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.
