Absorption of Riociguat (BAY 63-2521): Bioavailability,Food Effects,and Dose Proportionality

Abstract

Riociguat (BAY 63-2521) is the first member of a novel class of compounds, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide (NO) and stimulates sGC independent of NO availability. To characterize the biopharmaceutical properties of riociguat, including absolute bioavailability, food interactions, and dose proportionality, riociguat (intravenous/oral) was administered to healthy male subjects in 3 open-label, randomized, crossover studies: absolute bioavailability (1 mg; n = 22), food effect (2.5 mg; n = 23), and dose proportionality (0.5–2.5 mg; n = 24). Absolute bioavailability was 94% (95% confidence interval [CI], 83%–107%). Riociguat absorption was delayed by a high-fat breakfast with little effect on the extent of absorption (area under the concentration-time curve [AUC]_fed : AUC_fasted, 88% [90% CI, 82%–95%]). Exposure to riociguat was dose proportional over all doses (common slope of AUC, 1.09 [90% CI, 1.04–1.14]; maximum concentration, 0.98 [90% CI, 0.93–1.04]). Intraindividual variability was low; interindividual variability was moderate to high. Riociguat was well tolerated, and adverse events were consistent with the mode of action. In conclusion, riociguat shows complete oral absorption, no clinically relevant food effects, and a dose-proportional increase in systemic exposure (0.5–2.5 mg). These data support the suitability of the individualized dose adjustment scheme employed in the phase 3 clinical studies.

Keywords

pharmacokinetics food interaction pulmonary hypertension

Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature characterized by vasoconstriction, vascular remodeling, and pathologically increased pulmonary arterial pressure.¹ The workload of the right ventricle of the heart is therefore increased, leading to right ventricular failure and, eventually, death. PH is a devastating disease with a poor prognosis; despite the availability of modern therapies, 3-year mortality is 32% among patients with pulmonary arterial hypertension (PAH).²

In the healthy lung, a low-pressure state is maintained in the pulmonary vasculature via vasoconstrictive agents and vasodilatory agents, such as nitric oxide (NO).³ NO acts on soluble guanylate cyclase (sGC),⁴ catalyzing the generation of cyclic guanosine monophosphate (cGMP), which regulates vascular tone, proliferation, fibrosis, and inflammation.^5,6 In PH, endothelial dysfunction results in insufficient stimulation of the NO-sGC-cGMP pathway, leading to vascular injury, vasoconstriction, and vascular remodeling in the pulmonary circulation.^5,6

Riociguat (BAY 63-2521) is the first member of a novel class of compounds, the sGC stimulators.⁷ With a dual mode of action, riociguat sensitizes sGC to endogenous NO and also directly stimulates sGC independent of NO availability.⁷ Riociguat is the first drug to consistently demonstrate robust efficacy in two separate PH indications: PAH and chronic thromboembolic PH (CTEPH).^8,9

In the phase 3 CHEST-1 and PATENT-1 studies, riociguat (0.5–2.5 mg 3 times daily [tid]) significantly improved exercise capacity and a range of clinically meaningful secondary endpoints, including World Health Organization (WHO) functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and hemodynamic parameters, in patients with CTEPH or PAH.^8,9

Previous pharmacokinetic studies have indicated that riociguat is rapidly absorbed, has high oral bioavailability, and shows dose-proportional pharmacokinetics.^7,10,11 Here we report the results of 3 additional phase 1 clinical studies that characterize further the pharmacokinetic properties of riociguat with regard to absolute bioavailability, food effects, and dose proportionality in healthy male subjects. These novel data contribute to the pharmacokinetic profile of riociguat.

METHODS

Study population

Three separate open-label, randomized crossover studies were conducted between May and October 2009 at a single center (the in-house clinical research unit of the Clinical Pharmacology Department of the Bayer Research Center, Wuppertal, Germany). Healthy male subjects were eligible for the studies if they were white, aged 18–45 years, and had a body mass index (BMI) of 18–30 (calculated as weight in kilograms divided by the square of height in meters). Exclusion criteria included participation in another clinical study during the preceding 3 months; a febrile illness within 1 week before the start of the study; administration of medication within the 2 weeks preceding the study that could interfere with the investigational drug; and a medical disorder, condition, or history of such that would have impaired the subject's ability to participate or complete the study, such as cardiovascular disease, systemic hypotension, and hepatic or renal impairment. Women were excluded to minimize the variability of the pharmacokinetic results.

