Objective: To describe the pharmacokinetics and exposure of oral sildenafil in neonates (2-5 kg) with pulmonary hypertension.
Design: We included eleven neonates (body weight 2-5kg, PNA 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 (SIL) and desmethylsildenafil (DMS) pharmacokinetics.
Results: A one-compartment model was suitable for both SIL and DMS. Inter- and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). 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 (SIL+DMS) ranged from 625 to 13579 ng*h/mL. An oral dose of 4.2 mg/kg/24h would lead to a median AUC24 (SIL+DMS) of 2650 ng*h/mL equivalent to 20 mg t.i.d. in adults. Interpatient variability was large, with a simulated AUC24 (SIL+DMS) range (10th and 90th percentiles ) of 1000 - 8000 ng*h/mL.
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.
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