Clin Pharmacokinet (2018) 57:647–661 https://doi.org/10.1007/s40262-017-0604-7 REVIEW AR TICLE Clinical Pharmacokinetic and Pharmacodynamic Proﬁle of Riociguat 1 1 1 2 1 • • • • • Reiner Frey Corina Becker Soundos Saleh Sigrun Unger Dorina van der Mey Wolfgang Mu¨ck Published online: 30 October 2017 The Author(s) 2017. This article is an open access publication Abstract Oral riociguat is a soluble guanylate cyclase (sGC) and transporter proteins at therapeutic levels. Riociguat has stimulator that targets the nitric oxide (NO)–sGC–cyclic gua- been approved for the treatment of PAH and CTEPH that is nosine monophosphate pathway with a dual mode of action: inoperable or persistent/recurrent after surgical treatment. directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or Key Points without food and as crushed or whole tablets. Riociguat expo- sure shows pronounced interindividual (60%) and low intrain- The pharmacokinetics of oral riociguat are dividual (30%) variability in patients with pulmonary arterial characterized by rapid absorption, almost complete hypertension (PAH) or chronic thromboembolic pulmonary bioavailability, and dose-proportional exposure, which hypertension (CTEPH), and is therefore administered using an correlates with its pharmacodynamic effects. Riociguat individual dose-adjustment scheme at treatment initiation. The exposure varies substantially between patients; this has half-life of riociguat is approximately 12 h in patients and been addressed by use of an individual dose-adjustment approximately 7 h in healthy individuals. Riociguat and its scheme at treatment initiation, which has been proven metabolites are excreted via both renal (33–45%) and biliary to be safe and efﬁcacious in phase III studies in patients routes (48–59%), and dose adjustment should be performed with pulmonary arterial hypertension and chronic with particular care in patients with moderate hepatic impair- thromboembolic pulmonary hypertension, and appears ment or mild to severe renal impairment (no data exist for to be practical and straightforward in clinical practice. patients with severe hepatic impairment). The pharmacody- Most intrinsic and extrinsic factors that inﬂuence namic effects of riociguat reﬂect the action of a vasodilatory riociguat pharmacokinetics or pharmacodynamics do not agent, and the hemodynamic response to riociguat correlated with riociguat exposure in patients with PAH or CTEPH in warrant further dose adjustment beyond the individual dose-adjustment scheme; however, particular care should phase III population pharmacokinetic/pharmacodynamic be exercised during individual dose adjustment in elderly analyses. Riociguat has a low risk of clinically relevant drug patients and those with moderate hepatic impairment or interactions due to its clearance by multiple cytochrome P450 mild to severe renal impairment. Concomitant use of (CYP) enzymes and its lack of effect on major CYP isoforms riociguat with strong multipathway cytochrome P450 and P-glycoprotein/breast cancer resistance protein Electronic supplementary material The online version of this inhibitors should be avoided or approached with caution article (doi:10.1007/s40262-017-0604-7) contains supplementary material, which is available to authorized users. because of the risk of hypotension; a reduced starting dose of 0.5 mg three times daily might be considered. & Reiner Frey Smoking decreases riociguat exposure, and dose email@example.com adjustments may be necessary in patients who start or Clinical Pharmacology, Bayer AG, Wuppertal, Germany stop smoking during treatment. Global Biostatistics, Bayer AG, Wuppertal, Germany 648 R. Frey et al. 1 Introduction 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/ Pulmonary hypertension (PH) is a progressive disorder, recurrent after surgical treatment [18, 19]. Contraindica- deﬁned by a mean pulmonary arterial pressure C 25 mmHg tions are described in the product label [18, 19]. at rest measured by right heart catheterization, which can The role of riociguat in the management of PAH and be severely life-limiting for patients . PH is character- CTEPH is addressed in PH treatment guidelines  and a ized by pulmonary vasoconstriction, vascular remodeling, recent review , while the clinical use, efﬁcacy, and thrombosis, and inﬂammation , and has been classiﬁed tolerability of riociguat are described elsewhere into ﬁve groups based on the cause, pathologic ﬁndings, [12, 13, 15–17, 19–21]. In this review, we focus on the and hemodynamic characteristics . Two of these PH pharmacokinetic/pharmacodynamic proﬁle of riociguat, groups are pulmonary arterial hypertension (PAH; Group including drug–drug interaction data, population pharma- 1) and chronic thromboembolic PH (CTEPH; Group 4). cokinetic/pharmacodynamic relationships in patients with Nitric oxide (NO), endothelin, and prostacyclin signaling PAH or CTEPH, and the implications of these results for pathways have been implicated in the pathophysiology of clinical use. PAH . NO plays a key role in the regulation of pul- monary vascular tone: endogenous NO binds to the enzyme soluble guanylate cyclase (sGC) in vascular smooth muscle 2 Physiochemical Properties and Preclinical cells, stimulating sGC to produce the secondary messenger Pharmacology cyclic guanosine monophosphate (cGMP), which in turn activates cGMP-dependent protein kinase to reduce the 2.1 Physiochemical Properties intracellular calcium concentration and prevent smooth muscle contraction . Reduced levels of endogenous NO Riociguat (methyl 4,6-diamino-2-[1-(2-ﬂuorobenzyl)-1H- have been found in PH , and altered NO–sGC–cGMP pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carba- signaling has been implicated in the pathophysiology of mate) has a molecular weight of 422.42 g/mol . Its PH, including vasoconstriction, inﬂammation, and pul- chemical structure is shown in Fig. 1. Riociguat is highly monary vascular remodeling . soluble in aqueous acidic medium but poorly soluble in The various treatment options for PH have been pure water at neutral pH [15, 18]. In phase I clinical described in detail in the 2015 European Respiratory studies, riociguat was detected in plasma 15 min after Society/European Society of Cardiology (ERS/ESC) administration of an immediate-release (IR) tablet, sug- treatment guidelines . Riociguat is an oral medication gesting it is highly permeable. It is therefore designated as that targets the NO–sGC–cGMP pathway , and its a Class II (low solubility, high permeability) drug beneﬁts in the management of several PH groups have according to the Biopharmaceutics Classiﬁcation System 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 2.2 Mode of Action and Preclinical Pharmacology patients with PAH (n = 443) and CTEPH (n = 261), respectively [12, 13]. Patients in PATENT-1 and Riociguat has a dual mode of action: it directly stimulates CHEST-1 received placebo or riociguat individually dose sGC independently of NO, and sensitizes sGC to