Participants gave written informed consent to participate before any study-specific procedures. These studies were conducted in accordance with the currently accepted version of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice Guideline (Note for Guidance on Good Clinical Practice), the European Union Directive 2001/20/EC, and the German Drug Law (Arzneimittelgesetz). The independent ethics committee of the North-Rhine Medical Council, Düsseldorf, Germany, provided a favorable opinion on the study protocol. The principal investigators were our coauthors CH and MR.

Study Design

Absolute bioavailability study. After 10 hours of fasting, subjects were randomly assigned to receive a single oral dose of an immediate-release tablet of riociguat 1 mg and riociguat 1 mg as a 60-minute intravenous (iv) infusion in a crossover design. The primary parameters assessed were area under the concentration-time curve (AUC)/dose and maximum plasma concentration (C_max)/dose.

During phase 1 development, it became apparent that smoking, via induction of CYP1A1, accelerates the metabolism of riociguat leading to reduced riociguat exposure. Therefore, in this study, absolute bioavailability was assessed separately for smokers (n = 7) and nonsmokers (n = 15).

Food effects study. In this crossover study, subjects were randomly assigned to receive a riociguat 2.5-mg immediate-release tablet either after 10 hours of fasting or within 5 minutes of finishing a standardized high-fat and high-calorie breakfast (which had been eaten in ≤30 minutes). This procedure was in line with published guidance on assessing food-drug interactions.¹⁰ The primary parameters assessed were AUC and C_max.

Dose proportionality study. In this randomized, open-label, 5-fold crossover study, subjects received a single oral tablet of riociguat 0.5, 1.0, 1.5, 2.0, or 2.5 mg after fasting for 10 hours. For each subject, the study consisted of 5 separate dosing periods, each with 1 screening day and an in-house observation period from the evening before until 72 hours after riociguat administration. The primary parameters assessed were AUC, C_max, AUC/dose, and C_max/dose.

Pharmacokinetic evaluations

In all studies, blood was collected before dose administration (0 hour) and at regular intervals thereafter (up to 72 hours after dose administration) for the determination of plasma riociguat and M1 (BAY 60-4552; the major metabolite of riociguat) concentrations. Concentrations of riociguat and M1 were determined using a fully validated high-performance liquid chromatography/mass spectrometry assay, with methoxycarbonyl [²H₃]riociguat and [²H₃]M1 as the internal standards. The calibration ranges and quality control sample concentrations for riociguat and M1 in plasma are listed in Table S1, available online.

Quantitative urine analysis was performed using a fully validated high-performance liquid chromatography/mass spectrometry assay. [²H₃]riociguat and [²H₃]M1 were used as the internal standards. The calibration range was 1.00–100.00 μg/L for riociguat and 10–1,000 μg/L for M1. For the quantitative analysis of riociguat, quality control samples in the concentration range 3–800 μg/L were determined with an accuracy of 101%–107% and a precision of 2%–4%. For the quantitative analysis of M1, quality control samples in the concentration range 3–800 μg/L were determined with an accuracy of 99%–103% and a precision of 2%–4%.

Blood and urine samples were all stored at or below −15°C and analyzed within 3 months after sampling. Individual plasma concentration-time data were used to calculate the AUC, C_max, time to maximum plasma concentration (t_max), and terminal elimination half-life (t_1/2) utilizing model-independent methods with WinNonlin (version 4.1; Pharsight, Mountain View, CA) in conjunction with the Automation Extension (Bayer). The linear-logarithmic trapezoidal method was used to calculate AUC_0–∞ by linear least squares regression after logarithmic transformation of the terminal concentrations. Systemic clearance (CL) and the mean volume of distribution at steady state (V_SS) of riociguat were also calculated. Plasma concentration-time courses for riociguat (calculated when two-thirds or more of the individual values were greater than the lower limit of quantification) are presented as geometric mean values. Renal clearance (CL_R) was determined from the amount of riociguat excreted in the urine and the AUC.

