment is associated with reduced riociguat clearance. Dose adjustment of riociguat should be performed with particular care in patients with renal impairment [19, 30, 33]. Data are limited for patients with severe renal impairment (CrCl < 30 mL/min) and riociguat is therefore not recommended for these patients in the European label [19], although this restriction is not applied in the US label [18]. No data are available for patients with CrCl < 15 mL/min or on dialysis, and riociguat is therefore not recommended in these patients in both the European and US labels [18, 19].

Dose adjustment of riociguat should be performed with particular care in patients with moderate hepatic impairment (Child–Pugh B) because drug exposure is increased [32]. Mild hepatic impairment (Child–Pugh A) is not associated with significant alteration of riociguat exposure [32]. There is no experience in patients with severe hepatic impairment (Child–Pugh C); for these patients, riociguat is contraindicated in the European label [19] and is not recommended in the US label [18].

Smoking is one of the main factors contributing to the variability of riociguat exposure; quantitative variations in smoking habits or other environmental or dietary factors that induce CYP1A1 (e.g. consumption of cruciferous vegetables or charcoal-broiled meat [55, 56]) may contribute to interindividual variability in the separate subpopulations of smokers and non-smokers [15]. However, there is no reason to suspect that these factors differed substantially between smokers and non-smokers in the riociguat studies, and the effect of smoking on riociguat exposure has been observed in studies controlled for diet and environment [29]. CYP induction by smoking is dose-dependent [57] and a dedicated analysis of the phase II and III studies of riociguat suggested such a relationship; however, the number of patients was too small to permit firm conclusions (unpublished data). The European label advises that dose adjustments may be necessary in patients who start or stop smoking during riociguat treatment [19], while the US label notes that patients who smoke may require riociguat dosages higher than 2.5 mg three times daily if tolerated, and that a dose decrease may be required in patients who stop smoking [18].

To reduce the risk of hypotension, the use of riociguat in patients with SBP < 95 mmHg at treatment initiation is contraindicated in the European label [19]. During riociguat therapy, SBP < 95 mmHg is not a contraindication, although dose reduction is recommended if SBP below this level is accompanied by signs or symptoms of hypotension [19]. The US label does not have a contraindication based on SBP, but a dose reduction is recommended if the patient has symptoms of hypotension. Uptitration to a maximum dose of 2.5 mg three times daily is recommended if SBP remains > 95 mmHg and the patient has no signs or symptoms of hypotension [18].

The pharmacodynamic effects of riociguat on systemic and pulmonary circulation correlated with riociguat plasma concentrations [27, 35, 36], which showed moderate to high interindividual variability [27, 28]. The riociguat individual dose-adjustment scheme, including the three-times-daily dosing (Fig. S1 in the Online Resource) was developed in part to manage this variability and the individual sensitivity to riociguat exposure, and is based on data from phase I and II studies; the rationale, development, and implementation of the scheme have been described elsewhere [13, 14]. Briefly, riociguat doses are adjusted at 2-week intervals according to SBP (which correlates with riociguat plasma concentrations in patients with PAH or CTEPH [35, 36]) and signs/symptoms of hypotension [18, 19]. The 2-week interval was chosen based on the time taken to reach hemodynamic steady state, and convenience for the patient [14]. This approach allows for adjustment to the highest tolerated riociguat dose for each patient, has been proven in phase III clinical studies, and appears to be practical and straightforward in clinical practice. Three-times-daily dosing would be expected to provide a flat plasma concentration–time profile, which could be beneficial for an agent with hemodynamic effects. Intraindividual variability in riociguat plasma concentrations is low, suggesting that exposure should remain consistent over time once the appropriate dose for an individual patient has been established [15]. In support of this, the maintenance dose of riociguat was not changed in the majority of patients during the open-label phases of the long-term extension trials PATENT-2 and CHEST-2 [16, 17].