endoge- adjusted up to 2.5 mg three times daily according to nous NO by stabilizing NO–sGC binding [7, 23]. Further systolic blood pressure (SBP) and signs/symptoms of details regarding the mechanisms by which NO and sGC hypotension (Fig. S1 in the Online Resource) [12–15]. In stimulators affect sGC activity can be found elsewhere both studies, riociguat was generally well tolerated and [5, 6, 24, 25]. In preclinical studies, the activity of signiﬁcantly improved a range of clinical endpoints, recombinant sGC was increased by up to 73-fold by rio- including 6-min walking distance (6MWD), World ciguat alone, and by up to 112-fold by riociguat in com- Health Organization (WHO) functional class, and levels bination with an NO-releasing drug . Riociguat of N-terminal prohormone of brain natriuretic peptide promoted arterial relaxation in isolated saphenous artery (NT-proBNP), compared with placebo [12, 13]. These rings from normal and nitrate-resistant rabbits , and improvements were maintained after 2 years of riociguat showed beneﬁcial effects in rodent models of systemic treatment in the open-label extension studies—PATENT- hypertension, PAH, and PH due to left heart disease, 2 and CHEST-2—and no new safety signals were iden- chronic obstructive pulmonary disease, and pulmonary tiﬁed [16, 17]. ﬁbrosis (see Table S1 in the Online Resource) . Clinical Pharmacokinetics and Pharmacodynamics of Riociguat 649 to delay absorption of riociguat administered as a 2.5 mg H C IR tablet (likely by delaying gastric emptying): the median CH time to reach C was 4 h in the fed state compared with max O 3 H N 1 h in the fasted state. However, the breakfast had only a minimal effect on the extent of absorption (fed/fasted ratio NH for AUC 88.3%) . In the pivotal phase III clinical trials, riociguat tablets were administered irrespective of food intake . 3.2 Distribution Riociguat is mainly distributed into plasma, with a blood:plasma partition coefﬁcient of approximately 0.7. Riociguat plasma protein binding is approximately 95% in vitro and fully reversible; serum albumin and a-1 acid glycoprotein are the main binding components [15, 18, 19]. Fig. 1 Chemical structure of riociguat (methyl 4,6-diamino-2-[1-(2- The volume of distribution of riociguat at steady state after ﬂuorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) intravenous administration is 30.1 L, indicating a low carbamate) afﬁnity for tissues (Fig. 2)[15, 28]. Based on studies in rats, riociguat shows low penetration across the blood– 3 Pharmacokinetic Properties brain barrier and moderate penetration across the placental barrier. In lactating rats administered radiolabeled rio- 3.1 Absorption ciguat, an estimated 2.2% of the dose was excreted in milk within 32 h . Riociguat is rapidly absorbed after oral administration, the maximum concentration in plasma (C ) being reached max 3.3 Metabolism and Elimination after approximately 0.5–1.5 h with riociguat 0.25–5.0 mg administered as an oral solution , or after approxi- The main biotransformation pathway for riociguat is N- mately 0.8–1.0 h with riociguat 0.5–2.5 mg administered demethylation catalyzed by cytochrome P450 (CYP) 1A1, as an IR oral tablet  in healthy male volunteers. Sys- CYP3A4, CYP3A5, CYP2C8, and CYP2J2 [15, 18, 19] temic exposure to riociguat is dose proportional [27, 29]. (Fig. 2). CYP1A1 is primarily responsible for the forma- Riociguat exposure shows moderate to high interindividual tion of the major active metabolite M1, which has one- variability in healthy individuals [geometric mean coefﬁ- tenth to one-third of the biological activity of riociguat cient of variation of * 100% for area under the plasma [15, 19]. M1 is further metabolized by uridine diphosphate concentration–time curve from time zero to inﬁnity glucuronosyltransferase (UGT) 1A1 and UGT1A9 to pro- (AUC ) and * 45% for C ], whereas intraindividual ? max duce the inactive N-glucuronide M4. Of note, CYP1A1 is variability is low (geometric coefﬁcient of variation of induced by polycyclic aromatic hydrocarbons such as those \20% for AUC and C ). ? max present in cigarette smoke, leading to an increased rate of The mean AUC is similar for riociguat 1.0 mg adminis- riociguat metabolism in smokers compared with non- tered as an oral IR tablet or as an intravenous infusion over smokers [15, 18, 19, 29, 31]. 60 min (244 vs. 259 lgh/L, respectively) and the absolute Total riociguat (unchanged riociguat and its metabolites) bioavailability is 94.3% , indicating unrestrained is excreted via both renal (33–45%) and biliary/fecal absorption and a little presystemic ﬁrst-pass extraction (48–59%) routes. Overall, 27 to * 71% of the dose is (Fig. 2). There are no relevant differences in bioavailability eliminated by oxidative biotransformation (as M1, M3, and between oral riociguat 2.5 mg administered as a solution or as M4), 9–44% is excreted unchanged in feces (15–43% as an IR tablet . Riociguat bioavailability is also similar M1), and 4–19% is excreted unchanged in urine via between 1.0 mg IR tablets and 0.15, 0.3, and 2.4 mg oral glomerular ﬁltration (Fig. 2). Riociguat is a substrate suspensions (AUC/dose estimate ratio 93.6–104.3%), and of the transporter proteins P-glycoprotein (P-gp) and breast between whole 2.5 mg IR tablets and crushed 2.5 mg IR cancer resistance protein (BCRP] . It is a low-clearance tablets suspended in water (AUC estimate ratio: 103.3%) or drug, with an average systemic clearance of * 3.4 L/h in applesauce (AUC estimate ratio 98.5%) . healthy non-smokers (6.0 L/h in smokers) . The aver- Food has only a minor impact on the AUC of riociguat age terminal half-life of a single dose of riociguat 1 mg in (Table 1). A high-fat and high-calorie breakfast was shown 650 R. Frey et al. Volume of distribution V ~ 30 L (0.38 L/kg); F (fasted) SS abs low tissue penetration 94% for 1 mg tablet Ae High oral bioavailability F fec abs 48–59% of dose Owing to almost complete extent of absorption and lack of relevant pre-systemic first-pass extraction Metabolism 26–74% of riociguat dose circulating in plasma as unchanged drug, 59–11% Ae ur as main (active) metabolite M1 33–45% of dose Metabolism Clearance ~72–27% of riociguat oral dose cleared CL ~ 3–6 L/h (0.04–0.07 L/(h·kg)) SYS via biotransformation (liver, lung, intestine); CL ~ 0.4 L/h glomerular filtration CYP1A1, CYP2C8, CYP2J2, CYP3A4 In feces: In urine: 9–44% unchanged 4–19% unchanged 43–15% as M1 23–7% as M1 19–4% as M4 2–0.4% as M3 Fig. 2 Summary of riociguat mass-balance, excretion-pattern, distri- amount excreted into bile/feces, CL systemic (plasma) clearance, sys bution, and clearance properties in humans. All numbers are CL renal clearance (via glomerular ﬁltration), CYP cytochrome approximate; sum of percentages is 90–95%, which is the recovery P450, F absolute bioavailability, M1, M3, and M4 metabolites M1 abs of radiolabel in the human mass-balance study (n = 4). Percentages (BAY 60-4552), M3, and M4, V volume of distribution at steady ss separated by dashes indicate minimum–maximum observed values in state the mass-balance study. Ae amount excreted into urine, Ae ur fec healthy non-smokers is 8.2 h, decreasing to 4.5 h in 56.3 lg/L in non-smokers and 95.1 lg/L in smokers (an smokers . increase of ? 