Statistical analysis

Statistical evaluation was performed using SAS software (SAS Institute, Cary, NC). The logarithms of AUC/dose and C_max/dose of riociguat and M1 were subjected to an analysis of variance (ANOVA) with the factors “treatment,” “period,” “sequence,” and “subject (sequence).” In the absolute bioavailability study, point estimates (least squares means) and exploratory 95% confidence intervals (CIs) for the ratios of oral dose : iv dose of these kinetic parameters were calculated by retransformation of the logarithmic results (given by the ANOVA) using the intraindividual standard deviation; 90% CIs for the ratio fed : fasted of the primary targets were evaluated in the food effects study.

Dose proportionality was investigated using the power model, which was a linear regression between natural logarithm-transformed AUC_0–∞ and C_max, respectively, and the logarithm of the dose. Random between-subject variability was included so that possible differences in the size of the dose effect across subjects were included. The common slope β was fixed in this mixed-effects model. The point estimate of β together with its two-sided 90% CI was used to quantify the degree of nonproportionality. The prospectively defined relevant dose proportionality range for β was (β_L, β_U) where β_L = 1 + ln(0.8)/ln(2.5/0.5) = 0.86 and β_U = 1 + ln(1.25)/ln(2.5/0.5) = 1.14.

Safety and tolerability

Safety was assessed via physical examinations, electrocardiograms (ECGs), vital signs, and clinical laboratory tests conducted at screening, before dose administration at each treatment period, and at the conclusion of the study. Adverse events (AEs) were identified by subject questioning or self-reporting and assessed by the investigator for severity and relation to treatment. They were summarized using Medical Dictionary for Regulatory Activities (food effects study, version 12; absolute bioavailability and dose proportionality studies, version 12.1) preferred terms.

RESULTS

Demographic characteristics

Overall, 75 healthy white male volunteers were enrolled across the 3 studies; 22 of 24, 23 of 24, and 24 of 27 subjects completed their treatment regimens as scheduled and were included in the pharmacokinetic analysis for the absolute bioavailability, food effects, and dose proportionality studies, respectively. Mean age was 33–36 years, and the mean BMI in all studies was 24 (Table 1).

Table 1.

Mean baseline demographic characteristics of white male subjects who received riociguat in 3 randomized crossover studies (pharmacokinetic analysis sets)

Characteristic	Absolute bioavailability study (n = 22)	Food effects study (n = 23)	Dose proportionality study (n = 24)
Mean age (range), years	36.2 (18.0–45.0)	34.2 (21.0–43.0)	33.0 (21.0–45.0)
Mean BMI (±SD)	24.3 ± 2.3	24.5 ± 2.7	24.2 ± 2.7
Nonsmoker	15	14	17
Smoker	7	9	7

Note: Data are no. of patients, unless otherwise indicated. BMI: body mass index, calculated as the weight in kilograms divided by the square of height in meters; SD: standard deviation.

Pharmacokinetics

Absolute bioavailability study. Total systemic exposure to riociguat was similar when administered orally and intravenously (Table 2). After a single oral dose of riociguat 1 mg, the mean AUC_0–∞ was 244 μg·h/L (95% CI, 59.3–586.2 μg·h/L) compared with 259 μg·h/L (95% CI, 65.6–694 μg·h/L) following a single iv dose of 1 mg. Oral bioavailability of riociguat was 94.3% (95% CI, 83.1%–107%). The mean C_max of riociguat was slightly lower after oral administration than after iv administration (C_max/dose: 83.6% [95% CI, 76.4%–91.4%]). The lower mean C_max/dose suggests that the oral absorption of riociguat from the 1-mg immediate-release tablet was slightly slower than from the iv infusion rate over 60 minutes. The ratio (oral : iv) of the AUCs (least squares means) of M1 was 100%, corroborating the complete oral absorption from the 1-mg tablet (data not shown). The V_SS of riociguat after iv administration was 30.1 L. With an average systemic clearance after iv administration of 3.1 L/h in nonsmoking subjects and 6.0 L/h in smokers, riociguat can be classified as a low-clearance drug, lacking relevant first-pass extraction (Table 3). After oral dosing, the apparent clearance of riociguat from plasma (CL/f) was close to the systemic clearance determined after iv administration, supporting high bioavailability. Mean t_1/2 was comparable after iv administration and oral dosing (7.3 and 6.8 hours, respectively), but smaller for smokers, irrespective of the route of administration. The percentage of riociguat excreted in the urine (%Ae_ur) was also smaller for smokers than for nonsmokers (Table 3).

