Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension

Abstract

This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies-PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 12 weeks; PAH) and CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 16 weeks; CTEPH)-and long-term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed-effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one-compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time- or dose-dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan-treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6-minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one-compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT-1, NCT00810693; PATENT-2, NCT00863681; CHEST-1, NCT00855465; CHEST-2, NCT00910429.).

Keywords: chronic thromboembolic pulmonary hypertension; drug exposure; pulmonary arterial hypertension.

Figures

Figure 1

Molecular structure of riociguat.

Figure 2

Patient disposition. PD: pharmacodynamic; PK: pharmacokinetic; tid: three times daily.

Figure 3

Estimated riociguat plasma concentrations at steady state on the last day of the PATENT-1 (a; day 84) and CHEST-1 (b; day 112) studies.

Figure 4

Prediction-corrected visual predictive check of the final pharmacokinetic models for riociguat (a) and M1 (b). Gray areas (from top to bottom) show the 95% prediction intervals for the 95th, 50th, and 5th percentiles of the simulated prediction-corrected values. Lines (from top to bottom) show the 95th, 50th, and 5th percentiles of the observed prediction-corrected values. Circles show the individual prediction-corrected observations. PI: prediction interval.

Figure 5

Riociguat exposure (area under the plasma concentration–time curve [AUC]) per dose in the CHEST-1 (a) and PATENT-1 (b) studies. Boxes show 25th–75th percentiles, whiskers show 5th–95th percentiles, and horizontal lines show the median.

Figure 6

Box plots of riociguat dose-normalized area under the plasma concentration–time curve (AUC) by visits across the four studies.

Figure 7

Box plots of individual post hoc estimates of the apparent clearance of riociguat versus smoking status and bosentan comedication in the PATENT-1/2 (a) and CHEST-1/2 (b) studies. In PATENT-1/2, median values of riociguat clearance taking into account covariates effects (bilirubin and creatinine clearance) were 1.8 L/h in nonsmokers not receiving bosentan, 4.2 L/h in smokers not receiving bosentan, and 2.3 L/h in nonsmokers receiving bosentan as comedication. In CHEST-1/2, median values of riociguat clearance taking into account covariates effects (bilirubin and creatinine clearance) were 1.6 L/h in nonsmokers and 4.2 L/h in smokers.

Figure 8

Relationship between 6-minute walk distance (6MWD) and pulmonary vascular resistance (PVR) at the end of the PATENT-1 (day 84) and CHEST-1 (day 112) studies.

Figure 9

Exposure-response relationship between riociguat plasma trough concentration (Ctrough) and changes in pulmonary vascular resistance (PVR) in the PATENT-1 and CHEST-1 studies.

Figure 10

Exposure-response relationship between riociguat plasma trough concentration (Ctrough) and changes in systolic blood pressure (SBP) in the PATENT-1 and CHEST-1 studies.

Figure 11

Exposure-response relationship between riociguat plasma trough concentration (Ctrough) and changes in cardiac output in the PATENT-1 and CHEST-1 studies.