69%) . A study in healthy Chinese vol- unteers demonstrated a reduction by at least - 60% in riociguat exposure in smokers compared with non-smokers 4 Pharmacokinetic Properties in Special . C divided by dose per kilogram body weight max Populations (C ) was decreased in smokers by - 20% after a max,norm single dose and - 44% at steady state after multiple dosing 4.1 Smoking . Smoking also led to reduced riociguat exposure in individuals with renal or hepatic impairment (described CYP1A1 is induced by polycyclic aromatic hydrocarbons further in Sect. 4.3)[32, 33]. such as those present in cigarette smoke, leading to an increased rate of riociguat metabolism in smokers versus non-smokers [15, 18, 19, 29, 31]. Consequently, smoking 4.2 Ethnicity induces metabolism of riociguat to M1, leading to reduced riociguat exposure in smokers (Table 1), while metabolite Japanese people tend to have higher riociguat exposure M1 exposure is increased. In healthy Caucasian volunteers than other ethnic groups (Table 1), although this difference receiving riociguat 2.5 mg three times daily, mean rio- is less pronounced after normalization for body weight. ciguat AUC at steady state was 692.8 lgh/L in non- African American and Chinese individuals have riociguat smokers and 215.0 lgh/L in smokers (a reduction of exposures after body-weight normalization within the - 69%), whereas mean M1 AUC at steady state was range of interindividual variability seen for Caucasians 379.5 lgh/L in non-smokers and 633.5 lgh/L in smokers . In healthy Chinese volunteers, riociguat had nearly (an increase of ? 67%) . Mean riociguat C at steady dose-proportional pharmacokinetics with only slight accu- max state was 116.5 lg/L in non-smokers and 59.6 lg/L in mulation at steady state, with high interindividual vari- smokers (a reduction of - 49%), and mean M1 C was ability as seen previously in Caucasians . max Clinical Pharmacokinetics and Pharmacodynamics of Riociguat 651 Table 1 Impact of intrinsic and extrinsic factors on riociguat exposure Factors Effect on riociguat Comments/recommendations concentration Intrinsic factors Renal impairment Increase Riociguat exposure (AUC ) was increased in individuals with renal impairment (estimated norm  ratio of exposure vs. healthy controls: 143, 204, and 144% in those with mild, moderate, and severe renal impairment, respectively). Dose adjustment should be performed with particular care. No data are available for patients with creatinine clearance\15 mL/min or on dialysis, therefore riociguat is not recommended in these patients Hepatic impairment Increase Riociguat exposure (AUC ) was signiﬁcantly increased in individuals with moderate norm  (Child–Pugh B) but not mild (Child–Pugh A) hepatic impairment (estimated ratio of exposure vs. healthy controls: 153 and 106%, respectively). Dose adjustment should be performed with particular care in patients with moderate hepatic impairment. There is no experience in patients with severe hepatic impairment (Child–Pugh C), and riociguat should not be used in these patients Age (elderly vs. Increase Riociguat exposure showed a non-signiﬁcant increase in individuals aged 64.5–80 years young)  compared with individuals aged 18–45 years (AUC : ? 28%; C : ? 5%). Further norm max,norm dose adjustment beyond the individual dose-adjustment scheme is not necessary but particular care should be exercised in elderly patients Sex  No relevant Riociguat exposure was similar in both women and men [AUC: ? 9%; AUC : - 3% norm difference (women vs. men)] Japanese (vs. No relevant Body weight-normalized AUC was slightly higher in Japanese individuals vs. Caucasian Caucasian) ethnicity difference individuals (? 12%). No dose adjustment beyond the individual dose-adjustment scheme is necessary Extrinsic factors Food No relevant AUC was slightly reduced in the fed vs. fasted state (- 11.7%); this difference is not clinically difference relevant and riociguat can be taken with or without food. However, as a precautionary measure, switches between fed and fasted riociguat intake are not recommended for patients prone to hypotension Smoking [29, 31, 33] Decrease Riociguat exposure is reduced by 50–60% in smokers compared with non-smokers. Dose adjustments may be necessary in patients who start or stop smoking during riociguat treatment, and patients who smoke may require riociguat dosages higher than 2.5 mg tid if tolerated Drugs affecting gastric pH Antacid (Maalox ) Decrease Coadministration of aluminum hydroxide/magnesium hydroxide (Maalox ; 10 mL) reduced riociguat AUC by - 34%. Antacids should be taken at least 2 h before or 1 h after riociguat. Further riociguat dose adjustment beyond the individual dose-adjustment scheme is not necessary Omeprazole No relevant Pre- and coadministration of omeprazole (40 mg qd) reduced riociguat AUC by - 26%. difference Further riociguat dose adjustment beyond the individual dose-adjustment scheme is not necessary Ranitidine No relevant Coadministration of ranitidine (150 mg qd) reduced riociguat AUC by approximately - 10%. difference Further riociguat dose adjustment beyond the individual dose-adjustment scheme is not necessary Ketoconazole  Increase Pre- and coadministration of ketoconazole (400 mg qd) increased riociguat AUC by approximately ? 150% (C increased by approximately ? 46%). Concomitant use of max riociguat with strong multipathway CYP and P-gp/BCRP inhibitors, such as ketoconazole and HIV protease inhibitors, should be approached with caution Clarithromycin  No relevant Pre- and coadministration of clarithromycin (500 mg bid) increased riociguat AUC by difference ? 41% (C was unchanged). Further dose adjustment beyond the individual dose- max adjustment scheme is not necessary for patients receiving comedication inhibiting either the CYP3A4 pathway (e.g. clarithromycin) or the P-gp/BCRP-mediated excretion of riociguat Levonorgestrel– No relevant Coadministration of levonorgestrel–ethinylestradiol did not alter riociguat exposure. Riociguat ethinylestradiol difference pre- and coadministration did not alter the AUC of ethinylestradiol and levonorgestrel (estimated ratios of exposure: 102 and 100%, respectively). Further riociguat dose adjustment beyond the individual dose-adjustment scheme is not necessary Bosentan  No relevant Coadministration of bosentan in patients with PAH and CTEPH decreased riociguat AUC by difference - 27%. This small effect does not require riociguat dose adjustment beyond the individual dose-adjustment scheme 652 R. Frey et al. Table 1 continued Factors Effect on riociguat Comments/recommendations concentration Nitrates/nitric oxide Pharmacodynamic Riociguat (2.5 mg) potentiated the blood pressure-lowering effect of sublingual nitroglycerin donors