Table 2.

Absolute bioavailability study data giving geometric mean (range) pharmacokinetic parameters and point estimates (least squares means) of riociguat following a single oral dose of riociguat 1 mg and a 1-mg intravenous (iv) dose in the fasted state

	Riociguat, 1.0 mg
Parameter	Oral (n = 22)	iv (n = 22)	Parameter (oral : iv ratio)	Estimate (95% CI), %	CV
C_max, μg/L	37.8 (22.1–52.0)	45.3 (28.7–61.9)	C _max/dose	83.6 (76.4–91.4)	14.3
AUC_0-∞, μg·h/L	244.3 (59.3–586.2)	259.0 (65.6–693.5)	AUC_0∞/dose	94.3 (83.1–107.1)	20.3
t_1/2, hours	6.8 (0.9–16.7)	7.3 (1.8–25.0)	…	…	…
V_SS, L	…	30.1 (23.5–42.1)	…	…	…
CL/f, L/h	4.1 (1.7–16.9)	…	…	…	…
CL, L/h	…	3.9 (1.4–15.3)	…	…	…
CL_R, L/h	0.3 (0.2–0.6)	0.3 (0.2–0.5)	…	…	…
%Ae_ur^a	9.3 (1.2–25.6)	10.7 (2.9–30.3)	…	…	…

Note: The logarithms of AUC_0-∞/dose and C_max/dose of riociguat were analyzed using an analysis of variance (ANOVA) including sequence, subject (sequence), period, and treatment effects. On the basis of these analyses, point estimates (least squares means) and exploratory 95% CIs for the ratios of oral dose : iv dose of these kinetic parameters were calculated by retransformation of the logarithmic results (given by the ANOVA) using the intraindividual standard deviation. %Ae_ur: percentage of drug dose excreted in urine; AUC: area under the concentration-time curve; CI: confidence interval; CL: drug clearance from plasma (after iv administration); CL/f: apparent drug clearance from plasma (after oral administration); CL_R: renal clearance of drug; C_max: maximum plasma concentration; CV: coefficient of variation; t_1/2: terminal elimination half-life; V_SS: apparent volume of distribution at steady state (after iv administration).

Arithmetic mean (range).

Table 3.

	Nonsmokers (n = 15)					Smokers (n = 7)
Parameter	Oral riociguat 1.0 mg (n = 15)	iv riociguat 1.0 mg (n = 15)	Parameter (oral: iv ratio)	Estimate (95% CI), %	CV	Oral riociguat 1.0 mg (n = 7)	iv riociguat 1.0 mg (n = 7)	Parameter (oral: iv ratio)	Estimate (95% CI), %	CV
C_max, μg/L	38.0 (22.1–52.0)	46.9 (29.5–61.9)	C_max/dose	80.9 (72.9–89.9)	13.4	37.4 (28.1–50.9)	42.0 (28.7–57.2)	C_max/dose	87.9 (71.1–108.7)	15.4
AUC_0–∞, μg·h/L	293.2 (59.4–586.2)	318.6 (131.2–693.6)	AUC_0–∞/dose	91.6 (78.6–106.8)	19.6	165.3 (59.3–479.6)	166.3 (65.6–536.5)	AUC_0∞/dose	96.6 (76.9–121.3)	16.6
t_1/2, hours	8.2 (3.7–16.7)	9.1 (3.2-25.0)	…	…	…	4.5 (0.9–16.4)	4.5 (1.8–15.9)	…	…	…
V_SS, L	…	31.1 (24.8–42.1)	…	…	…	…	28.1 (23.5–31.2)	…	…	…
CL/f, L/h	3.4 (1.7–16.8)	…	…	…	…	6.0 (2.1–16.9)	…	…	…	…
CL, L/h	…	3.1 (1.4–7.6)	…	…	…	…	6.0 (1.9–15.3)	…	…	…
CL_R, L/h	0.3 (0.2–0.6)	0.3 (0.2–0.5)	…	…	…	0.3 (0.2–0.4)	0.4 (0.3–0.4)	…	…	…
%Ae_ur^a	10.7 (1.8–25.6)	12.2 (3.7–30.3)	…	…	…	6.2 (1.2–12.4)	7.7 (2.9–21.2)	…	…	…

