Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials.

2nd Department of Medicine Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

2nd Department of Surgery Department of Cardiovascular Surgery 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Analytical Chemistry Faculty of Science Charles University Prague Czech Republic

Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University Leiden The Netherlands

Institute of Forensic Medicine and Toxicology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Institute of Pharmacology 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

Zobrazit více v PubMed

Galiè N, Humbert M, Vachiery J, et al. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016; 37: 67–119. PubMed

Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D42–D50. PubMed

Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH) results from an international prospective registry. Circulation 2011; 124: 1973–1981. PubMed

McLaughlin VV, Jansa P, Nielsen-Kudsk JE, et al. Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study. BMC Pulm Med 2017; 17: 216. PubMed PMC

Schermuly RT, Janssen W, Weissmann N, et al. Riociguat for the treatment of pulmonary hypertension. Expert Opin Inv Drug 2011; 20: 567–576. PubMed

Khaybullina D, Patel A, Zerilli T. Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Pharm Ther 2014; 39: 749. PubMed PMC

Frey R, Becker C, Saleh S, et al. Clinical pharmacokinetic and pharmacodynamic profile of riociguat. Clin Pharmacokinet 2018; 57: 647–661. PubMed PMC

Ghofrani H-A, D'armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369: 319–329. PubMed

Saleh S, Becker C, Frey R, et al. Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulm Circ 2016; 6: S86–S96. PubMed PMC

Ghofrani H-A, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330–340. PubMed

Grapow MT, von Wattenwyl R, Guller U, et al. Randomized controlled trials do not reflect reality: real-world analyses are critical for treatment guidelines!. J Thorac Cardiovasc Surg 2006; 132: 5–7. PubMed

Wang D-d, Chen X, Fu M, et al. Model extrapolation to a real-world dataset: evaluation of tacrolimus population pharmacokinetics and drug interaction in pediatric liver transplantation patients. Xenobiotica 2019; 3: 1–9. PubMed

Toxicology SWGfF. Scientific Working Group for Forensic Toxicology (SWGTOX) standard practices for method validation in forensic toxicology. J Anal Toxicol 2013; 37: 452–474. PubMed

Krekels EH, van Ham S, Allegaert K, et al. Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants. Eur J Clin Pharmacol 2015; 71: 1075–1082. PubMed PMC

Shivva V, Korell J, Tucker I, et al. An approach for identifiability of population pharmacokinetic–pharmacodynamic models. CPT Pharmacometrics Syst Pharmacol 2013; 2: 1–9. PubMed PMC

Bertrand J, Laffont CM, Mentré F, et al. Development of a complex parent-metabolite joint population pharmacokinetic model. AAPS J 2011; 13: 390–404. PubMed PMC

Saleh S, Becker C, Frey R, et al. Population pharmacokinetics of single-dose riociguat in patients with renal or hepatic impairment. Pulm Circ 2016; 6: S75–S85. PubMed PMC

Becker C, Frey R, Hesse C, et al. Absorption of riociguat (BAY 63-2521): bioavailability, food effects, and dose proportionality. Pulm Circ 2016; 6: S27–S34. PubMed PMC

Comets E, Brendel K, Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed 2008; 90: 154–166. PubMed