interaction (0.4 mg). Syncope was reported in some patients. Coadministration of riociguat with nitrates or nitric oxide donors is therefore contraindicated Sildenaﬁl  Pharmacodynamic Addition of riociguat to sildenaﬁl therapy resulted in additive hemodynamic effects and interaction potentially unfavorable safety signals with no evidence for a positive beneﬁt/risk ratio. Coadministration of riociguat with phosphodiesterase-5 inhibitors is therefore contraindicated Warfarin  No relevant Pre- and coadministration of riociguat 2.5 mg tid had no relevant effect on warfarin AUC difference (estimated ratio 101%) or pharmacodynamics (prothrombin time and percentage activities of factor VII, factor II, and factor X). Coadministration of warfarin (25 mg) did not signiﬁcantly alter riociguat AUC (estimated ratio 96%). Further riociguat dose adjustment s,ss beyond the individual dose-adjustment scheme is not necessary Acetylsalicylic acid No relevant Pre- and coadministration of acetylsalicylic acid (500 mg qd) did not signiﬁcantly alter  difference riociguat AUC (estimated ratio 96%). Riociguat did not potentiate the effect of acetylsalicylic acid on bleeding time or platelet aggregation. Further riociguat dose adjustment beyond the individual dose-adjustment scheme is not necessary AUC area under the plasma concentration–time curve, AUC AUC from time zero to inﬁnity, AUC AUC divided by dose per kilogram body ? norm weight, AUC AUC for the dose interval s at steady state, BCRP breast cancer resistance protein, bid twice daily, C maximum concentration s,ss max in plasma, C C divided by dose per kilogram body weight, CTEPH chronic thromboembolic pulmonary hypertension, CYP cyto- max,norm max chrome P450, HIV human immunodeﬁciency virus, PAH pulmonary arterial hypertension, P-gp P-glycoprotein, qd once daily, tid three times daily 4.3 Comorbidities total study populations of smokers and non-smokers com- bined, irrespective of renal function (Table 2). 4.3.1 Renal Impairment In a mechanistic population pharmacokinetic analysis of data from studies in individuals with hepatic or renal Individuals with renal impairment were found to have impairment, riociguat pharmacokinetics were well descri- reduced apparent oral clearance (CL/F) of riociguat com- bed by a two-compartment model . Total riociguat pared with healthy controls after administration of a single clearance occurred predominantly via metabolism to M1. dose, but no direct relationship was observed with the Renal impairment reduced riociguat and M1 clearance but severity of impairment (4.07 L/h in healthy controls vs. had only moderate effects on drug exposure in this model 2.67, 2.00, and 2.61 L/h in individuals with mild, moder- because of the contribution of biliary/fecal excretion to the ate, and severe renal impairment, respectively) . total clearance of riociguat . However, renal clearance of riociguat progressively decreased with increasing renal impairment (- 32, - 67, 4.3.2 Hepatic Impairment and - 82% reductions for mild, moderate, and severe renal impairment, respectively, vs. healthy controls), and showed Compared with healthy controls, single-dose riociguat a monotonically increasing relationship with creatinine exposure was signiﬁcantly increased by moderate hepatic clearance (CrCl; calculated using the Cockcroft–Gault impairment (Child–Pugh B; estimated ratio 153%) but not formula, as in all pharmacokinetic/pharmacodynamic by mild hepatic impairment (Child–Pugh A; estimated ratio studies). Both CL/F and renal clearance of M1 decreased 106%) (Table 1). The half-life of M1 was prolonged progressively with increasing renal impairment . by approximately ? 24 and ? 43% in individuals with mild Riociguat exposure (AUC ) was increased in the and moderate hepatic impairment, respectively, compared norm presence of renal impairment but showed no consistent with healthy controls. The antagonistic effects of reduced pattern with increasing severity of renal impairment: the formation and elimination of metabolite M1 in individuals estimated ratio of exposure versus healthy controls was with hepatic impairment led to M1 exposures that were 143, 204, and 144% in those with mild, moderate, and broadly similar to those observed in healthy controls . severe renal impairment, respectively (Table 1). Rio- Non-smokers with hepatic impairment had greater expo- ciguat and M1 exposures were highly variable and the sure to riociguat than the total study populations (smokers ranges overlapped with those observed in healthy controls. and non-smokers combined) with hepatic impairment Non-smokers had greater exposure to riociguat than the (Table 2). Clinical Pharmacokinetics and Pharmacodynamics of Riociguat 653 Table 2 Riociguat exposure by Median AUC (kgh/L) ?,norm smoking status (non-smokers compared with smokers and Non-smokers Smokers and non-smokers non-smokers combined) in Renal impairment study  healthy individuals and individuals with renal or hepatic Normal (CrCl [80 mL/min) 22.0 21.4 impairment Mild impairment (CrCl 50–80 mL/min) 40.4 33.9 Moderate impairment (CrCl 30–49 mL/min) 65.2 40.9 Severe impairment (CrCl \ 30 mL/min) 40.4 33.6 Hepatic impairment study  Mild impairment (Child–Pugh A) 43.3 32.7 Control A 30.2 30.2 Moderate impairment (Child–Pugh B) 39.4 36.3 Control B 31.5 30.5 AUC area under the plasma concentration–time curve from time zero to inﬁnity divided by dose per ?,norm kilogram body weight, CrCl creatinine clearance In the mechanistic population pharmacokinetic model 5 Pharmacokinetic Properties in Patients described in Sect. 4.3.1, hepatic impairment had a limited with Pulmonary Arterial Hypertension effect on total riociguat exposure and no signiﬁcant effect and Chronic Thromboembolic Pulmonary on riociguat or M1 clearance. Hypertension 4.4 Age Key assessments of riociguat pharmacokinetics were per- formed in patients with PAH or CTEPH in a phase II, Riociguat half-life was prolonged by ? 41% and riociguat proof-of-concept, single-dose study , a phase II, open- renal clearance was decreased by - 28% in healthy elderly label, multiple-dose study (ClinicalTrials.gov identiﬁer: individuals (aged 64.5–80 years) compared with healthy NCT00454558) , and a population pharmacokinetic young individuals (aged 18–45 years) . Renal clear- analysis of patients in the PATENT and CHEST studies ance showed a 28% reduction in elderly versus young . As in healthy individuals, riociguat is rapidly absor- individuals, as determined by direct assessment of renal bed in patients with PAH or CTEPH (time to reach C max clearance. The elderly had ? 40% higher riociguat expo- after a single dose 0.25–1.5 h) . Riociguat exposure is sure (AUC) than the young (Table 1) but this difference dose proportional, with pronounced interindividual vari- was not statistically signiﬁcant and was reduced to ? 