Objectives: Sildenafil, a substrate of CYP3A, is a treatment standard of children with pulmonary arterial hypertension (PAH). The current dosing recommendation for sildenafil in children is 0.5–2.0 mg/kg thrice daily. The objective of this study was to generate a dataset of sildenafil plasma concentrations during routine in-patient treatment in infants and children with PAH using opportunistic blood sampling for pharmacokinetic analysis.
Methods: After obtaining informed consent, sparse remnant blood samples from routine blood analyses were analyzed if drawn within 8 hour after the last oral sildenafil administration using a validated LC/MS/MS assay. In addition, patient characteristics, diagnoses, and current co-medication were extracted from the medical records to screen for drug interactions (especially mediated via CYP3A). Obtained plasma concentrations were compared with those of traditional studies in children using serial sampling.
Results: Fifteen patients (8 males) with a median age of 0.9 years (range: 0.3–9.5), median weight of 7.05 kg (4.01–26.7) were included. Twelve patients had pulmonary hypertension associated with congenital heart disease and one had idiopathic PAH. Mean pulmonary artery pressure was 31 ± 21 mm Hg during therapy. Monotherapy was administered to 13 of patients, one also received bosentan. 5 patients were treated with the CYP3A inductor phenobarbital initiated 1–6 days before the first sample was collected. Five patients were Rosenthal class B and 10 were class C. In total, 112 blood samples were collected (3–16 samples per patient). Maximum sildenafil concentration ranged from 1.66 to 374 ng/mL (median Cmax 61.5 ng/mL), time of maximum plasma concentration (Tmax) ranged from 0.15 to 7.36 hour after dosing (median 2 hour). Mean administered dose was 0.77 ± 0.22 mg/kg (0.49–1.07 mg/kg) three or four times a day. Cmax normalized to dose was 30.9 ± 41.9 ng/mL/mg.
Conclusion: The mean sildenafil dose matches the recommended dose range of 0.5 to 2.0 mg/kg. Plasma concentrations using remnant samples were comparable to those of previously conducted pediatric studies, indicating rapid elimination in children. Phenobarbital did not induce sildenafil metabolism by CYP3A during short-term use. Sildenafil plasma concentrations showed substantial inter-patient variability; the correlation between plasma and effect site concentrations and the predictive value of plasma concentration measurements, however, still have to be investigated in children.
