Population pharmacokinetics of riociguat in a pediatric population (aged ≥ 6 years) with pulmonary arterial hypertension.

Background: The PATENT-CHILD study investigated riociguat in children aged ≥ 6 to <18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight-adjusted dosing of up to 2.5 mg three times daily. PATENT-CHILD demonstrated an acceptable riociguat safety profile and individual plasma concentrations in pediatric patients were consistent with those in adult patients.

Methods: Using the data set from PATENT-CHILD and building on existing population pharmacokinetic (PK) models for riociguat and its major metabolite (M1) in adults with PAH, a coupled riociguat-M1 PK model was developed. The final model developed incorporated a one-compartment model for riociguat, coupled to a one-compartment model for M1, allowing for presystemic formation of M1. It included allometric scaling exponents for bodyweight.

Results: Apparent clearance of riociguat was similar in children and adult patients with PAH (median [interquartile range] 2.20 [1.75-3.44] and 2.08 L/h [1.55-2.97]). Factors contributing to lower PK exposure were lower riociguat maintenance dose in PATENT-CHILD, and a higher riociguat clearance in some adolescent patients, compared with adult patients. No effects of formulation, sex, or age on riociguat PK were observed. An exploratory PK/pharmacodynamics analysis found the increase in 6-min walking distance in pediatric patients treated with riociguat was not related to riociguat PK.

Conclusions: Body size is the main determinant of PK in growing children, and the model supports clinical data that, for children weighing < 50 kg, a bodyweight-adjusted dose of riociguat should be used to achieve a similar exposure to that observed in adults with PAH.