28% ability (60%) but low intraindividual variability (35%) when exposure was normalized to body weight. M1 . The half-life of riociguat is approximately 12 h in showed less pronounced differences between the elderly patients compared with approximately 7 h in healthy and the young than riociguat. Despite the pharmacokinetic individuals [18, 19]. The resulting exposure is approxi- differences, riociguat was well tolerated with a comparable mately two- to threefold higher at steady state compared safety proﬁle in both age groups . On population with healthy subjects . Mean AUC after single doses pharmacokinetic analysis, age itself was not a signiﬁcant of 1 and 2.5 mg in the proof-of-concept study was 602 and covariate for riociguat clearance, but was strongly corre- 1411 lgh/L, respectively . Mean AUC under steady- lated with CrCl, which was a signiﬁcant covariate . state conditions following multiple doses of riociguat 0.5–2.5 mg three times daily in the pivotal phase III trials 4.5 Sex was 1174 lgh/L in patients with PAH and 1433 lgh/L in patients with CTEPH (Table 3). Based on investiga- In healthy volunteers who received a single 1 or 2.5 mg tions early in the clinical trial program, riociguat accu- dose, riociguat C was ? 32 and ? 35% higher, respec- mulation up to steady state is anticipated within the ﬁrst max tively, in women than in men . The difference became few days of administration (unpublished data). No undue smaller when riociguat C was adjusted for body weight accumulation beyond steady state was observed; exposure max (approximately ? 20%), but remained signiﬁcant. How- in the phase III trials remained stable from day 14 to day ever, riociguat AUC showed no signiﬁcant difference 168 . In the phase III trials, riociguat/M1 plasma between women and men [30, 32]. M1 pharmacokinetics concentrations were well described by a linear one-com- showed a similar pattern . partment model, with no evidence for time- or dose- 654 R. Frey et al. Table 3 Riociguat exposure data at steady state following multiple doses (individual dose adjustment up to 2.5 mg three times daily) of riociguat in PATENT-1 and CHEST-1 Riociguat pharmacokinetic parameter Patients with PAH: PATENT-1 Patients with CTEPH: CHEST-1 study (n = 228) study (n = 153) AUC (lgh/L) Geometric mean (CV) 1174 (55.0) 1433 (45.2) Median 1226 1475 C (lg/L) max Geometric mean (CV) 176 (47.8) 207 (38.9) Median 178 213 C (lg/L) trough Geometric mean (CV) 113 (69.6) 145 (58.4) Median 124 152 AUC area under the plasma concentration–time curve at steady state, C maximum concentration in plasma, CTEPH chronic thromboembolic T max pulmonary hypertension, C minimum concentration in plasma, CV coefﬁcient of variation, PAH pulmonary arterial hypertension trough dependent alterations . The absorption rate constant, compensatory response to a vasodilating agent . Heart clearance, and volume of distribution for riociguat were rate correlated directly with riociguat plasma concentra- estimated to be 2.17/h, 1.81 L/h, and 32.3 L, respectively tions (Fig. 3). Mean arterial and diastolic blood pressure . Covariate effects in the model included smoking were slightly but signiﬁcantly decreased following status, comedication with the endothelin receptor antago- administration of riociguat 1 or 5 mg compared with pla- nist bosentan, bilirubin concentration, and baseline CrCl. cebo, whereas SBP was not signiﬁcantly affected, likely Smokers had higher riociguat clearance than non-smokers; because of the compensatory increase in heart rate and in patients not receiving bosentan, taking into account presumably cardiac output. Orthostatic reactions were most other covariate effects (bilirubin concentration and CrCl), common in the 5 mg dose group, which was also the only median riociguat clearance was 1.8 L/h in non-smokers dose group to show a signiﬁcant increase in levels of and 4.2 L/h in smokers in the PATENT studies, and 1.6 L/ norepinephrine compared with placebo. A signiﬁcant, h in non-smokers and 4.2 L/h in smokers in the CHEST dose-dependent increase in plasma renin activity was studies. The ﬁnal pharmacokinetic model in patients indi- observed after administration of riociguat 1–5 mg but this cated that smoking was associated with a 120% increase in was not accompanied by increases in plasma aldosterone or riociguat clearance . Bosentan comedication was angiotensin II levels . associated with a slight increase in riociguat clearance in the PATENT studies (described further in Sect. 7.1). 6.2 Pharmacodynamics in Patients with Pulmonary Consistent with ﬁndings in healthy individuals, riociguat Hypertension exposure showed a modest increase with age in patients with PAH or CTEPH in PATENT-1 and CHEST-1, In patients with PAH or CTEPH, single doses of riociguat respectively . Riociguat AUC was approximately 10% [1 mg (n = 5) or 2.5 mg (n = 10)] caused clinically rele- higher in women than in men , and this modest dif- vant, statistically signiﬁcant, concentration-dependent ference may be partly due to differences in body weight decreases from baseline in mean pulmonary arterial pres- between women and men. sure, pulmonary vascular resistance (PVR), SBP, and sys- temic vascular resistance (SVR), as well as an increase in cardiac index . Heart rate was signiﬁcantly increased from baseline by riociguat 2.5 mg but not 1 mg. Both 6 Pharmacodynamics and Pharmacokinetic/ doses of riociguat showed greater potency and duration of Pharmacodynamic Relationships action than inhaled NO (10–20 ppm for 10 min) in reducing PVR, SBP, and SVR, and increasing cardiac 6.1 Pharmacodynamics in Healthy Volunteers index. The 2.5 mg dose of riociguat reduced mean pul- monary arterial pressure to a greater extent than NO. In healthy young volunteers, single doses of riociguat Riociguat did not worsen gas exchange or ventilation/per- (1–5 mg) led to a dose-dependent increase in heart rate by fusion matching despite causing strong pulmonary 4–11 beats/min compared with placebo, reﬂecting a vasodilation . Clinical Pharmacokinetics and Pharmacodynamics of Riociguat 655 EC treatment with the proton pump inhibitor omeprazole 1.5 40 mg once daily reduced riociguat C and AUC by - 35 max and - 26%, respectively . Co-treatment with the H 1.4 antagonist ranitidine (150 mg once daily) reduced riociguat 1.3 C by approximately - 15% and AUC by approximately max 1.2 - 10% . Riociguat is a substrate of speciﬁc CYP proteins and the 1.1 transporter proteins P-gp and BCRP [15, 18, 19]. Riociguat 1.0 and M1 are neither inhibitors nor inducers of any major 0.9 CYP isoforms in vitro at therapeutic concentrations, but they inhibit CYP1A1 (inhibition constant 0.6 lM each) 0 50 100 150 . Therefore, clinically relevant interactions of riociguat Plasma concentration of riociguat (µg/L) with comedications that are signiﬁcantly cleared via Fig. 3 Relationship between riociguat plasma concentration and CYP1A1 (e.g. erlotinib or granisetron) cannot be ruled out. heart rate over 1 min, described using a sigmoid E model. Relative max Pre- and coadministration of clarithromycin (500 mg change in heart rate = 1 ? [(0.47 9 Cp)/(82.3 ? Cp)]. The shaded twice daily), a strong and selective CYP3A4 inhibitor and a area represents the effective concentrations as characterized using the weak-to-moderate P-gp inhibitor, moderately increased sigmoid E model. Cp riociguat plasma concentration, EC half max 50 maximal effective concentration, E half of E , E estimated riociguat AUC by ? 