Note: The logarithms of AUC_0–∞/dose and C_max/dose of riociguat were analyzed using an analysis of variance (ANOVA) including sequence, subject (sequence), period, and treatment effects. On the basis of these analyses, point estimates (least squares means) and exploratory 95% confidence intervals (CIs) for the ratios of oral dose : iv dose of these kinetic parameters were calculated by retransformation of the logarithmic results (given by the ANOVA) using the intraindividual standard deviation. %Ae_ur: percentage of drug dose excreted in urine; AUC: area under the concentration-time curve; CL: drug clearance from plasma (after iv administration); CL/f. apparent drug clearance from plasma (after oral administration); CL_R: renal clearance of drug; C_max: maximum plasma concentration; CV: coefficient of variation; iv: intravenous; t_1/2: terminal elimination half-life; V_SS: apparent volume of distribution at steady state (after iv administration).

Arithmetic mean (range).

Food effects study. A high-fat breakfast delayed riociguat absorption, although it had a minimal effect on the extent of absorption (Table 4; AUC_fed : AUC_fasted ratio: 88.3% [90% CI: 82.2%–95.0%]). The 90% CI of the fed : fasted ratio for the AUC_0–∞ values of riociguat was fully contained in the bioequivalence range of 80%–125%. Furthermore, the ratio AUC_fed : AUC_fasted for M1 was also within the bioequivalence range (94.5% [90% CI: 89.4%–99.8%]; data not shown). As expected, administration of a high-fat breakfast delayed gastric emptying; thus, the least squares mean C_max value of riociguat and M1 in the fed state decreased by 35.3% and 20.5%, respectively, relative to the fasted state (data not shown), and the absorption of riociguat was delayed, with a 4-fold increase in t_max in the fed state compared with the fasted state.

Table 4.

Food effects study data giving geometric mean (range) pharmacokinetic parameters and point estimates (least squares means) of riociguat following administration of a single oral dose of riociguat 2.5 mg in the fed and fasted state

Parameter	Fasted (n = 23)	Fed (n = 23)	Estimated fed : fasted ratio (90% CI), %	CV
C_max, μg/L	84.2 (44.7–152.7)	54.8 (28.9–91.4)	64.7 (57.8–72.5)	22.5
Median t_max, hours	1 (0.5–4.0)	4 (1.5–6.0)	…	…
AUC_0-∞ μg·h/L	572.2 (112.3–1,300)	505.6 (113.3–1,205)	88.3 (82.2–95.0)	14.3

Note: The logarithms of AUC_0–∞ and C_max were subjected to an analysis of variance with the factors “treatment,” “period,” “sequence,” and “subject(sequence).” AUC: area under the concentration-time curve; CI: confidence interval; C_max: maximum plasma concentration; CV: coefficient of variation; t_max: time to maximum plasma concentration.

Dose proportionality study. Riociguat was readily absorbed with a median t_max of 0.8–1.0 hours (range, 0.5–4.0 hours) after all 5 doses. Mean AUC_0–∞/dose and C_max/dose values of riociguat were highly comparable after all 5 doses (Table 5). Mean t_1/2 of riociguat ranged from 5.4 to 7.2 hours with a high variability (range: 1.0–19.2 hours). Geometric mean plasma concentrations of riociguat 0.5–2.5 mg are shown in Figure 1. Results of the power model revealed that systemic exposure to riociguat was dose proportional over the dose range 0.5–2.5 mg, as evidenced by the common slope of AUC_0–∞ (1.09 [90% CI: 1.04–1.14]) and C_max (0.99 [90% CI: 0.93–1.04]) approximating unity. Intraindividual variability was low as indicated by the geometric CV of <20% for AUC_0–∞ and C_max. In contrast, for interindividual variability, the geometric CV for AUC_0–∞ was approximately 100% (range: 95.4%–115.3%), and for C_max, it was approximately 45% (range: 40.0%–49.2%), indicating moderate to high variability.

