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.