41% (Table 1) without a signiﬁcant 50 max max maximal effect. Reproduced from Frey R, et al. J Clin Pharmacol. change in C . Metabolite M1 AUC increased by max 2008;48(8):926–34, with permission. Copyright 2008 John Wiley ? 19%, again with no signiﬁcant change in C . Pre- and max & Sons, Inc. coadministration of the strong CYP3A4 and P-gp inhibitor ketoconazole (400 mg once daily) increased riociguat 6.3 Pharmacokinetic/Pharmacodynamic C , and AUC increased by approximately ? 46 and max Relationships ? 150%, respectively (Table 1). Riociguat half-life increased from 7.4 to 9.2 h, and CL/F of riociguat In an analysis of patients with PAH or CTEPH in the decreased from 6.1 to 2.4 L/h. Metabolite M1 C and max PATENT and CHEST studies, respectively, trough rio- AUC decreased by approximately - 49 and - 24%, ciguat plasma concentrations were correlated with changes respectively, and M1 half-life increased from 16.2 to from baseline in hemodynamic parameters, including PVR, 18.3 h . SBP, and cardiac output, demonstrating correspondence The sensitive CYP3A4 substrate midazolam (7.5 mg) between exposure and hemodynamic response . The showed no signiﬁcant interaction with riociguat pre- and change from baseline in 6MWD did not correlate directly co-treatment, conﬁrming that riociguat does not inﬂuence with riociguat exposure (data not shown), but it did cor- the metabolism of other drugs via CYP3A4 . relate with the changes in hemodynamic parameters, par- Female patients with PAH are advised to avoid preg- ticularly PVR. The lack of direct correlation between nancy , and oral contraception is the main method used riociguat exposure and 6MWD suggests that many differ- . The interaction of riociguat with levonorgestrel ent factors determine exercise capacity in patients with (0.15 mg) and ethinylestradiol (0.03 mg) in a combined PAH or CTEPH . The correlation between 6MWD and oral contraceptive was therefore assessed. Riociguat pre- hemodynamic parameters suggests that an improvement in and co-treatment did not alter the AUC of levonorgestrel or blood supply to skeletal muscles (possibly via an increase ethinylestradiol, or the C of levonorgestrel; the C of max max in cardiac output ) may contribute to the improvement ethinylestradiol was increased by ? 20% but this was not in exercise capacity. expected to have an adverse impact on the efﬁcacy of the contraceptive. Riociguat exposure was not inﬂuenced by coadministration of levonorgestrel-ethinylestradiol . 7 Drug–Drug Interactions Bosentan is a PAH-targeted therapy that induces CYP3A4 and may be coadministered with riociguat . 7.1 Pharmacokinetic Interactions Bosentan was associated with a moderate decrease in rio- ciguat AUC (- 27%) in patients with PAH and CTEPH in As riociguat solubility is inﬂuenced by pH, drugs that alter the PATENT and CHEST studies (Table 1). This gastric pH may affect riociguat absorption (Table 1). Co- effect was not considered sufﬁcient to necessitate dose treatment with an antacid [10 mL of aluminum hydrox- adjustment of riociguat [19, 42]. Riociguat and the PAH- ide/magnesium hydroxide (Maalox )] reduced riociguat speciﬁc therapy sildenaﬁl [a phosphodiesterase-5 (PDE-5) C and AUC by - 56 and - 34%, respectively . Co- max inhibitor] showed no mutual pharmacokinetic interaction Heart rate over 1 min, ratio of post dosing versus baseline 50 656 R. Frey et al. in vivo, but an additive hemodynamic effect was observed to adverse events occurred in two patients (1%) in the in a small interaction study (NCT00680654) [15, 18, 19] 2.5 mg–maximum group and in three patients (2%) in the and potentially unfavorable safety signals were observed in placebo group. None of the deaths were considered related to a long-term study of the combination of riociguat with the study drug . In PATENT-2, the estimated survival sildenaﬁl (PATENT PLUS)  (see Sect. 7.2). rate was 97% at 1 year . In CHEST-1, deaths related to No clinically relevant drug–drug interactions due to adverse events occurred in two patients (1%) in the riociguat inhibition of transporters such as P-gp or BCRP, or organic group and three patients (3%) in the placebo group . In anion transporting polypeptides OATP1B1 and OATP1B3, CHEST-2, estimated overall survival at 1 year was 97% organic anion transporters OAT1 and OAT3, or organic . cation transporters (OCTs) by riociguat are expected . Thrombosis contributes to the pulmonary arteriopathy Furthermore, metabolite M1 (BAY 60-4552) is not an that is present in CTEPH and PAH [44, 45], and long-term inhibitor of P-gp, BCRP, or OCTs at relevant therapeutic use of oral anticoagulants is recommended for patients with concentrations . CTEPH and some patients with PAH [1, 46]. Riociguat is All clinically relevant interactions are described in the thus likely to be coadministered with warfarin . product labels . Therefore, potential interactions between riociguat and warfarin were investigated in healthy volunteers. Pre- and 7.2 Pharmacodynamic Interactions coadministration of riociguat 2.5 mg three times daily did not inﬂuence warfarin pharmacodynamics: the 90% conﬁ- As described in Sect. 2.2, sGC activity is increased to a dence interval (CI) for the ratio (warfarin ? riociguat)/ greater extent by riociguat in combination with an NO- (warfarin ? placebo) was 0.97–1.01 for prothrombin time releasing drug than by riociguat alone . Thus, riociguat AUC and 1.00–1.06 for factor VII percentage activity 96h and NO-releasing drugs may be expected to have an AUC . Warfarin and riociguat showed no clinically rel- 96h additive effect on the systemic circulation. In a phase I evant mutual pharmacokinetic interactions . study in healthy volunteers, administration of sublingual In patients with PAH, acetylsalicylic acid might be nitroglycerin 0.4 mg 4 h after a single dose of riociguat administered at a low dose for anticoagulant activity, or at 2.5 mg resulted in a pronounced pharmacodynamic inter- a high dose for pain relief. The potential of riociguat to action with signiﬁcant hypotensive effects necessitating increase the anti-aggregatory effect of acetylsalicylic acid drug withdrawal (which could not be quantiﬁed because was therefore evaluated . In healthy individuals, the the study was terminated after only six patients had been effects of acetylsalicylic acid 500 mg on bleeding time, enrolled) . platelet aggregation, and serum thromboxane B levels As riociguat and PDE-5 inhibitors, such as sildenaﬁl, both were not inﬂuenced by coadministration of riociguat act on the NO–sGC–cGMP pathway, with different targets/ 2.5 mg. Thus, no clinically relevant pharmacodynamic mechanisms of action, they may be expected to have an interaction between riociguat and