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.

Effects on posture by different neuromuscular afferent stimulations and proprioceptive insoles: Rasterstereographic evaluation.

BACKGROUND: Proprioceptive neuromuscular stimulating insoles are increasingly applied in treating functional complaints, chronic pain, foot disorders and so on. OBJECTIVES: To evaluate rasterstereography as a tool in objectifying postural changes resulting from neuromuscular afferent stimulation and proprioceptive neuromuscular stimulating insoles and to compare the respective effects on posture. STUDY DESIGN: This is a prospective experimental study. METHODS: A total of 27 healthy volunteers were consecutively exposed to six different varying intense neuromuscular afferent stimulating test conditions at three different times. One test condition featured proprioceptive neuromuscular stimulating insoles. In each test condition, a sequence of 12 rasterstereographic recordings of back shape was documented. Changes between six different test conditions and over time for 14 posture characterising parameters were investigated, for example, trunk inclination, pelvic torsion, lateral deviation of the spine's amplitude or sagittal spinal curve. RESULTS: Standard deviation of our rasterstereographic measurements (±2.67 mm) was better than in most comparable reference values. Different neuromuscular stimuli were found to provoke significant changes to various posture parameters, including trunk inclination, pelvic torsion and so on ( each p < 0.001, F-tests). Proprioceptive neuromuscular stimulating insoles induced significant changes for parameter lateral deviation of the spine's amplitude (p = 0.03). CONCLUSION: Neuromuscular afferent stimulation and proprioceptive neuromuscular stimulating insoles induce postural changes, which can be detected reliably by rasterstereography. CLINICAL RELEVANCE: We demonstrated that rasterstereography - a radiation-free imaging modality - enables visualisation and documentation of subtle postural changes induced by varying intense neuromuscular afferent stimulation and the application of proprioceptive neuromuscular stimulating insoles.