Pharmacokinetics of sildenafil in neonates with pulmonary hypertension

Objective: To describe the pharmacokinetics of and exposure to oral sildenafil in neonates with pulmonary hypertension. Design and methods: We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received sildenafil and ECMO treatment for pulmonary hypertension. Sildenafil capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify sildenafil and metabolite plasma levels (219 samples). Nonlinear mixed effects modelling was used to describe sildenafil and desmethylsildenafil pharmacokinetics. Results: A one-compartment model was suitable for both sildenafil and desmethylsildenafil. Inter- and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (sildenafil) and 62% and 26% (desmethylsildenafil). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in sildenafil clearance. The exposure expressed as AUC24 (sildenafil + desmethylsildenafil) ranged from 625 to 13.579 ng·mh-1·h. An oral dose of 4.2 mg·kg -1·d-1 would lead to a median AUC24 (sildenafil + desmethylsildenafil) of 2650 ng·ml-1·h, equivalent to 20 mg t.i.d. in adults. Interpatient variability was large, with a simulated AUC24 (sildenafil + desmethylsildenafil) range (10th and 90th percentiles) of 1000-8000 ng·ml-1·h. Conclusions: Sildenafil pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg q.i.d. leads to an exposure comparable to the recommended adult dose of 20 mg t.i.d. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population PK/PD analysis to assign a suitable exposure window or target concentration.