Figure 1.

Plasma concentrations (geometric mean) of riociguat following single oral doses of riociguat 0.5-mg, 1.0-mg, 1.5-mg, 2.0-mg, and 2.5-mg immediate-release tablets. Linear scale, all subjects valid for pharmacokinetic analysis, n = 24. LLOQ: lower limit of quantification.

Table 5.

Dose proportionality study data giving geometric mean (range) pharmacokinetic parameters for riociguat following administration of ascending single oral doses in the fasted state

	Dose (n = 24)
Parameter	0.5 mg	1.0 mg	1.5 mg	2.0 mg	2.5 mg
C_max, μg/L	15.8 (5.1–30.3)	34.1 (12.5–82.1)	46.4 (20.7–86.0)	62.4 (16.2–114.5)	80.1 (27.4–162.1)
C_max/dose, L⁻¹	0.032 (0.01–0.06)	0.034 (0.01–0.08)	0.031 (0.01–0.06)	0.031 (0.01–0.06)	0.032 (0.01–0.06)
Median t_max, hours	0.8 (0.5–4.0)	1.0 (0.5–4.0)	1.0 (0.5–4.0)	1.0 (0.8–4.0)	1.0 (0.5–4.0)
AUC_0–∞ μg·h/L	98.5 (15.2–296.0)	226.4 (24.2–584.8)	325.4 (33.9–877.5)	475.6 (59.9–1,122)	565.5 (68.9–1,610)
AUC_0–∞/dose, h/L	0.20 (0.03–0.6)	0.23 (0.02–0.6)	0.22 (0.02–0.6)	0.24 (0.03–0.6)	0.23 (0.03–0.6)

Note: AUC: area under the concentration-time curve; C_max: maximum plasma concentration; CV: coefficient of variation; t_max: time to maximum plasma concentration.

Median (range) t_max of M1 also varied substantially after all 5 doses of riociguat: 6.0–12.0 hours (1.5–36.0 hours; data not shown). However, mean AUC/dose (0.22–0.24 h/L; range: 0.11–0.53), C_max/dose (0.008–0.009; range: 0.003–0.04), and t_1/2 (14.1–16.4 hours; range: 7.7–32.9 hours) values of M1 were very similar after all 5 doses of riociguat, with low variability.

Safety and tolerability

Seven patients did not complete the studies. Three were eliminated during screening before receiving study drug (2 due to AEs, including hypertension in one patient and acute gouty arthritis of the right hand in the other, and 1 for receipt of concomitant medication deemed unsuitable by the investigator), and 1 patient was eliminated during screening at part II of the study due to an AE of bronchitis. Three patients discontinued the study due to AEs (mild nasopharyngitis in 1 patient, moderately elevated creatine phosphokinase that was normal at screening and during the first 3 treatment periods in 1 patient [both AEs unrelated to study drug], and mildly elevated glutamate dehydrogenase in 1 patient [related to study drug]). Overall, riociguat was well tolerated in all 3 studies. The types of AEs reported were consistent with the mode of action of riociguat (Table 6). All treatment-emergent AEs had resolved by the end of the study.

Table 6.