Riociguat has a low risk of clinically relevant drug interactions due to its clearance and excretion by multiple CYP and transporter enzymes and its lack of effect on major CYP isoforms at therapeutic levels [15]. However, absorption is affected by gastric pH, and antacids should not be administered within 1 h of receiving riociguat according to the US label [18]. The European label advises that antacids should be taken at least 2 h before or 1 h after riociguat [19]. Proton pump inhibitors and H₂ antagonists also affect riociguat bioavailability, but to a lesser extent than antacids [15]; the use of proton pump inhibitors or H₂ antagonists does not require adaptation of dosing beyond the individual dose-adjustment scheme. The same is true for coadministration of riociguat with strong selective CYP3A4 inhibitors, combined oral contraceptives [40], acetylsalicylic acid [49], or warfarin [18, 19, 48]. By contrast, the PDE-5 inhibitors sildenafil and tadalafil are metabolized predominantly by CYP3A, and concomitant use of strong CYP3A inhibitors is not recommended or requires dose reductions [58‐61].

Although coadministration of riociguat with selective CYP3A4 inhibitors does not require additional dose adaptation [31], concomitant use with strong multipathway CYP and P-gp/BCRP inhibitors, such as ketoconazole and HIV protease inhibitors, should be approached with caution as there is a risk of hypotension, as explained above [19, 31]; the US label recommends considering a reduced riociguat starting dose of 0.5 mg three times daily in this context [18]. Evaluation of data from a recently completed, non-randomized, open-label, parallel-group study exploring the concomitant use of riociguat and HIV protease inhibitors in the most widely used antiretroviral combinations is ongoing (NCT02556268; n = 40). This trial was based on in vitro studies of interactions between riociguat and anti-HIV drugs (unpublished data). The aims of the study were to investigate the pharmacokinetic drug–drug interaction potential between riociguat and fixed-dose HIV antiretroviral therapies (Atripla^®, Complera^®, Stribild^®, or Triumeq^®) or any approved antiretroviral protease inhibitor in combination with (preferably) Triumeq^®, and to assess the safety and tolerability of riociguat treatment in combination with these therapies. The potential importance of such studies is illustrated by the increased risk of developing PAH in patients with HIV [62] and the recognition of PAH associated with HIV in the international classification of PH [3].

Because of its low potential for drug–drug interactions, riociguat can be used in combination with endothelin receptor antagonists and/or prostanoids, as confirmed in the PATENT study [13, 16]. In contrast to riociguat, bosentan is an inducer of CYP3A4 and CYP2C9 and therefore interacts with multiple other drugs [63, 64]. Coadministration of riociguat with bosentan is associated with increased clearance and reduced plasma concentrations of riociguat, but does not necessitate any changes in treatment beyond the individual dose-adjustment scheme [19, 30].

Coadministration of riociguat with nitrates or NO donors is contraindicated in the European and US labels because of the risk of developing hypotension [15, 18, 19]. Coadministration of riociguat with PDE-5 inhibitors is also contraindicated [18, 19], based on the unfavorable safety signals and lack of favorable clinical effect observed following addition of riociguat to sildenafil in the PATENT PLUS study [43].

However, it is possible that patients who are not achieving treatment goals on a PDE-5 inhibitor may benefit from switching to riociguat, as suggested by data from the RESPITE study [65]. This is consistent with the modes of action of riociguat and PDE-5 inhibitors: riociguat can stimulate sGC independently of NO, while sensitizing sGC to low levels of NO, whereas PDE-5 inhibitors (which prevent degradation of cGMP) depend on the presence of sufficient upstream NO and may therefore be limited by the NO deficiency found in PH [6]. In cases of switching from a PDE-5 inhibitor to riociguat (and vice versa), the transition must include a washout phase to avoid an overlap in exposure. Based on the half-lives of the respective drugs, riociguat should not be administered within 24 h of receiving sildenafil, or within 24 h before or 48 h after receiving tadalafil, as described in the US label [18].

The pharmacodynamic and pharmacokinetic properties of riociguat have been comprehensively evaluated in healthy individuals and patients with PH. These properties support the individual dose-adjustment scheme used in phase II and III clinical trials of riociguat and are reflected in the prescribing information for riociguat [18]. The novel mode of action of riociguat, its individualized dose-adjustment regimen, and its low risk of drug–drug interactions support its uptake in the pharmacologic treatment of PAH and as the only approved pharmacotherapy for inoperable or persistent/recurrent CTEPH.