acetylsalicylic acid was additive or synergistic effect by increasing the intracellular detected . cGMP concentration if used in combination. The addition of riociguat (up to 2.5 mg three times daily) in patients with PAH receiving stable sildenaﬁl therapy (20 mg three times 8 Discussion daily) was evaluated in the small PATENT PLUS study (n = 18), which had a 12-week placebo-controlled phase The pharmacokinetic and pharmacodynamic data for rio- followed by an uncontrolled long-term extension phase . ciguat have been used to guide its clinical use in patients The addition of riociguat to sildenaﬁl had no signiﬁcant with PAH and CTEPH. The pharmacokinetics of riociguat beneﬁcial effect on WHO functional class, 6MWD, or have been extensively characterized in phase I and II hemodynamic parameters, including mean pulmonary arte- studies and in population pharmacokinetic modeling anal- rial pressure, PVR, or cardiac index, in the placebo-con- yses. Based on data from pharmacokinetic studies, rio- trolled phase. Adverse events were reported by 12 patients ciguat shows complete oral absorption with dose- receiving riociguat during the randomized phase; these were proportional exposure over the therapeutic dose range considered to be drug-related in seven patients. During the (0.5–2.5 mg) and can be taken with or without food extension phase (mean total treatment duration 305 days), [18, 19, 28, 30]. Crushed tablets and oral suspensions of there were high rates of discontinuation due to hypotension riociguat are interchangeable with whole tablets . This (23.5%; three adverse events and one serious adverse event, may be useful in populations who have difﬁculty swal- all considered related to study drug) and a mortality rate of lowing whole tablets. 18% (3/17 patients); none of the deaths were considered to be Population pharmacokinetic analyses conﬁrm that rio- drug-related. For comparison, in PATENT-1, deaths related ciguat pharmacokinetics are described by a one- Clinical Pharmacokinetics and Pharmacodynamics of Riociguat 657 compartment model in patients with PAH or CTEPH and that induce CYP1A1 (e.g. consumption of cruciferous are similar in the two conditions, but exposure is increased vegetables or charcoal-broiled meat [55, 56]) may con- compared with healthy individuals [32, 33]. While some of tribute to interindividual variability in the separate sub- the expected intrinsic factors, such as age (with reductions populations of smokers and non-smokers . However, in renal excretion and/or hepatobiliary clearance), may there is no reason to suspect that these factors differed contribute in part to this increase in exposure, the under- substantially between smokers and non-smokers in the lying disease per se alters renal and/or hepatobiliary riociguat studies, and the effect of smoking on riociguat elimination of drugs owing to various factors, including exposure has been observed in studies controlled for diet reduced cardiac output, liver shunts, and worsening renal and environment . CYP induction by smoking is dose- function [50–54]. Accordingly, patient covariates such as dependent  and a dedicated analysis of the phase II and renal function and bilirubin reduced unexplained III studies of riociguat suggested such a relationship; interindividual variability of systemic clearance in patients however, the number of patients was too small to permit with PAH or CTEPH described via population pharma- ﬁrm conclusions (unpublished data). The European label cokinetic approaches [34, 37]. In the population pharma- advises that dose adjustments may be necessary in patients cokinetic analyses, only renal function appeared to be a who start or stop smoking during riociguat treatment , signiﬁcant covariate affecting exposure . Of note, while the US label notes that patients who smoke may median CrCl levels at baseline in the PATENT and CHEST require riociguat dosages higher than 2.5 mg three times studies were 86.6 and 72.8 mL/min, respectively, sug- daily if tolerated, and that a dose decrease may be required gesting a degree of renal impairment . Mean cardiac in patients who stop smoking . index at baseline in the CHEST study population was To reduce the risk of hypotension, the use of riociguat in 2.2–2.3 L/min/m , suggesting impaired cardiac function patients with SBP\95 mmHg at treatment initiation is . contraindicated in the European label . During rio- Differences in riociguat exposure due to age or sex are ciguat therapy, SBP\95 mmHg is not a contraindication, not clinically relevant and do not warrant further dose although dose reduction is recommended if SBP below this adjustment beyond the approved individual dose-adjust- level is accompanied by signs or symptoms of hypotension ment scheme [30, 32, 40]. However, particular care should . The US label does not have a contraindication based be exercised during individual dose adjustment in elderly on SBP, but a dose reduction is recommended if the patient patients because riociguat exposure tends to be somewhat has symptoms of hypotension. Uptitration to a maximum higher in older versus younger individuals, partly due to dose of 2.5 mg three times daily is recommended if SBP differences in body weight and renal clearance [19, 32]. remains [95 mmHg and the patient has no signs or Renal impairment is associated with reduced riociguat symptoms of hypotension . clearance. Dose adjustment of riociguat should be per- The pharmacodynamic effects of riociguat on systemic formed with particular care in patients with renal impair- and pulmonary circulation correlated with riociguat plasma ment [19, 30, 33]. Data are limited for patients with severe concentrations [27, 35, 36], which showed moderate to renal impairment (CrCl\30 mL/min) and riociguat is high interindividual variability [27, 28]. The riociguat therefore not recommended for these patients in the individual dose-adjustment scheme, including the three- European label , although this restriction is not applied times-daily dosing (Fig. S1 in the Online Resource) was in the US label . No data are available for patients with developed in part to manage this variability and the indi- CrCl\15 mL/min or on dialysis, and riociguat is therefore vidual sensitivity to riociguat exposure, and is based on not recommended in these patients in both the European data from phase I and II studies; the rationale, develop- and US labels [18, 19]. ment, and implementation of the scheme have been Dose adjustment of riociguat should be performed with described elsewhere [13, 14]. Brieﬂy, riociguat doses are particular care in patients with moderate hepatic impair- adjusted at 2-week intervals according to SBP (which ment (Child–Pugh B) because drug exposure is increased correlates with riociguat plasma concentrations in patients . Mild hepatic impairment (Child–Pugh A) is not with PAH or CTEPH [35, 36]) and signs/symptoms of associated with signiﬁcant alteration of riociguat exposure hypotension [18, 19]. The 2-week interval was