No. (%) of subjects who experienced treatment-emergent riociguat-related adverse events (AEs) in the safety analysis sets of the 3 studies

	Absolute bioavailability study (riociguat 1 mg)		Food effects study (riociguat 2.5 mg tablet)		Dose proportionality study, by riociguat dose
MedDRA preferred term	Oral tablet (n = 22)	iv solution (n = 23)	Fasted (n = 23)	Fed (n = 23)	.5 mg (n = 26)	1.0 mg (n = 26)	1.5 mg (n = 26)	2.0 mg (n = 26)	2.5 mg (n = 24)
Any related AE	8 (36)	11 (48)	8 (35)	4 (17)	4(15)	5 (19)	11 (42)	8 (31)	9 (38)
Abnormal sensation in eye	…	…	…	…	1 (4)	…	…	…	…
Abdominal pain	…	…	…	1 (4)	…	…	…	…	…
Abdominal discomfort	…	…	…	…	…	…	…	1 (4)	…
Diarrhea	…	…	…	…	1 (4)	…	…	…	…
Dyspepsia	…	…	1 (4)	…	1 (4)	1 (4)	…	…	…
Nausea	1 (5)	…	…	1 (4)	…	…	…	…	…
Feeling hot	…	…	1 (4)	…	…	…	1 (4)	1 (4)	…
Vomiting	2 (9)	1 (4)	…	…	…	…	…	…	…
Headache	2 (9)	5 (22)	6 (26)	2 (9)	2(8)	3 (12)	5 (19)	4(15)	4 (17)
Glutamate dehydrogenase increased	…	1 (4)	…	…	…	…	…	…	…
Micturition urgency	…	2 (9)	…	…	…	…	…	1 (4)	…
Erection increased	…	…	…	…	…	…	1 (4)	…	…
Cough	…	…	…	1 (4)	…	…	…	…	…
Nasal congestion	…	…	4 (17)	2 (9)	…	…	1 (4)	1 (4)	1 (4)
Flushing	6 (27)	5 (22)	3 (13)	…	…	1 (4)	5 (19)	4 (15)	4 (17)
Hypotension	…	1 (4)	…	…	…	…	…	…	…

Note: iv: intravenous; MedDRA: Medical Dictionary for Regulatory Activities.

In the absolute bioavailability study, 11 of 23 subjects and 8 of 22 subjects reported at least 1 treatment-emergent, drug-related AE after the iv and oral doses of riociguat 1.0 mg, respectively. All AEs were of mild intensity apart from moderate headache, which was experienced by one subject after both doses and by another subject after the oral dose, and moderate hypotension, which occurred in a single subject after the iv dose. Flushing (reported by 27% and 22% of patients taking oral and iv riociguat, respectively) and headache (reported by 9% and 22% of patients taking oral and iv riociguat, respectively) were the most frequently reported drug-related AEs.

In the food effects study, 10 of 23 subjects experienced at least 1 treatment-emergent, drug-related AE after at least 1 of the 2 riociguat administrations. Headache (26%), nasal congestion (17%), and flushing (13%) were the most frequently occurring drug-related AEs after riociguat administration in the fasted state. In contrast, those drug-related AEs were less frequent after riociguat administration in the fed state (headache, 9%; nasal congestion, 9%; flushing, 0%).

In the dose proportionality study, 21 subjects experienced a total of 44 treatment-emergent, drug-related AEs. All treatment-emergent drug-related AEs were mild. The most frequent drug-related AEs were headache and flushing, experienced by a total of 12 and 9 subjects, respectively. Headache and flushing were more frequent at riociguat doses >1.5 mg.

All laboratory values reported above the upper limit of normal were minor transient changes and without clinical relevance, except for a single case of moderately increased creatine kinase in the dose proportionality study (already elevated before riociguat administration and decreased after dosing) and a single case of mildly increased glutamate dehydrogenase that resulted in premature discontinuation of riociguat in a subject in the absolute bioavailability study. There were no signals for riociguat-induced laboratory parameter changes in any of the studies. ECG findings, in particular QTc analyses, did not reveal any unexpected or untoward effects attributable to riociguat.

DISCUSSION

This article presents the results of 3 separate phase 1 clinical studies involving healthy male volunteers to characterize the absorption properties of riociguat. Absolute bioavailability; the effects of a high-fat, high-calorie breakfast; and dose proportionality of riociguat were assessed. Riociguat showed complete oral absorption and no clinically relevant food effect. Over the riociguat 0.5–2.5-mg dose range, systemic exposure increased dose proportionately with moderate to high interindividual and low intraindividual variability.

Taken together, these data add to the pharmacokinetic profile of riociguat and are in accordance with previous clinical studies involving healthy subjects. In 2 previous phase 1 studies, riociguat was readily absorbed and showed dose-dependent increases in plasma concentrations following a single oral dose of riociguat solution.^7,11 Furthermore, plasma concentrations and AUC showed dose-dependent increases with increasing doses of riociguat, with no obvious deviation from dose proportionality or linear pharmacokinetics.^7,11 A comparison between two 2.5-mg formulations of riociguat (oral solution and immediate-release tablet) indicated comparable bioavailability.¹¹ Thus, the present study corroborates the two pivotal studies showing the dose proportionality of oral immediate-release riociguat tablets and the high bioavailability of this formulation in healthy subjects. A standardized high-fat, high-calorie breakfast decreased the rate of absorption of riociguat compared with the absorption rate in fasted subjects. However, because there was no relevant difference in the extent of absorption between fed and fasted patients, this food effect is considered to be without clinical relevance, and riociguat can be administered with or without food.

Although oral absorption and first-pass effects, distribution, and bioavailability remained unaffected by smoking status, induction of CYP1A1 in smokers increased mean clearance of riociguat by approximately two-fold, markedly reduced mean elimination half-life (irrespective of administration route), and significantly contributed to the overall variability of drug exposure, as explored in the absolute bioavailability study. The effect of smoking on the pharmacokinetics of riociguat was subsequently investigated further in a separate study.¹²

Riociguat had a favorable safety profile and was well tolerated in all 3 phase 1 studies presented here. AEs were consistent with the mechanism of action of riociguat and were in accordance with previously published clinical studies.^7,11,13,14 Overall, the most frequently reported treatment-emergent drug-related AEs were headache, flushing, and nasal congestion. The observed AEs were all mild or moderate in severity, with no serious AEs being reported.

The pronounced interindividual variability and low intraindividual variability observed with regard to the pharmacokinetic properties of riociguat in all 3 studies have also been observed in previous pharmacokinetic studies in healthy subjects, suggesting that this characteristic needs to be considered when administering riociguat in a clinical setting.^7,11 Indeed, this issue is addressed by the riociguat dose adjustment scheme employed in previously published phase 2 studies and in the recently completed phase 3 CHEST-1 and PATENT-1 studies.^8,9,14 In these studies, riociguat was titrated in 0.5 mg increments at 2-week intervals from a starting dose of 1 mg tid according to systolic blood pressure over the range of 0.5–2.5 mg tid.^8,9,14

This administration scheme translated into successful phase 3 trials. In the PATENT-1 study, riociguat significantly improved exercise capacity and a range of secondary endpoints, including pulmonary vascular resistance, NT-proBNP, WHO functional class, time to clinical worsening, and Borg dyspnea score in patients with symptomatic PAH.⁸ The CHEST-1 study investigated the efficacy and safety of riociguat in patients with inoperable CTEPH or persistent/recurrent PH after pulmonary endarterectomy (PEA). Significant improvements in exercise capacity and consistent and significant improvements across a range of clinically relevant secondary endpoints, including hemodynamic characteristics, WHO functional class, and NT-proBNP, were shown.⁹ Riociguat was well tolerated in both studies and had a good safety profile.^8,9 These phase 3 studies have demonstrated the efficacy of riociguat, and the drug has been approved in the United States, Europe, and several other countries for patients with PAH and inoperable CTEPH or persistent/recurrent PH after PEA.^15–17

In conclusion, riociguat shows complete oral absorption over the therapeutic dose range (0.5–2.5 mg) and can be taken with or without food. Moreover, these data support the suitability of the individualized dose adjustment regimen that was employed in the phase 3 studies of riociguat for treatment of PAH, inoperable CTEPH, and persistent/recurrent PH after PEA.

Footnotes

Source of Support: This study was supported by Bayer Pharma (Berlin, Germany). Editorial assistance was provided by Adelphi Communications (Bollington, UK), sponsored by Bayer Pharma.

Conflict of Interest: All of the authors are employees of Bayer Pharma.

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