chosen . There is no experience in patients with severe hepatic based on the time taken to reach hemodynamic steady impairment (Child–Pugh C); for these patients, riociguat is state, and convenience for the patient . This approach contraindicated in the European label  and is not rec- allows for adjustment to the highest tolerated riociguat ommended in the US label . dose for each patient, has been proven in phase III clinical Smoking is one of the main factors contributing to the studies, and appears to be practical and straightforward in variability of riociguat exposure; quantitative variations in clinical practice. Three-times-daily dosing would be smoking habits or other environmental or dietary factors expected to provide a ﬂat plasma concentration–time 658 R. Frey et al. proﬁle, which could be beneﬁcial for an agent with risk of developing PAH in patients with HIV  and the hemodynamic effects. Intraindividual variability in rio- recognition of PAH associated with HIV in the interna- ciguat plasma concentrations is low, suggesting that tional classiﬁcation of PH . exposure should remain consistent over time once the Because of its low potential for drug–drug interactions, appropriate dose for an individual patient has been estab- riociguat can be used in combination with endothelin lished . In support of this, the maintenance dose of receptor antagonists and/or prostanoids, as conﬁrmed in the riociguat was not changed in the majority of patients during PATENT study [13, 16]. In contrast to riociguat, bosentan the open-label phases of the long-term extension trials is an inducer of CYP3A4 and CYP2C9 and therefore PATENT-2 and CHEST-2 [16, 17]. interacts with multiple other drugs [63, 64]. Coadminis- Riociguat has a low risk of clinically relevant drug tration of riociguat with bosentan is associated with interactions due to its clearance and excretion by multiple increased clearance and reduced plasma concentrations of CYP and transporter enzymes and its lack of effect on riociguat, but does not necessitate any changes in treatment major CYP isoforms at therapeutic levels . However, beyond the individual dose-adjustment scheme [19, 30]. absorption is affected by gastric pH, and antacids should Coadministration of riociguat with nitrates or NO not be administered within 1 h of receiving riociguat donors is contraindicated in the European and US labels according to the US label . The European label advises because of the risk of developing hypotension [15, 18, 19]. that antacids should be taken at least 2 h before or 1 h after Coadministration of riociguat with PDE-5 inhibitors is also riociguat . Proton pump inhibitors and H antagonists contraindicated [18, 19], based on the unfavorable safety also affect riociguat bioavailability, but to a lesser extent signals and lack of favorable clinical effect observed fol- than antacids ; the use of proton pump inhibitors or H lowing addition of riociguat to sildenaﬁl in the PATENT antagonists does not require adaptation of dosing beyond PLUS study . the individual dose-adjustment scheme. The same is true However, it is possible that patients who are not for coadministration of riociguat with strong selective achieving treatment goals on a PDE-5 inhibitor may beneﬁt CYP3A4 inhibitors, combined oral contraceptives , from switching to riociguat, as suggested by data from the acetylsalicylic acid , or warfarin [18, 19, 48]. By RESPITE study . This is consistent with the modes of contrast, the PDE-5 inhibitors sildenaﬁl and tadalaﬁl are action of riociguat and PDE-5 inhibitors: riociguat can metabolized predominantly by CYP3A, and concomitant stimulate sGC independently of NO, while sensitizing sGC use of strong CYP3A inhibitors is not recommended or to low levels of NO, whereas PDE-5 inhibitors (which requires dose reductions [58–61]. prevent degradation of cGMP) depend on the presence of Although coadministration of riociguat with selective sufﬁcient upstream NO and may therefore be limited by the CYP3A4 inhibitors does not require additional dose NO deﬁciency found in PH . In cases of switching from adaptation , concomitant use with strong multipath- a PDE-5 inhibitor to riociguat (and vice versa), the tran- way CYP and P-gp/BCRP inhibitors, such as ketocona- sition must include a washout phase to avoid an overlap in zole and HIV protease inhibitors, should be approached exposure. Based on the half-lives of the respective drugs, with caution as there is a risk of hypotension, as riociguat should not be administered within 24 h of explained above [19, 31]; the US label recommends receiving sildenaﬁl, or within 24 h before or 48 h after considering a reduced riociguat starting dose of 0.5 mg receiving tadalaﬁl, as described in the US label . three times daily in this context . 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 9 Conclusions used antiretroviral combinations is ongoing (NCT02556268; n = 40). This trial was based on in vitro The pharmacodynamic and pharmacokinetic properties of studies of interactions between riociguat and anti-HIV riociguat have been comprehensively evaluated in healthy drugs (unpublished data). The aims of the study were to individuals and patients with PH. These properties support investigate the pharmacokinetic drug–drug interaction the individual dose-adjustment scheme used in phase II and potential between riociguat and ﬁxed-dose HIV III clinical trials of riociguat and are reﬂected in the pre- antiretroviral therapies (Atripla , Complera , Stribild , scribing information for riociguat . The novel mode of or Triumeq ) or any approved antiretroviral protease action of riociguat, its individualized dose-adjustment inhibitor in combination with (preferably) Triumeq , and regimen, and its low risk of drug–drug interactions support to assess the safety and tolerability of riociguat treatment its uptake in the pharmacologic treatment of PAH and as in combination with these therapies. The potential the only approved pharmacotherapy for inoperable or importance of such studies is illustrated by the increased persistent/recurrent CTEPH. Clinical Pharmacokinetics and Pharmacodynamics of Riociguat 659 Acknowledgements Medical writing assistance was provided by double-blind, randomized, placebo-controlled, dose-ranging Adelphi Communications Ltd, funded by Bayer AG. hemodynamic study. Circulation. 2013;128(5):502–11. 11. Bonderman D, Pretsch I, Steringer-Mascherbauer R, Jansa P, Compliance with Ethical Standards Rosenkranz S, Tufaro C, et al. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, Funding Support for the preparation of this manuscript was provided placebo-controlled, single-dose study. Chest. 2014;146(5): by Bayer AG. 1274–85. 12. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa Conﬂict of interest Reiner Frey is a former employee of, and now a P, Kim NH, et al. Riociguat for the treatment of chronic throm- consultant to, Bayer AG. 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Published: Oct 30, 2017